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The diagnosis of a major clinical entity like Down's syndrome enables a rather concrete prediction of intellectual performance at school age. However, in most instances, the prediction of intellectual development is not so certain. In an attempt to evaluate the validity of such predictions, 315 children were studied with the Griffiths test starting at nine months up to two years. One hundred nineteen children were healthy, 118 were preterm children who were considered at risk for developmental problems, and 78 were known to be retarded. The normal and preterm children were further tested at three, four, five, seven, and nine years of age with a variety of other tests of intellectual performance. The results of the study were in keeping with the results of other studies. The predictive value of the Griffiths test at nine months of age was less than that of the test at 24 months, as might be expected. Furthermore, the predictive value of the test was also related to the intellectual performance of the child. That is, the performance on the test was least predictive of intellectual performance for the normal children, and most predictive of future performance for the retarded children. The correlation coefficient for normal children ranged from zero at nine months to 0.37 at 24 months. (For purposes of comparison, a correlation coefficient of 0.37 implies that 0.37 times 0.37, or 14 percent, of the variability of the intellectual performance can be predicted by the test at 24 months.) Among the retarded children, the correlation coefficient was about 0.8 at 24 months. The study demonstrates that, in general, a low performance score is in general more predictive than a high score, and that predictions are unreliable for borderline scores. It may be that children with borderline scores are more greatly affected by their environment, socioeconomic conditions, and other factors. (Consumer Summary produced by Reliance Medical Information, Inc.)

The MAPK pathway is activated in the majority of melanomas and is the target of therapeutic approaches. Under normal conditions, it initiates the so-called immediate early response, which encompasses the transient transcription of several genes belonging to the AP-1 transcription factor family. Under pathological conditions, such as continuous MAPK pathway overactivation due to oncogenic alterations occurring in melanoma, these genes are constitutively expressed. The consequences of a permanent expression of these genes are largely unknown. Here, we show that FOSL1 is the main immediate early AP-1 member induced by melanoma oncogenes. We first examined its role in established melanoma cells. We found that FOSL1 is involved in melanoma cell migration as well as cell proliferation and anoikis-independent growth, which is mediated by the gene product of its target gene HMGA1, encoding a multipotent chromatin modifier. As FOSL1 expression is increased in patient melanoma samples compared to nevi, we investigated the effect of enhanced FOSL1 expression on melanocytes. Intriguingly, we found that FOSL1 acts oncogenic and transforms melanocytes, enabling subcutaneous tumor growth in vivo. During the process of transformation, FOSL1 reprogrammed the melanocytes and downregulated MITF in a HMGA1-dependent manner. At the same time, AXL was upregulated, leading to a shift in the MITF/AXL balance. Furthermore, FOSL1 re-enforced pro-tumorigenic transcription factors MYC, E2F3 and AP-1. Together, this led to the enhancement of several growth-promoting processes, such as ribosome biogenesis, cellular detachment and pyrimidine metabolism. Overall, we demonstrate that FOSL1 is a novel reprogramming factor for melanocytes with potent tumor transformation potential.

Das Beschwerdebild Dysphagie ist ein weites diagnostisches Feld, in dem der Hausarzt eine zentrale Position einnimmt. In der Erstdiagnostik gilt es, mögliche Ursachen sowie Komorbiditäten genau abzuklären. Darauf aufbauend werden fachärztliche Kollegen hinzugezogen, denn die meisten Fälle sind nur interdisziplinär erfolgreich zu behandeln. Ein Wegweiser.

Zusammenfassung: Neuere Studien haben Gemeinsamkeiten in der sehr komplexen Pathogenese des Diabetes mellitus und rheumatischer Erkrankungen, insbesondere der rheumatoiden Arthritis (RA), nachweisen können. Neben z. T. gemeinsamen HLA-Merkmalen beim Diabetes mellitus Typ 1 und der RA sind Polymorphismen proinflammatorischer Zytokine wie Interleukin 1 und 6 sowie TNF-α bei beiden Erkrankungsformen von besonderer Bedeutung. Das metabolische Syndrom, das häufig mit einem gestörten Glukosestoffwechsel und einem Diabetes mellitus Typ 2 einhergeht, zeigt neben einer Insulinresistenz nicht selten Zeichen eines subklinischen inflammatorischen Prozesses. Auch hier spielen Interaktionen mit den gleichen Zytokinen eine Rolle. Bei der RA haben neue Therapieansätze mit monoklonalen Antikörpern gegen proinflammatorische Zytokine, die gezielt in die Schlüsselvorgänge der Entzündung eingreifen, eine neue Ära der Therapie eingeleitet. Auch beim Typ-1- und Typ-2-Diabetes werden erste Therapiestudien mit diesen sog. „Biologika“ durchgeführt, da auch beim Diabetes die Inflammation eine Rolle zu spielen scheint. Bei Vorliegen eines Typ-1-Diabetes und bei autoimmunen rheumatischen Erkrankungen müssen wir die Möglichkeit weiterer assoziierter Autoimmunerkrankungen in Betracht ziehen.

ABSTRACTWe used a PCR method to quantify the loads of Chlamydia trachomatisorganisms in self-collected urine and vulvovaginal swab (VVS) samples from 93 women and 30 men participating in the Chlamydia Screening Studies Project, a community-based study of individuals not seeking health care. For women, self-collected VVS had a higher mean chlamydial load (10,405 organisms/ml; 95% confidence interval [95% CI], 5,167 to 21,163 organisms/ml) than did first-void urines (FVU) (503 organisms/ml; 95% CI, 250 to 1,022 organisms/ml; P< 0.001). Chlamydial loads in female and male self-collected FVU specimens were similar (P= 0.634). The mean chlamydial load in FVU specimens decreased with increasing age in females and males. There was no strong statistical evidence of differences in chlamydial load in repeat male and female FVU specimens taken when patients attended for treatment a median of 23.5 (range, 14 to 62) and 28 (range, 13 to 132) days later, respectively, or in VVS taken a median of 35 (range, 14 to 217) days later. In this study, chlamydial load values for infected persons in the community who were not seeking treatment were lower than those published in other studies involving symptomatic patients attending clinical settings. This might have implications for estimates of the infectiousness of chlamydia. The results of this study provide a scientific rationale for preferring VVS to FVU specimens from women.

Zusammenfassung

We have searched for rare molecules and radicals in the coma of P/Halley using the ion data obtained by IMS-Giotto. Whereas our established methods were used in the ionosphere, a new model was developed for the interpretation of the ion data in the outer coma. Ne/H2O < 1.5 × 10-3was determined in the coma of the comet. Upper limits for the production of Na were derived from the very low abundance of Na+. Methyl cyanide and (probably) ethyl cyanide were identified with abundances of CH3CN/H2O = (1.4 ± .6) × 10-3and C2H5CN/H2O = (2.8 ± 1.6) × 10-4. These results and upper limits for other N-bearing species confirm that nitrogen is depleted in the Halley material. C4H was identified and a point source strength of C4H/H2O = (2.3 ± .8) × 10-3was derived. Our upper limit for C3H is lower than the abundance of C4H. This is in agreement with the enhanced abundances of CnH species with even numbers of C-atoms found in interstellar molecular clouds, suggesting that the C4H in Halley was synthesized under molecular cloud conditions. Thus, C4H and other organics with unpaired electrons may turn out to be indicators for a molecular cloud origin of cometary constituents.

(R,S)-3-Hydroxy-4-pentenoate rapidly and selectively depletes the mitochondrial glutathione pool in rat hepatocytes, but shows little cytotoxicity and does not induce mitochondrial dysfunction [Shan, X., et al. (1993) Chem. Res. Toxicol. 6, 75−81]. The objective of the present studies was to investigate the 3-hydroxybutanoate dehydrogenase-dependent oxidation of (R)- and (S)-3-hydroxy-4-pentenoate and the enantioselectivity of 3-hydroxy-4-pentenoate-induced depletion of mitochondrial glutathione concentrations in isolated rat liver mitochondria and hepatocytes. (S)-3-Hydroxy-4-pentenoate, but not (R)-3-hydroxy-4-pentenoate, was a substrate for 3-hydroxybutanoate dehydrogenase. Incubation of rat liver mitochondria or hepatocytes with (S)-3-hydroxy-4-pentenoate resulted in a time- and concentration-dependent depletion of mitochondrial glutathione concentrations, whereas (R)-3-hydroxy-4-pentenoate produced little depletion. These results show that (S)-3-hydroxy-4-pentenoate is a substrate for 3-hydroxybutanoate dehydrogenase and is converted to the Michael acceptor 3-oxo-4-pentenoate, which reacts with glutathione and thereby depletes the mitochondrial glutathione pool. (S)-3-Hydroxy-4-pentenoate may find use in the study of mitochondrial glutathione homeostasis and the role of mitochondrial glutathione in cellular protection.

Motivated mainly by yet unexplained data from heavy ion collisions, various attempts have been recently made to search for new light, short-lived neutral particles. Channeling of very high energy electrons can provide new ways to search for particles whose peculiar properties require for their production the presence of strong fields, such as particles with internal structure. We also discuss the possibility of enhancing the rate of Higgs boson production at high energy electron linear colliders by crystal channeling.

Resonant two-photon ionization (R2PI) and fluorescence spectra of the 1-naphthol·H2O and 1-naphthol-d1·D2O cluster are reported and interpreted with emphasis on intracomplex vibrational energy redistribution (IVR) and vibronic coupling. The analysis included an ab initio normal-coordinate calculation of both complexes at the 6-31G (d,p) level. In S1 ← S0 R2PI spectra, the intermolecular modes were found to be very weak; only one such S1 vibration was observed at 57 cm^-1 (54 cm^-1 for 1-naphthol-OD·D2O). At excitations less than 400 cm^-1 above the S1← S0 origin, the fluorescence spectra retain a simple 1-naphthol-like pattern. At higher excess energies, the fluorescence exhibits complex structure due to emission from both relaxed and unrelaxed S1 vibrational states, showing efficient coupling through the hydrogen bond. This restricted IVR behavior changes to dissipative IVR at about 834 cm^-1 above the S1 ← S0 origin. Exceptions to general IVR are observed. The S1 + 403 cm^-1 level is a restricted IVR case, while the nearby S1 + 400 cm^-1 level undergoes nearly dissipative IVR. On the other hand, a nearly “frozen” mode is observed at 553 cm^-1 above the S1← S0 origin. By use of the ab initio vibrational analysis and lowest-order anharmonic coupling, the IVR-active vibrational “bath” states can be predicted, enabling tentative assignment of much of the relaxed fluorescence structure. Ion-dip spectroscopy shows that IVR in the electronic ground state may have a higher onset threshold than in the S1 by ≥130 cm^-1. Exciting one quantum of the 57 cm^-1 intermolecular mode results in a decreased S0 IVR threshold. The strong vibronic S1−S2 coupling earlier observed for vibrations at S1 + 410 and S1 + 414 cm^-1 in free 1-naphthol was found to be partially inhibited in 1-naphthol·H2O but still significant in 1-naphthol-OD·D2O. This is attributed to harmonic mode mixing. In contrast, vibronic coupling becomes active in the S1 + 292 cm^-1 level of 1-naphthol·H2O.

The following result is proved: Let $ X$ be compact topological groups and $ p$ onto $ X$ from $ X$ such that $ p \circ q = {\text{i}}{{\text{d}}_X}$ $ {q^{ - 1}}(B)$ for every Baire subset $ B$.

The anomalous electron-positron coincidences observed in heavy-ion collisions have been interpreted as signal for the pair decay of hitherto unknown neutral objects with masses around 1.8 MeV. We discuss the decay modes of such extended composite particles when they are bound to a nucleus. In particular we investigate the angular correlation of the emitted pair and the competing single-photon decay channel. We confront the particle hypothesis with recent negative results from experiments searching for resonances in Bhabha scattering. The induced pair decay of a metastable 1++ state in secondary collisions with target atoms is discussed as a possible explanation.

Summary The effect of a new complex oligosaccharide (Bay g 5421) of microbial origin on human intestinala-glucosidehydrolase activity was tested in mucosal homogenate from human small bowel biopsy specimens.

Recently measuredd-electron spectra from elastic U + Pd-collisions at 6.1 MeV/u show for small impact parameters enhancements up to two orders of magnitude relative to coupled-channel calculations which described-electron production for larger impact parameters almost perfectly. If these deviations are interpreted as due to modified nuclear trajectories they imply most interesting structures of the internuclear potential at the Coulomb-barrier. We show that an alternative explanation, namely and-electron enhancement due to strong collective nuclear excitations, e.g. giant resonances, does not reproduce the experimental finding.

Several characterizations of isometries of measure algebras, equipped with the Nikodym metric, and of some of their subspaces are given.

We study property preserving transformations for reactive systems. The main idea is the use of simulations parameterized by Galois connections (a, ?), relating the lattices of properties of two systems. We propose and study a notion of preservation of properties expressed by formulas of a logic, by a function a mapping sets of states of a systemS into sets of states of a systemS'. We give results on the preservation of properties expressed in sublanguages of the branching time µ-calculus when two systemsS andS' are related via (a, ?)-simulations. They can be used to verify a property for a system by verifying the same property on a simpler system which is an abstraction of it. We show also under which conditions abstraction of concurrent systems can be computed from the abstraction of their components. This allows a compositional application of the proposed verification method.

The aim of this study was to evaluate 3D CISS, unenhanced 3D MP-RAGE and contrast enhanced 3D MP-RAGE for the diagnosis of neoplastic, vascular and inflammatory lesions of the cerebellopontine angle, the inner auditory canal, the labyrinth and the facial nerve 42 MR examinations were performed on a total of 38 patients (25 males, 13 females; aged 1-77 years, mean age 43 +/- 20 years) using a 1.5 T MR unit. A T2* weighted 3D CISS sequence (TR 14.65 ms, TE 21 ms, flip angle 65 degrees, voxel size 0.7 x 0.7 x 0.7 mm3) and a T1 weighted 3D MP-RAGE sequence (TR 12.5 ms, TE 5 ms, T1 300 ms, flip angle 15 degrees, voxel size 1.0 x 0.9 x 0.9 mm3) with and without contrast medium (gadolinium-DTPA, 0.1 mmol kg-1 body weight) were used. Results of contrast enhanced 3D MP-RAGE-pathological enhancement was found in the following lesions: schwannomas of the cerebellopontine angle (CPA) and the internal auditory canal (IAC), 4; schwannomas of the IAC, 7 and labyrinthine tumours, 3; posterior fossa lymphoma, 1; meatal meningioma, 1; acute labyrinthitis, 15 and neuritis of the seventh cranial nerve, 10. Results of 3D CISS-filling defects were found with the following lesions: schwannomas of the CPA, the IAC or labyrinth, 14; lymphoma, 1; meningioma, 1; labyrinthine fibrosis, 13 and scar in the IAC, 4. These results suggest that unenhanced and contrast enhanced 3D MP-RAGE and 3D CISS are complementary MR imaging modalities. T1 weighted 3D MP-RAGE is preferred to T1 weighted 2D (turbo) spin echo sequences because of the multiplanar reconstruction possibilities of 3D sequences, which are very useful in the case of the inner ear and facial nerve.

Review of blood distribution by blood type in 37 hospitals served by one blood center revealed that bloods collected from a random population of donors and transfused to a random population of recipients show a normal distribution of types. However, 35 per cent of donors who are drawn in the hospitals are Rh‐negative and 19 per cent of bloods returned outdated are Rh‐negative. Examination of the data indicates the low‐frequency blood types are stored out of proportion to their utilization rate and are more likely to be lost through outdating. Alternative solutions are suggested.

The exact Hausdorff dimension function is determined for sets in Rmconstructed by using a recursion that is governed by some given law of randomness.

RationaleThere is increasing evidence of a link between abnormalities in the myeloid cell lineage and pulmonary arterial hypertension (PAH). Heterozygous mutations in the gene encoding the bone morphogenetic protein type 2 receptor (BMPR2) are the most common genetic cause of PAH. We sought to characterise the impact of the genetic loss/reduction of BMPR2function in the myeloid lineage in mice and humans, and whether this altered susceptibility to PAH.MethodsMx1-cre mice were crossed with bmpr2flox/floxmice. At approximately 8 weeks of age cre-recombinase was induced with polyinosinic-polycytidylic acid (Poly I:C). Control mice (bmpr2flox/floxmice with no cre) were also induced with Poly I:C. At approximately 16 weeks post-induction mice underwent right-heart catheterisation, exsanguination and tissue was removed for analysis. The spleens were weighed and histology was performed on the femurs. Mouse data are presented as mean ±SEM. In a large cohort of PAH patients with (n=160) and without (n=831) BMPR2mutations blood count indices were analysed. Data presented as median [IQR].Results16 weeks after induction of cre-recombinase in Mx1-cre/bmpr2flox/floxmice we observed significant increases (p<0.05) in red blood cells (x106/mm3) (12.7±0.9 compared with 12.1±0.2), haematocrit (%) (64.8±0.7 compared with 62.6±1) and haemoglobin (g/dl) (16±0.9 compared with 15.4±0.2) compared with bmpr2flox/floxmice alone. A significant increase in circulating monocytes (x103/mm3) was also observed (p<0.05) (0.4±0.05 compared with 0.3±0.05). In addition, we identified a significant increase (p<0.05) in megakaryocytes in the femurs (80±10 compared with 17±5) and a significant increase (p<0.01) in the ratio of spleen weight/body weight (0.003±0.0001 compared with 0.002±0.0001) in Mx1-cre/bmpr2flox/floxmice. During right heart catheterisation right ventricular systolic pressures were similar in both groups. In PAH patients significant differences (p<0.05) were seen in haemoglobin (BMPR2mutation: 162 g/L [151.75–173]) vs. no mutation: 150 g/L [135 – 163]), haematocrit (0.48 [0.45–0.52] vs. 0.44 [0.41–0.48]) and white blood cells (8.8 [7.3–10.4] vs. 8.11 [6.77–9.61]).Conclusionswe have identified a role for bmpr2in the differentiation of the mouse myeloid lineage, which was also confirmed in PAH patients with BMPR2mutations. BMPR2appears particularly important in the differentiation of megakaryocyte-erythrocyte lineage.

IntroductionChronic thromboembolic pulmonary hypertension (CTEPH) Results from failure of thrombus resolution following acute pulmonary embolism. Abnormalities in haemostasis are implicated in the pathobiology, including elevated levels of von Willebrand factor (VWF), which is normally regulated by ADAMTS13. Interim analysis of a genome-wide association study (GWAS) identified a significant association in CTEPH with the ADAMTS13andABOgene loci. We aimed to determine if ADAMTS13 protein levels are altered in CTEPH.MethodsADAMTS13 and VWF plasma antigen levels were measured by ELISA in 208 individuals with CTEPH and compared to 68 healthy controls. Levels were also measured in subjects with chronic thromboembolic disease but without pulmonary hypertension (CTED), and other disease comparator groups summarised in figure 1. In 22 CTEPH individuals ADAMTS13 and VWF levels were measured pre-operatively and at least 3 months post-pulmonary endarterectomy (PEA).ResultsADAMTS13 levels were decreased in CTEPH (median ±IQR: 0.88±0.40 µg/ml; p=5.7x10-09) and CTED (0.83±0.22 µg/ml; p=2.1x10-06) patients compared to healthy controls (1.15±0.30 µg/ml) (figure 1). ADAMTS13 levels remained low in CTEPH patients following PEA (pre: 0.78±0.27 µg/ml vs. post: 0.83±0.29 µg/ml; p=0.92) even in those with normalised mean pulmonary arterial pressures (<25 mmHg) after PEA. Furthermore, ADAMTS13 levels were lowest in the CTEPH and CTED groups when covariates (age, gender and batch) were included in multivariate rank regression models. VWF levels were increased in CTEPH (16.7±15.2 µg/ml; p=4.0x10-12) and CTED (17.0±10.1 µg/ml; p=3.9x10-06) compared to healthy controls (8.5±8.8 µg/ml). There was no change post-PEA (pre: 22.2±17.3 µg/ml vs. post: 19.6±14.2 µg/ml; p=0.24).ConclusionsPlasma ADAMTS13 antigen levels are markedly decreased in CTEPH. This is not secondary to pulmonary hypertension, as demonstrated by the similarly low levels in CTED, and individuals with normal pulmonary artery pressures post-PEA. Thus, the VWF/ADAMTS13 axis is implicated in the underlying disease pathophysiology. Ongoing work will clarify if there is a causal link by defining whether genetic variation at the ADAMTS13locus contributes to reduced ADAMTS13 protein levels and CTEPH.[Figure]

IntroductionChronic thromboembolic pulmonary hypertension (CTEPH) is an infrequent but important complication of acute pulmonary embolism (PE). Thrombophilias and non-O blood groups are genetic risk factors for venous thromboembolism (VTE), however they are not independently associated with CTEPH. Identifying genetic risk factors for CTEPH would provide important insights into pathobiology and might allow risk-stratification following PE. We undertook a genome-wide association study (GWAS) in CTEPH to identify novel disease loci.MethodsTo date, 1457 Caucasian CTEPH patients were enrolled from 10 European and US Centres and compared to 1536 healthy Caucasian controls from the Wellcome Trust Case Control Consortium. Genotyping was performed using the HumanOmniExpressExome-8 array. Quality control criteria and statistical analysis are summarised in figure 1.Results1250 CTEPH cases, 1492 controls and 7 million single-nucleotide polymorphisms (SNPs) were included after quality control exclusions. Two loci, in chromosomes 4 and 9 were significantly associated with CTEPH (figure 1). The lead SNP in chr9 (rs532436, OR=2.38, p=4.6x10-32) is highly correlated with the tagging SNP for the A1 blood group (rs507666, R2=0.99). Reconstructing genetic ABO groups confirmed an over-representation of the A1A1 group in CTEPH compared to controls (7% vs. 2.9%, OR 4.5). Additionally, there were 11 significant SNPs in the chr9 ADAMTS13gene locus that is moderately correlated with ABO(R2=0.33).The lead SNP in chr4 (rs13130318, OR=1.4, p=5.6x10-8) is highly correlated with a missense variant in FGG(rs6050, R2=0.89) associated with decreased fibrinogen protein and increased resistance to fibrinolysis in CTEPH. There were no associations at the F5locus, which is highly significant in VTE.ConclusionsWe report the first GWAS in CTEPH, identifying at least 2 genetic loci associated with the disease. The ABOassociation is driven by the A1 blood group and represents the largest population attributable genetic risk factor for CTEPH, which is higher than previously reported for VTE. The potential ADAMTS13association is a plausible biological candidate, and further work will establish whether it is independent from ABO. The lack of associations with other loci found in VTE suggests that ABOmight have a pathobiological role in CTEPH in addition to its contribution to VTE.[Figure]

A patient had endocarditis caused by Streptococcus bovis twice 8 years apart. According to pulsed-field gel electrophoresis (PFGE) the two isolates were identical. Seven unrelated blood isolates of S. bovis yielded unique PFGE patterns. Considering this heterogeneous population structure our findings demonstrate the long-term persistence of an S. bovis clone in a patient with recurrent endocarditis.