Maternal mood disorders and lithium exposure in utero were not associated with poor cognitive development during childhood.

AIM: This study evaluated whether maternal mood disorders (MMD), particularly bipolar disorder, and lithium treatment during pregnancy influenced the neonatal health and cognition of children born from 2006 to 2010. METHODS: Our study at Karolinska University Hospital, Stockholm, Sweden, focused on women with and without mood disorders and their children. Information on pharmacotherapy, mental health, delivery and neonatal complications was retrospectively collected from electronic patient records. Children were tested in a blinded manner at four to five years of age with the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition. Maternal health, child health and social situations were evaluated. RESULTS: Of the 39 children, 20 were exposed to lithium and MMD during pregnancy, eight were exposed to MMD but not lithium and 11 were not exposed to MMD or lithium. The children's full scale intelligence quotient (IQ), performance IQ and verbal IQ results did not differ significantly between the groups. The processing speed quotient was significantly lower in children exposed to mood disorders, but there was a high level of missing data for this subtest. CONCLUSION: This small, clinical cohort showed no significant association between mothers' prenatal exposure to lithium or mood disorders and their offspring's IQ.

[Paul Nitsche: psychiatric reformer and main protagonist of Nazi euthanasia]. / Paul Nitsche - Reformpsychiater und Hauptakteur der NS-"Euthanasie".

The professional career of Paul Nitsche reflects the contradictory path taken by a German institutional psychiatrist who was a leader in the field at the time. During the Weimar Republic he advocated improving the institutional system based on principles of psychiatric reform, but was already receptive to concepts of racial hygiene. Shortly after the National Socialists seized power, Nitsche was already an influential proponent and participant in eugenic measures in Saxony and actively involved in implementing the "Law for the Prevention of Genetically Diseased Offspring." He increasingly appraised the value of a patient according to the person's economic performance. It was also Nitsche's opinion that the consequence of this extreme rationalization of human life was to exterminate "life unworthy of life." As a T4 appointed head assessor he decided in the last instance whether thousands of people would live or die. As the Medical Director of the T4 program, he was later directly responsible for continuing the massacre as "decentralized euthanasia." At the euthanasia trial in Dresden he was condemned to death and executed in 1948.

[A 31-year-old pregnant woman with refractory hypercalcemia]. / 31-jährige Schwangere mit refraktärer Hyperkalzämie.

A 31-year-old pregnant woman presented with refractory severe hypercalcemia due to an advanced neuroendocrine tumor masquerading as hyperemesis gravidarum. Octreotide therapy and extensive tumor debulking surgery resulted in symptom control. After a prolonged stay in the intensive care unit due to parapneumonic acute respiratory distress syndrome, the patient delivered a healthy child. Neuroendocrine tumors are a rare complication of pregnancy and a seldom cause of refractory hypercalcemia.

C-11 methionine positron emission tomography/computed tomography localizes parathyroid adenomas in primary hyperparathyroidism.

In patients with primary hyperparathyroidism (pHPT), positive preoperative localization studies enable to perform a minimally invasive approach for parathyroid surgery. However, current imaging techniques are not always successful. We therefore conducted a study to determine the sensitivity of C-11 methionine positron emission tomography/computed tomography (Met-PET/CT) in localizing parathyroid adenomas in pHPT. Met-PET/CT scans of the neck and mediastinum of 33 patients undergoing parathyroidectomy for primary HPT were compared with intraoperative and histological findings. Primary HPT was caused by a single gland adenoma in 30 patients, while another 3 patients had multiglandular disease. Met-PET/CT scan correctly located a single gland adenoma in 25 out of 30 (83%) patients with pHPT, among them 2 patients with persistent disease, 7 patients with prior neck surgery, and 8 patients with concomitant thyroid nodules. In 3 patients with multiglandular disease, Met-PET/CT showed only one enlarged parathyroid gland in two individuals and was negative in the third patient. Statistical analysis found a significant correlation between true-positive results and the weight (2.42+/-4.05 g) and diameter (2.0+/-1.18 cm) of parathyroid adenomas while the subgroup with false negative findings had significantly smaller (0.98+/-0.54 cm) and lighter (0.5+/-0.38 g) glands. Sensitivity was 83% for single gland adenomas and 67% for multiglandular disease. Met-PET/CT correctly localized 83% of single gland parathyroid adenomas in patients with pHPT. However, preoperative localization of multiglandular disease due to double adenomas or parathyroid hyperplasia remained difficult.

Glucokinase-activating GCKR polymorphisms increase plasma levels of triglycerides and free fatty acids, but do not elevate cardiovascular risk in the Ludwigshafen Risk and Cardiovascular Health Study.

Two strongly correlated polymorphisms located within the gene of the glucokinase regulator protein (GKRP), rs780094 and rs1260326, are associated with increased plasma triglyceride levels and provide a genetic model for the long-term activation of hepatic glucokinase. Because pharmacological glucokinase activators are evaluated for the treatment of diabetes, the aim of the study was to assess if these polymorphisms could provide evidence for an increased cardiovascular risk of long-term glucokinase activation. Therefore, these polymorphisms were tested in 3 500 patients of the Ludwigshafen Risk and Cardiovascular Health study, which was designed to assess cardiovascular risk factors. The two variants were associated with a significant increase of both plasma triglycerides (p<0.0001) and VLDL triglyceride levels (p<0.0001). Plasma free fatty acid concentrations were also significantly elevated (p<0.0078). LDL and HDL cholesterol levels were unchanged. No association was found with respect to coronary stenosis, myocardial infarction, left ventricular wall hypertrophy, and hypertension. In conclusion, long-term genetic glucokinase activation by the GKRP polymorphisms was not associated with an increased cardiovascular risk in the study population.

Splenic rupture following endoscopic polypectomy.

A 70-year-old man presented with two medium-sized colon polyps at the office of a gastroenterologist. After endoscopic polypectomy in a hospital, the patient was admitted to another hospital because of collapse and increasing abdominal pain. CT scan revealed hematoperitoneum and splenic subcapsular hematoma. Laparotomy with splenectomy was performed because of extended splenic rupture. The postoperative course was unremarkable except late wound dehiscence.

Gallstone prevalence and risk factors for gallstone disease in an urban population of children and adolescents.

BACKGROUND: At present only a few sonography-based studies have assessed gallstone prevalence and associated risk factors in children and adolescents in randomly selected urban population samples. The aim of the present study was to analyze the prevalence of cholecystolithiasis and associated risk factors in children and adolescents. METHODS: From a randomly selected urban population sample a total of 307 children and adolescents (157 girls, 150 boys; age 12 - 18 years, mean age 15.1 +/- 2.0 years) were studied using ultrasonography, standardized questionnaires and blood samples. RESULTS: Three adolescents (one girl, two boys), corresponding to a prevalence of 1.0 %, showed gallstones. One 14-year-old girl and one 17-year-old boy were overweight using Cole's classification. A positive family history and female gender could not be confirmed as risk factors. CONCLUSION: Obesity appears to be a risk factor in the development of gallstones in childhood and adolescence.

Association between asymmetric dimethylarginine and neopterin in patients with and without angiographic coronary artery disease.

The increase of circulating asymmetric dimethylarginine (ADMA) concentrations, a competitive inhibitor of the nitric oxide synthases, is associated with an increased cardiovascular risk and is considered to play a role in endothelial dysfunction. Recently, ADMA production was observed in stimulated human peripheral mononuclear cells. In this study, we examined a potential relationship between concentrations of ADMA and of the immune activation marker neopterin in patients scheduled for coronary angiography. In a cross-sectional approach, blood concentrations of ADMA, homocysteine, neopterin, folic acid and vitamins B6 and B12 were compared in 2030 patients, which were recruited as participants of the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study. ADMA concentrations did not differ between patients with coronary artery disease (CAD) (mean +/- SD: 0.82 +/- 0.15 micromol/l) and controls (0.81 +/- 0.14 micromol/l; Welch's t-test: P = n.s.). ADMA concentrations correlated with homocysteine (r(s) = 0.207) and vitamin B6 (r(s) = -0.190), and an even stronger correlation with neopterin (r(s) = 0.276; all P < 0.0001) was observed. In conclusion, increased ADMA concentrations in patients at risk for atherosclerosis are associated with increased neopterin concentrations. Data suggest that immune activation may contribute to increased ADMA production in CAD patients.

MHC-environment interactions leading to type 1 diabetes: feasibility of an analysis of HLA DR-DQ alleles in relation to manifestation periods and dates of birth.

AIM: The region on chromosome 6p21 (IDDM1) confers the largest part of genetic susceptibility to type 1 diabetes (T1D) with particular human leucocyte antigen (HLA) alleles predisposing and others protecting from it. As T1D is primarily a "sporadic" disease, the pathophysiology must involve gene-environment interactions. We searched for indirect evidence for such major histocompatibility complex (MHC)-environment interactions by asking two questions: (i) can the degree of an HLA association vary over time periods? and (ii) if a prenatal event like an intrauterine infection - that might cluster in seasons - leads to differences of HLA associations in patients with particular birth months? METHODS: We screened the Type 1 Diabetes Genetics Consortium (T1DGC) database (in addition our own database and the original UK, US and SCAND databases) for MHC DR-DQ and CTLA4 associations. First, we separated the groups of patients with onset of disease before 1980 in comparison with onset after 1980. Second, we analysed the data according to dates of birth (grouped in months). Not all patients' dates of birth or manifestation periods were available, leading to different group sizes. There were 282 patients analysed for manifestation periods and 329 for birth month. RESULTS: The cohorts of manifestation before 1980 demonstrated a significantly lower frequency of DQ2/X (2 vs. 14.2%; p = 0.03). There was a trend for DQ8/x to be more frequent for manifestations before 1980 (34 vs. 21.6%; p < 0.10). Other alleles did not differ significantly. The months of birth were not evenly distributed. Significant deviations from the whole group were seen in August (DQ2/8 trough and DQx/x high), whereas birth in September was more frequent in DQ8/x or DQ8/8 carriers. This pattern was significantly different from the expected distribution of months at birth (13.9 vs. 7.6%; p < 0.04). CONCLUSIONS: We demonstrate the feasibility of an analysis that searches for indirect evidence of gene-environment interactions. These preliminary data need to be confirmed in larger data sets.

Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo.

BACKGROUND: Pancreatic ductal adenocarcinomas (PDACs) are highly resistant to treatment due to changes in various signalling pathways. CK1 isoforms play important regulatory roles in these pathways. AIMS: We analysed the expression levels of CK1 delta and epsilon (CK1delta/in) in pancreatic tumour cells in order to validate the effects of CK1 inhibition by 3-[2,4,6-(trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261) on their proliferation and sensitivity to anti-CD95 and gemcitabine. METHODS: CK1delta/in expression levels were investigated by using western blotting and immunohistochemistry. Cell death was analysed by FACS analysis. Gene expression was assessed by real-time PCR and western blotting. The putative anti-tumoral effects of IC261 were tested in vivo in a subcutaneous mouse xenotransplantation model for pancreatic cancer. RESULTS: We found that CK1delta/in are highly expressed in pancreatic tumour cell lines and in higher graded PDACs. Inhibition of CK1delta/in by IC261 reduced pancreatic tumour cell growth in vitro and in vivo. Moreover, IC261 decreased the expression levels of several anti-apoptotic proteins and sensitised cells to CD95-mediated apoptosis. However, IC261 did not enhance gemcitabine-mediated cell death either in vitro or in vivo. CONCLUSIONS: Targeting CK1 isoforms by IC261 influences both pancreatic tumour cell growth and apoptosis sensitivity in vitro and the growth of induced tumours in vivo, thus providing a promising new strategy for the treatment of pancreatic tumours.

Simple Categorization of Human Figure Drawings at 5 Years of Age as an Indicator of Developmental Delay.

Purpose: To elucidate the association between developmental stage of human figure drawing(HFD) and fine motor control, visual perception, and further investigate its potential to be used for screening developmental delay. Methods: Participants were 301 children at 5½ years of age, 176 born preterm and 125 at term, whose HFDs were categorized into six developmental stages. Motor-Free-Visual-Perception Test, Movement-ABC, Performance Intelligence Quotient (PIQ: Wechsler Scale), and the Visual-Motor Integration test were used. Fine motor functions were explored using ImageJ. Results: Age-expected HFDs were drawn by 87% of the children, while 13%, mostly preterm boys, drew immature ones. Stages of HFD were related to both PIQ and Movement-ABC. Visuomotor control and visual perception significantly explained the HFD. The sensitivity and specificity of HFD as a screening tool was moderate to good. Conclusions: HFD is influenced by visual perception and visuomotor control and can be used for screening developmental delay at preschool age.

Lazy Sundays: role of day of the week and reactivity on objectively measured physical activity in older people.

BACKGROUND: The aim of this study was to assess the effect of day of the week and wearing a device (reactivity) on objectively measured physical activity (PA) in older people. METHODS: Walking duration as a measure for PA was recorded from 1333 German community-dwelling older people (≥65 years, 43.8% women) over 5 days using accelerometers (activPAL). Least-square means of PA with 95%-confidence intervals (95%-CI) from multi-level analysis were calculated for each day of the week and each measurement day (days after sensor attachment). RESULTS: Walking duration on Sundays was significantly lower compared to working days (Sunday vs. Monday-Friday: - 12.8 min (95%-CI: - 14.7; - 10.9)). No statistically significant difference compared to working days was present for Saturdays. The linear slope for measurement day and walking duration was marginal and not statistically significant. CONCLUSIONS: Studies using PA sensors in older people should assess Sundays and working days to adequately determine the activity level of the participants.

Mental and motor development before and during growth hormone treatment in infants and toddlers with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, feeding difficulties and failure to thrive in infancy. GH treatment improves growth velocity and body composition. Research on the effects of GH on psychomotor development in infants with PWS is limited. OBJECTIVE: To evaluate psychomotor development in PWS infants and toddlers during GH treatment compared to randomized controls. DESIGN/PATIENTS: Forty-three PWS infants were evaluated at baseline. Twenty-nine of them were randomized into a GH group (n = 15) receiving 1 mg/m(2)/day GH or a non-GH-treated control group (n = 14). At baseline and after 12 months of follow-up, analysis with Bayley Scales of Infant Development II (BSID-II) was performed. Data were converted to percentage of expected development for age (%ed), and changes during follow-up were calculated. RESULTS: Infants in the GH group had a median age of 2.3 years [interquartile range (IQR) 1.7-3.0] and in the control group of 1.5 years (IQR 1.2-2.7) (P = 0.17). Both mental and motor development improved significantly during the first year of study in the GH group vs. the control group: median (IQR) change was +9.3% (-5.3 to 13.3) vs.-2.9% (-8.1 to 4.9) (P < 0.05) in mental development and +11.2% (-4.9 to 22.5) vs.-18.5% (-27.9 to 1.8) (P < 0.05) in motor development, respectively. CONCLUSION: One year of GH treatment significantly improved mental and motor development in PWS infants compared to randomized controls.

Nuclear factor-kappaB is constitutively active in C-cell carcinoma and required for RET-induced transformation.

Specific point mutations of the RET proto-oncogene have been demonstrated to be responsible for multiple endocrine neoplasia (MEN) types 2A and 2B, for familial medullary thyroid carcinoma (MTC) syndromes, as well as for sporadic MTC. Here we show that nuclear factor (NF)-kappaB is activated in RET-associated C-cell carcinoma specimens. TT cells, a human MTC cell line expressing MEN 2A type RET, display transcriptionally active RelA(p65) in the nucleus. NF-kappaB activity in these cells is attributable to constitutive IkappaB kinase (IKK) activity and high turn over of IkappaBalpha. RET harboring the mutations C634R (MEN 2A) or M918T (MEN 2B), in contrast to wild-type RET, activates a NF-kappaB-dependent reporter construct upon transient transfection in HeLa cells. We show that the prototype RET mutation C634R enhances phosphorylation of IkappaBalpha by IKKbeta but not by IKKalpha. RET-induced NF-kappaB and IKKbeta activity requires Ras function but does neither involve the classical mitogen-activated protein kinase kinase/extracellular signal-regulated kinase nor the phosphoinositide 3-kinase/Akt pathways. In contrast, RET-induced NF-kappaB activity is dependent on Raf and MEKK1. Inhibition of constitutive NF-kappaB activity results in cell death of TT cells and blocks focus formation induced by oncogenic forms of RET in NIH 3T3 cells. These results suggest that RET-mediated carcinogenesis critically depends on IKK activity and subsequent NF-kappaB activation.

A porcine model of osteosarcoma.

We previously produced pigs with a latent oncogenic TP53 mutation. Humans with TP53 germline mutations are predisposed to a wide spectrum of early-onset cancers, predominantly breast, brain, adrenal gland cancer, soft tissue sarcomas and osteosarcomas. Loss of p53 function has been observed in >50% of human cancers. Here we demonstrate that porcine mesenchymal stem cells (MSCs) convert to a transformed phenotype after activation of latent oncogenic TP53(R167H) and KRAS(G12D), and overexpression of MYC promotes tumorigenesis. The process mimics key molecular aspects of human sarcomagenesis. Transformed porcine MSCs exhibit genomic instability, with complex karyotypes, and develop into sarcomas on transplantation into immune-deficient mice. In pigs, heterozygous knockout of TP53 was sufficient for spontaneous osteosarcoma development in older animals, whereas homozygous TP53 knockout resulted in multiple large osteosarcomas in 7-8-month-old animals. This is the first report that engineered mutation of an endogenous tumour-suppressor gene leads to invasive cancer in pigs. Unlike in Trp53 mutant mice, osteosarcoma developed in the long bones and skull, closely recapitulating the human disease. These animals thus promise a model for juvenile osteosarcoma, a relatively uncommon but devastating disease.

Combined analysis and single-step detection of GAD65 and IA2 autoantibodies in IDDM can replace the histochemical islet cell antibody test.

Cytoplasmic islet cell antibodies (ICAs) are the classical serological markers for diagnosis and prediction of IDDM, but high technical demands have limited the widespread use of the histochemical ICA test. To investigate whether combined analysis of autoantibodies to two defined islet antigens can replace the histochemical ICA test, we established quantitative radioimmunoassays for autoantibodies to glutamate decarboxylase (GAD65-A), the tyrosine phosphatase IA2/ICA512 (IA2-A), and the cytoplasmic part of IA2 (IA2c-A). The GAD65-A and IA2c-A profiles of 920 sera from healthy individuals and from patients with IDDM, other organ-specific autoimmune diseases, and polyendocrine autoimmune syndrome were compared with the ICA profiles from these same individuals. Combined analysis of GAD65-A and IA2c-A detected 93-100% of the ICA+ sera, and, at equal specificity, improved the diagnostic sensitivity (85%) for IDDM compared with that of ICA (74%). This effect was especially pronounced in children with disease onset before 16 years of age (91% sensitivity). To replace ICA testing in risk assessment for IDDM, we designed a strategy adapted to study groups with low antibody prevalence. A combined radioimmunoassay for single-step detection of GAD65-A and IA2c-A was developed, and positive sera were reanalyzed to define their single autoantibody specificity. We identified 93% of the ICA+ sera from 204 first-degree relatives of IDDM patients. Single-step detection reduced costs and effort by more than 40% compared with separate testing, allowing an efficient large-scale screening of sera for GAD65-A and IA2c-A in IDDM. In sum, GAD65-A and IA2c-A detected much ICA reactivity, and their combined evaluation and detection is suitable to replace the histochemical ICA test.

[Long-term cosmetic results following thyroid resection]. / Kosmetische Spätergebnisse nach Schilddrüsenresektionen.

BACKGROUND: The long-term cosmetic results following thyroid resection may soon become more relevant because minimally invasive techniques are also being promoted. PATIENTS AND METHODS: Two hundred forty-four patients were prospectively enrolled for a questionnaire regarding long-term results following thyroid resection. Ninety of these patients were clinically examined. RESULTS: The cosmetic results were judged by more than 90% of the patients as excellent or good. Women were slightly more critical about their results (P=0.06). Some kind of wound infection was reported in 4.1%, hypertrophic scar in 4.1%, and mild dysphagia in 7%. The results were not associated with the kind or extent of resection. The length of the scars was 4 cm (range 3-7) and the width 2 mm (range 1-4). The surgeons also judged the scars as good or excellent in most cases but were more critical than the patients. CONCLUSION: Since the long-term results of conventional surgery are, in most cases, so good, it seems difficult to improve the results by new minimally invasive techniques.

T-cell-receptor repertoire in chronic plaque-stage psoriasis is restricted and lacks enrichment of superantigen-associated V beta regions.

Preferential usage of certain T-cell receptors by the lymphocytic infiltrate in psoriasis might indicate the involvement of an antigen in the pathogenesis of this disease. However, to date there are no data on the complete T-cell-receptor V alpha and V beta repertoire in psoriatic patients. We therefore compared the usage of T-cell-receptor variable regions in blood and skin of 10 patients with chronic plaque-stage psoriasis by means of semiquantitative polymerase chain reaction. Additionally, HLA class II alleles were analyzed by means of sequence-specific oligonucleotide typing. A considerable restriction of the T-cell-receptor repertoire was observed in the skin, where up to 20% of the variable regions present in the blood were not detectable. This was true for both alpha- and beta-chains. However, no interindividually constant pattern of T-cell-receptor restriction was deducible. Inconsistently, a certain preferential usage of some beta chains occurred within the cutaneous compartment. This report on the complete T-cell-receptor V alpha and V beta repertoire in psoriasis documents the restricted receptor repertoire of infiltrating T cells and a lack of enrichment of superantigen-associated V beta regions. Thus superantigens seem not to play a pathogenetically relevant role in chronic plaque-stage psoriasis.