Novel homozygous RARS2 mutation in two siblings without pontocerebellar hypoplasia - further expansion of the phenotypic spectrum.

BACKGROUND: Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease caused by mutations in the RARS2 gene. RARS2 encodes mitochondrial arginyl transfer RNA synthetase, an enzyme involved in mitochondrial protein translation. A total of 27 patients from 14 families have been reported so far. Characteristic clinical features comprise neonatal lactic acidosis, severe encephalopathy, intractable seizures, feeding problems and profound developmental delay. Most patients show typical neuroradiologic abnormalities including cerebellar hypoplasia and progressive pontocerebellar atrophy. METHODS: We describe the clinical, biochemical and molecular features of 2 siblings with a novel homozygous mutation in RARS2. Both patients presented neonatally with lactic acidosis. While the older sibling had severe neurological symptoms with microcephaly, seizures and developmental delay, the younger patient was still neurologically asymptomatic at the age of 2 months. RESULTS: MRI studies in both children lacked pontocerebellar involvement. The expression of the OXPHOS complex proteins was decreased in both patients, whereas oxygen consumption was increased. CONCLUSIONS: Characteristic neuroradiological abnormalities of PCH6 such as vermis and cerebellar hypoplasia and progressive pontocerebellar atrophy may be missing in patients with RARS2 mutations. RARS2 testing should therefore also be performed in patients without pontocerebellar hypoplasia but otherwise typical clinical symptoms.

Elevation of plasma 1-deoxy-sphingolipids in type 2 diabetes mellitus: a susceptibility to neuropathy?

BACKGROUND AND PURPOSE: Diabetic distal sensorimotor polyneuropathy (DSPN) is a frequent, disabling complication of diabetes mellitus. There is increasing evidence that sphingolipids play a role in insulin resistance and type 2 diabetes (T2DM). Whether neurotoxic 1-deoxy-sphingolipids are elevated in DSPN patients' plasma and whether levels correlate to the DSPN stage were examined. METHODS: The plasma profile of 12 sphingoid bases in patients with DSPN and T2DM(n = 39) were cross-sectionally compared to other nerve disorders including chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 13), transthyretin-related familial amyloid polyneuropathy (FAP) (n = 10), amyotrophic lateral sclerosis (ALS) (n = 13) and small fibre neuropathy (n = 12) by liquid chromatography mass spectrometry. Correlations to the DSPN stage were additionally performed. Furthermore, the sphingoid base distribution in sural nerve specimens was measured in patients with DSPN (n = 6) compared to CIDP (n = 3). RESULTS: A significantly increased amount of 1-deoxy-sphingolipids [1-deoxy-sphinganine (0.11 ± 0.06 µmol/l), 1-deoxy-sphingosine (0.24 ± 0.16 µmol/l)] in patients with DSPN was observed compared to age-matched healthy controls (0.06 ± 0.03 µmol/l; 0.12 ± 0.05 µmol/l) and to the other groups. (Para)clinical parameters including sensory loss, neuropathic pain, weakness, vibration perception, nerve conduction velocity, sensory nerve action potentials (sural nerve) and duration of T2DM did not correlate with plasma 1-deoxy-sphingolipid levels, neither did the clinical stage according to the Dyck classification for DSPN. Sphingolipid levels in sural nerve biopsies showed no differences between DSPN and CIDP. Contrarily, patients with a small fibre neuropathy had decreased C20-sphingosine plasma levels. CONCLUSION: 1-deoxy-sphingolipid plasma levels are significantly elevated in DSPN. They are already detectable in early disease stages but do not correlate with the clinical course. Further knowledge on 1-deoxy-sphingolipids might lead to a better pathophysiological understanding and future treatment options in DSPN.

[Neurodevelopmental outcome of very low birth weight infants born at the Perinatal Centre in Ulm, Germany]. / Entwicklungsneurologische Nachuntersuchung von sehr unreifen Frühgeborenen im Perinatalzentrum Ulm.

BACKGROUND: Since 2006 an assessment of the neurodevelopmental outcome of very low birth weight infants (VLBWI) at a corrected age of 2 years is mandatory for every perinatal centre in Germany. The aim of our study was to check how complete these assessments were performed in our population of infants born at our perinatal centre and receiving treatment within our local neonatal network. Furthermore, the data obtained will be used for prenatal consultations. Another objective was to identify risk factors for adverse neurodevelopmental outcomes. METHODS: All VLBWI were invited for a follow-up exam using the Bayley Scales of Infant Development II (BSID-II) or III (BSID-III), or Griffiths Mental Developmental Scales) at 2 years corrected age. The results of children assessed by other institutions were collected. RESULTS: 142 (69.3%) of the 205 VLBWI, born and finally discharged alive at the perinatal centre in Ulm were assessed at a median (minimum - maximum) corrected age of 23 (18-27) months. The BSID-II Psychomotor Development Index (PDI) 91 was (< 50-128) (n=115), the BSID-II Mental Development Index (MDI) was 87 (< 50-134) (n=96), BSID-III MDI 95 (60-112) (n=29) and the Griffiths Score was 93 (67-140) (n=17). Severe disability was diagnosed in 36 (25.4%) of the children studied. Gestational age and higher grade intraventricular haemorrhage were associated independently with severe disability. CONCLUSIONS: It is very difficult to achieve a high rate of follow-up examinations in preterm infants <1,500 g in a neonatal network. Severe impairment in VLBWI is not rare. Improving neurodevelopmental outcome remains a challenge.

[Children with learning disabilities and handicaps in inclusive schools or in special schools? The view of parents and professionals]. / Kinder mit Lernstörungen und Behinderungen inintegrativen Schulen oder in Sonderschulen? Die Sichtweise von Eltern und Fachleuten.

BACKGROUND: To investigate the view of parents and professionals on sending children with special educational needs to inclusive schools. PROBANDS: 54 preschool children in the year before school entry and 155 school children attending a Social Pediatric Center. They displayed motor-, mental-, speech- or sensory handicaps, learning or behavioral disabilities. METHODS: Questionnaires for parents of preschool- and of school children and questionnaires for the professional caring for the child were evaluated and compared. Parental expectations, experiences concerning school and the severity of disability were determined. RESULTS: 135 pupils attended special schools and 20 integrative schools. The parents were generally very content with both types of schools despite the fact that 33% of parents had not have a free choice of the school. They had a positive attitude to inclusive education. Preference for inclusive schooling decreased with increasing severity of the child's disability. The severity of disability was rated similar by parents and by professionals. Parents of preschool children tended more often and parents of school children less often than professionals towards sending the individual child to an inclusive school. CONCLUSIONS: Some parents of children with special educational needs would like to send their child to a special school, others prefer inclusive schools. It is paramount to improve the professional advice and guidance to parents since parental options to choose the school for their child are increasing in Germany.

[Sexual and contraceptive behavior of teenagers and young adults. Selected results of the BZgA study "Youth Sexuality 2010"]. / Sexual- und Verhütungsverhalten Jugendlicher und junger Erwachsener. Ausgewählte Ergebnisse von Befragungen der Bundeszentrale für gesundheitliche Aufklärung (BZgA).

The BZgA study "Youth Sexuality 2010" clarifies the changes that have occurred in the sexual and contraceptive behavior of teenagers and young adults over the last 30 years. Among young Germans, there is now more gender similarity regarding both the age at which intercourse first takes place and contraceptive behavior. The proportion of German teenagers who take no contraceptive precautions when they have intercourse for the first time is now 8%, a lower figure than ever previously recorded. Communication about contraception, both at home and between the partners, is making a substantial contribution to responsible contraceptive behavior on the part of teenagers and young adults. Alongside education about sexuality in the family and at school, there are also structural influences on the positive developments witnessed in Germany. And yet there are still target groups that are inadequately reached. Many migrants are less well informed about bodily processes, their contraceptive practice is not as good, and their religious background tends to exclude them from access to information. Disabled teenagers and young adults constitute a target group about which to date we have insufficient knowledge. Education and social deprivation continue to be important factors in the differences seen in sexual and contraceptive behavior. In this area, proactive efforts are necessary.

Neuro-endocrine and neuropsychological outcome after aneurysmal subarachnoid hemorrhage (aSAH): a prospective cohort study.

OBJECTIVE: Neuropsychological sequelae are common after aneurysmal subarachnoid hemorrhage (aSAH) and may be associated with or caused by supposed hypothalamic-pituitary dysfunction. We evaluated the incidence of neuro-endocrine and neuropsychological deficits after aSAH and their interrelations in a standardized manner. METHODS: 26 patients (20 females) were prospectively screened for neuro-endocrine and neuropsychological deficits 3 and 6 months after aSAH. We measured GH, IGF-1, prolactin, LH, FSH, estradiol, TSH, fT4, total T3, testosterone, ACTH as well as cortisol before and after ACTH-stimulation. Neuropsychological analysis covered verbal comprehension, short term and working memory, visuospatial construction, figural memory, psychomotor speed, attention, and concentration. RESULTS: After 3 months central hypogonadism was observed in 2 patients accompanied by central hypothyroidism in 1 male subject. Central hypogonadism resolved spontaneously after 6 months in both. After 3 months, neuropsychological deficits were detected in 57% of the examined patients (44% attention deficits, 38% memory impairment, 12% psychomotor deficits). Neuropsychological deficits were still present in 53% after 6 months. CONCLUSION: We found a low prevalence of neuro-endocrine and a high prevalence of neuropsychological deficits in patients 3 and 6 months after aSAH. Thus, the absent co-incidence of central hormonal and psychological dysfunction leaves a causal association questionable.

SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases.

Pituitary carcinomas are rare and neurosurgically challenging lesions, as they commonly relapse after surgical removal. Their prognosis is dismal due to their limited response to radiotherapy and chemotherapy. In recent studies, temozolomide was administered in very few patients with partial effects. We report a patient with an ACTH-secreting pituitary carcinoma and widespread intracranial, spinal and systemic metastases despite repeated surgical treatment, bilateral adrenalectomy, medical treatment and radiotherapy. Additionally to chemotherapy with temozolomide, the patient received SOM230 as salvage therapy with an improvement of the patient's clinical status, and a reduction of ACTH levels. After 12 months of combination therapy a sustained tumor control was achieved and persisted upon monotherapy with SOM230 for more than 9 months thereafter. Thus, temozolomide in combination with SOM230 seems to be promising in patients with ACTH-secreting metastasized pituitary carcinoma.

Growth, neurological and cognitive development in infants with a birthweight <501 g at age 5 years.

AIM: To determine growth, neurological and cognitive development at 5 years of preterm infants with birthweights <501 g born in three German tertiary perinatal centres between 1998 and 2001. METHODS: Structured neurological examination, the Gross Motor Function Classification Scale and the Kaufman-Assessment-Battery Test for Children. RESULTS: Of 107 infants, 48 received immediate life support (gestational age 25.2 weeks [21-30.7]; birth weight 435 g [290-500]) median [range]), 27 (56%) survived until follow-up [95% CI 39-69%], 19 (70%) could be tested. In few infants had catch-up growth taken place. Neurological test results were normal in five infants (26%) and mildly abnormal/severely abnormal in 11 (58%)/3 (16%) infants. Visual impairment was present in eight (42%), and hearing disability in three (16%). The mean mental processing composite (IQ) was 82 [50-104] (median [range]). CONCLUSION: Of all resuscitated infants with a birthweight <501 g, 56% survived to school age. Of these, composite outcome score showed normal development or mild disability in one-half, and moderate or severe disability in the other half of them. Investigators should include such infants in studies and their reports should give specific information about them.

Comparative analysis of mononuclear cells isolated from mucosal lymphoid follicles of the human ileum and colon.

Studies of human mucosal lymphoid follicles are rare and have been limited to children's Peyer's patches, which are visible at endoscopy. We investigated lymphoid follicles in ileum biopsies of 87 patients and surgical colon specimens from 66 cancer patients, and examined phenotype and function of isolated follicular immune cells. Two (0-10) and 12 (0-117) follicles per patient were found in ileum and colon samples respectively (P < 0.001). The number of lymphoid follicles mononuclear cells (LFMC) that could be isolated per patient was higher from colon compared with ileum specimens [725 000 (0-23 Mio) versus 100 000 (0-1.3 Mio), P < 0.001]. T cells were predominant in both LFMC and lamina propria mononuclear cells (LPMC), but B cells were more and plasma cells less frequent in LFMC. T cells from mucosal follicles were more frequently CD4-positive and CD62L-positive, but less frequently CD8-positive, CD103-positive and CD69-positive than lamina propria T cells. LFMC from ileum compared with colon showed no differences in mononuclear cell composition. Anti-CD3/CD28 stimulation induced similar proliferation of LFMC and LPMC from ileum and colon, as well as secretion of high levels of interferon-gamma, tumour necrosis factor-alpha and interleukin (IL)-2, but lower levels of IL-4, IL-6 and IL-10. LFMC from colon secreted more IL-2 than those from ileum. Our study shows that mucosal lymphoid follicles can be identified clearly in adult human colon and yield viable immune cells sufficient for phenotypical and functional analysis. The cellular composition of LFMC from ileum and colon is similar, and both secrete predominantly T helper type 1 cytokines.

Sexual precocity associated with an abdominal tumor in an African boy.

We report a 3 year-old boy in Tanzania with an abdominal mass and isosexual precocity due to an hCG-secreting hepatoblastoma. Due to the limited availability of local diagnostic testing, surgery and chemotherapy were completed before immunohistochemical and endocrine results were available.

[Clinical impact of fetal MRI in addition to ultrasonography in brain anomalies--three case reports]. / Klinische Bedeutung der MRT in Ergänzung zur Sonografie bei fetalen Hirnfehlbildungen--drei Fallberichte.

Fetal magnetic resonance imaging (MRI) is a reliable method to further evaluate brain anomalies detected on ultrasonography. MRI can reveal additional brain abnormalities which are consequential for counselling parents about the fetal prognosis and subsequently influence the decision about continuing the pregnancy. In case of fatal malformations, MRI can confirm a diagnosis established on ultrasonography, supplying more reliability.

Long-term treatment of central Cushing's syndrome with rosiglitazone.

CONTEXT: Central Cushing's syndrome is not always curable by surgery or radiation of the pituitary. Medical treatment is often not possible or effective. Some studies revealed beneficial effects of the PPARgamma (Peroxisome-Proliferator-Activator- Receptor-gamma)-agonist rosiglitazone (RG) in in vitro studies, animal models and short term clinical studies. OBJECTIVE: of this study was to observe the long-term effects of RG-treatment on cortisol- and ACTH -secretion, clinical outcomes and morphological changes of the pituitary in patients with persistent ACTH-overproduction despite previous operation and radiation. DESIGN, SETTING AND PATIENTS: 14 patients with persistent central ACTH -production were included and monitored over a period up to 12 months. RG was administered daily and increased to a maximum dosage of 24 mg daily, according to the response of ACTH and cortisol secretion. ACTH and cortisol were measured at least every 4 weeks during RG treatment. RESULTS: Patients were treated between 4 and 12 months with RG (mean 6.8 months). Compared to baseline, ACTH- and cortisol levels dropped significantly (p<0.01) after 12, 16, 20, 24 and 28 weeks but thereafter rose again during the study period, despite continuous RG- treatment and dose increase up to the maximum dosage. This was paralleled by reocurrence of clinical symptoms. MRI-scans were performed in 6 patients because of persisting visible adenoma, but showed no morphological changes. CONCLUSION: RG seems not to be a long-term treatment option for patients with persistent central ACTH-evcess. Though, in order to reduce perioperative complications, short term treatment of patients could be an alternative.

Eosinophilic glomerulonephritis in children in Southwestern Uganda.

Acute renal disease is common in sub-Saharan Africa, with high mortality. Its etiology is poorly understood; quartan malaria owing to Plasmodium malariae was implicated in previous series. Few previous studies have included histological data; furthermore, much of the literature pre-dates the human immunodeficiency virus (HIV) epidemic. We report prospective analysis of acute proteinuric renal disease in children in rural Uganda. Clinical and laboratory data are presented on 65 patients (aged 2-14 years, mean 8.4; 35 male, 30 female) in 41 of whom histological diagnosis was obtained by renal biopsy. The most frequent histological finding was endocapillary proliferative glomerulonephritis (GN) in 27/41 cases, in 20 of which eosinophils were very prominent. No cases showed features of HIV nephropathy. Malarial films were positive in 11 cases: all owing to Plasmodium falciparum. Patients were treated with diuretics, antihypertensives, and supportive measures. Corticosteroids were rarely used, being reserved for patients with minimal changes on renal biopsy. Clinical outcomes were fair: 91% of patients survived to discharge. We conclude that acute GN is common in children in Uganda, that an unusual eosinophilic proliferative GN is the most frequent histological finding, that HIV is not implicated as an important factor in this age group, and that good outcomes can be achieved using simple clinical and laboratory diagnostic methods. Renal biopsy in selected cases is feasible and helpful, especially in allowing rational use of corticosteroids and other potentially toxic treatments. Symptomatic treatments and careful supportive care will allow the majority of children to recover.

Type of kindergarten and other potential determinants of overweight in pre-school children.

OBJECTIVE: The study aimed to assess the relationship of various types of kindergarten differing in length of care and food availability with the development of overweight in pre-school children. DESIGN, SETTING AND SUBJECTS: A cross-sectional study was carried out in 2002 in Stuttgart, Germany, as part of the school entrance examination. Height and weight of 2140 children (participation 70.2%) were measured and information on type of kindergarten and other potential determinants of overweight was collected by a parental questionnaire. Change in relative body mass index (BMI) position between the ages of 4 and 6 years was assessed using medical records. RESULTS: The prevalence of overweight or change in relative BMI position did not differ according to the type of kindergarten. For the prevalence of overweight in German children, adjusted odds ratios (OR) comparing institutions that open only in the morning with those opening in the morning and afternoon or for the full day were 0.86 (95% confidence interval (CI) 0.40, 1.83) and 0.63 (95% CI 0.25, 1.58), respectively. Parental BMI and duration of television watching were positively associated, and maternal educational status and duration of breast-feeding were negatively associated, with overweight and/or change in relative BMI position. The prevalence of overweight was substantially higher among non-German than among German children (adjusted OR 2.17 (95% CI 1.53, 3.07)). CONCLUSIONS: These data show no association between different types of kindergarten and the development of overweight in early childhood. Duration of television watching and breast-feeding, as well as the relatively high prevalence of overweight in ethnic minorities, deserve further attention.

The effect of public or private structures in wastewater treatment on the conditions for the design, construction and operation of wastewater treatment plants.

Organised in public or private structures, wastewater services have to cope with different framework conditions as regards planning, construction, financing and operation. This leads quite often to different modes of management. In recent years there has been a push for privatisation on the water sector in general, the reasons for which are manifold, ranging from access to external know-how and capital to synergistic effects through integration of wastewater treatment into other tasks of similar or equal nature. Discussed are various models of public/private partnership (PPP) in wastewater treatment, encompassing for example the delegation of partial tasks or even the proportional or entire transfer of ownership of treatment facilities to private third parties. Decisive for high performance and efficiency is not the legal or organisational form, but rather the clear and unmistakable definition of tasks which are to be assigned to the different parties, customers and all other partners involved, as well as of clear-cut interfaces. On account of the (of course legitimate) profit-oriented perspective of the private sector, some decision-making processes in relation to project implementation (design and construction) and to operational aspects will differ from those typically found on the public sector. This does apply to decisions on investments, financing and on technical solutions too. On the other hand, core competencies in wastewater treatment should not be outsourced, but remain the public bodies' responsibility, even with 'far-reaching' privatisation models. Such core competencies are all efforts geared to sustainable wastewater treatment as life-supporting provision for the future or as contribution to the protection of health and the environment and to the development of infrastructure. Major areas of wastewater treatment and other related tasks are reviewed. The paper concludes with a list of questions on the issue of outsourcing.

Integrated water resources management in the Ruhr River Basin, Germany.

The Ruhr, with an average flow of 80.5 m3/s at its mouth, is a comparatively small tributary to the Rhine River that has to perform an important task: to secure the water supply of more than 5 million people and of the industry in the densely populated region north of the river. The complex water management system and network applied by the Ruhrverband in the natural Ruhr River Basin has been developed step by step, over decades since 1913. And from the beginning, its major goal has been to achieve optimal conditions for the people living in the region. For this purpose, a functional water supply and wastewater disposal infrastructure has been built up. The development of these structures required and still requires multi-dimensional planning and performance. Since the river serves as receiving water and at the same time as a source of drinking water, the above-standard efforts of Ruhrverband for cleaner water also help to conserve nature and wildlife. Ruhrverband has summed up its environmental awareness in the slogan: "For the people and for the environment". This basic water philosophy, successfully applied to the Ruhr for more than 80 years, will be continued in accordance with the new European Water Framework Directive, enacted in 2000, which demands integrated water resources management in natural river basins, by including the good ecological status of surface waterbodies as an additional goal.

Selective inhibition of protein kinases blocks the formation of a new axis, the beginning of budding, in Hydra.

In Hydra, head regeneration and bud formation appear to be very similar processes. The fact that there are genes whose expression is specific for one of the two processes suggests that they do not have identical molecular bases. We analyzed the signal transduction pathways regulating bud development using inhibitors of protein kinase C, Src, PI3K and ERK. The four inhibitors reversibly blocked bud formation in Hydra when applied before stage 1. Once the bud reached stage 3, three of them had no effect and the bud developed normally. The inhibitors blocked the expression of Budhead, an early head marker, and of CnOtx which are specific for bud formation. The results are in agreement with the central role of a signaling pathway mediated by Src on bud development.

The influence of stormwater treatment on the hydraulic and pollution load--balance for an entire river basin.

The installation of about 500 stormwater detention facilities (SDFs) led to a significant drop of the pollution originating from stormwater runoff in the river basin of the Ruhr which covers 4,488 km2. The German technical directives on the design of SDFs are briefly outlined and the specific costs for such plants are given. The average costs for one kilogram COD held back by SDFs in combined systems amount to Euro 3.73 (calculated without consideration of the subsequent removal in the municipal wastewater treatment plant (WWTP)). The tank volume for stormwater storage can be minimised by application of real-time management systems which allow a dynamic operation of all SDFs in a catchment area.