[Bleeding origin, patient-related risk factors, and prognostic indicators in patients with acute gastrointestinal hemorrhages requiring intensive care treatment. A retrospective analysis from 1999 to 2010]. / Ursachen, patientenspezifische Risikofaktoren und prognostische Indikatoren bei akuter gastrointestinaler Blutung und intensivmedizinischer Therapieindikation. Eine retrospektive Untersuchung der Jahre 1999-2010.

BACKGROUND: Gastrointestinal bleeding (GIB) is a common problem in elderly patients involving severe comorbidities and concomitant antiplatelet or anticoagulatory therapy. The risk factors and prognostic indicators of patients with severe GIB requiring intensive care medical treatment have not been well evaluated. METHODS: A retrospective analysis of 7,376 patients from the medical intensive care unit (ICU) at the University Hospital Aachen was carried out between 1999 and 2010. RESULTS: Of 614 patients admitted to the ICU because of acute GIB, 463 (75%) presented with upper GIB (UGIB) and 151 (25%) with lower GIB (LGIB). Despite early endoscopic intervention and ICU treatment, UGIB had a mortality rate of 16%, whereas LGIB showed a significantly better prognosis (mortality <5%) in the ICU setting. Risk factors for OGIB-related mortality were hemodynamic instability, organ failure, comorbidities (especially liver cirrhosis), and rebleeding. In total, 218 patients (36%) were treated with antiplatelet or anticoagulatory drugs, which were associated with a favorable prognosis in the UGIB group. Elevated serum lactate levels upon admission were superior in predicting mortality than established indicators of prognosis such as the Rockall or the Glasgow-Blatchford score. CONCLUSIONS: Despite successful endoscopic intervention, severe acute UGIB is associated with a significant mortality rate of 16% in the ICU setting, determined by hemodynamic failure, organ dysfunction, and comorbidities. The serum lactate levels of patients with GIB on the day of admission to the ICU are prognostic.

European multidisciplinary consensus statement on the use and monitoring of metal-on-metal bearings for total hip replacement and hip resurfacing.

INTRODUCTION: There is an ongoing debate about the optimal use of metal-on-metal (MoM) bearings in total hip replacement, since there are uncertainties about local and systemic adverse effects due to wear and corrosion of these bearings. Despite various national recommendations, efforts to achieve international harmonization of specific evidence-based recommendations for best practice are still lacking. HYPOTHESIS: An international consensus study group should be able to develop recommendations on the use and monitoring of MoM bearings, preferably at the European level, through a multidisciplinary approach, by integrating the perspectives of various stakeholders. MATERIALS AND METHODS: Twenty-one experts representing three stakeholder groups and eight countries participated in this European consensus study, which consisted of a consensus meeting, subsequent structured discussion, and consensus voting. RESULTS: The current statement defines first of all benefits, local and systemic risks, as well as uncertain issues related to MoM bearings. Safety assessment after implantation of MoM comprises all patients. A closer follow-up is recommended for large head MoM (≥36mm) and resurfacing. In these implants basic follow-up should consist of x-rays and metal ion measurement of cobalt in whole blood, performed with GF-AAS or ICP-MS. Clinical and/or radiographic abnormality as well as elevated ion levels needs additional imaging (ultrasound, CT-scan and/or MARS-MRI). Cobalt values less than 2 µg/L are probably devoid of clinical concern, the threshold value for clinical concern is expected to be within the range of 2-7 µg/L. DISCUSSION: This is the first multinational, interdisciplinary, and multiprofessional approach for developing a recommendation for the use and monitoring of MoM bearings in total hip replacement. The current recommendations are in partial agreement with previous statements regarding the extent of follow-up and imaging techniques. They however differ from previous communications regarding measurement of metal ions and especially the investigated medium, technique, and eventual threshold levels. LEVEL OF EVIDENCE: Level V, expert opinion/agreement conference.

A review on phosphate based, solid state, protonic conductors for intermediate temperature fuel cells.

The electrolytes currently used for proton exchange membrane fuel cells are mainly based on polymers such as Nafion which limits the operation regime of the cell to ∼80 °C. Solid oxide fuel cells operate at much elevated temperatures compared to proton exchange membrane fuel cells (∼1000 °C) and employ oxide electrolytes such as yttrium stabilized zirconia and gadolinium doped ceria. So far an intermediate temperature operation regime (300 °C) has not been widely explored which would open new pathways for novel fuel cell systems. In this review we summarize the potential use of phosphate compounds as electrolytes for intermediate temperature fuel cells. Various examples on ammonium polyphosphate, pyrophosphate, cesium phosphate and other phosphate based electrolytes are presented and their preparation methods, conduction mechanism and conductivity values are demonstrated.

[Cutaneous malignant peripheral nerve sheath tumor in neurofibromatosis type 1]. / Kutaner maligner peripherer Nervenscheidentumor bei Neurofibromatose Typ 1.

Patients with neurofibromatosis have an increased risk of developing malignant tumors in comparison to the general population. We describe a woman who developed a malignant peripheral nerve sheath tumor in a pre-existing neurofibroma.

[Juvenile hyaline fibromatosis]. / Juvenile hyaline Fibromatose.

Juvenile hyaline fibromatosis is a rare autosomal recessive disease of the connective tissue. We present the case of a 6-year-old normal mental developed boy with confluent pearly papules behind the ears and in the paranasal folds, firm nodules of the scalp, the back and metaphalangs, and severe gingival hypertrophy.

Spondyloepiphyseal dysplasia Omani type: a new recessive type of SED with progressive spinal involvement.

We report a large inbred kindred from Oman with a distinct type of spondyloepiphyseal dysplasia (SED). We evaluated eight individuals from two consanguineous sibships, one male and seven females between the ages of 2 and 22. The pedigrees strongly suggest autosomal recessive inheritance and both families are likely to be related through distant consanguineous loops. The clinical features include near to normal length at birth, short stature with final height of 110-130 cm, shortening of the upper segment due to severe progressive kyphoscoliosis, severe arthritic changes with joint dislocations, rhizomelic limbs, genu valgum, cubitus valgus, mild brachydactyly, camptodactyly, microdontia, and normal intelligence. Minor radiographic metaphyseal changes were found, but major manifestations were in the spine and the epiphyses. During the first year of life the vertebral bodies are of normal height but the endplates are irregular and intervertebral space is narrow. With age, the vertebral endplates become increasingly irregular, the intervertebral space diminishes further and individual vertebrae start to fuse resulting in a severe short trunk dwarfism with kyphoscoliosis. The epiphysis are small and precocious osteoarthropathy was observed involving small and large joints. The elbow, wrist, and hip joints were affected starting in infancy and showed restricted movement. Osteoarthropathy and spinal involvement resulted in physical handicap in early adulthood. Comparison of these patients with other skeletal dysplasias suggests that they represent a previously undescribed variant of SED.

Prenatal diagnosis in Coffin-Lowry syndrome demonstrates germinal mosaicism confirmed by mutation analysis.

Coffin-Lowry syndrome is a rare X-linked, semi-dominant mental retardation syndrome resulting from mutations of the ribosomal S6 kinase 2 (RSK2) gene. In the present report, a male patient affected with Coffin-Lowry syndrome is shown to have a nonsense mutation of the RSK2 gene. His unaffected mother does not have this mutation in her lymphocytes. In her third pregnancy prenatal diagnosis by mutation analysis has detected gonadal mosaicism. As this is the second report of germinal mosaicism in Coffin-Lowry syndrome, the finding has important implication for genetic counselling.

Mesomelic campomelia, polydactyly and Dandy-Walker cyst in siblings.

The present report describes two fetuses, one female and one male, with thus far undescribed skeletal malformations. The mother was a gravida 2, para 0. Both pregnancies were terminated in the second trimester because of multiple congenital anomalies diagnosed ultrasonographically resembling a short rib-polydactyly syndrome. Both fetuses were found to have postaxial hexadactyly of the hands and feet, marked bilateral campomelia of the forearm and shank bones, and a Dandy-Walker cyst. In addition, the fourth ventricle was dilated in the first sibling and the second sibling had an inverse intestinal malrotation. A literature search failed to reveal similar observations.

Preclinical diagnosis of pseudoxanthoma elasticum - methodological restrictions and ethical problems.

Pseudoxanthoma elasticum (PXE) is an inherited connective tissue disease. Only recently, mutations in the MRP6 gene on chromosome 16p13.1 have been identified in PXE families. Up to now, predictive testing has not been available. Since ultrastructural connective tissue alterations in overtly normal skin of predilection sites have supported preclinical diagnosis in children of affected individuals, we have screened the daughters of a PXE patient for these alterations. The patient's biopsy from lesional skin revealed elastin and collagen fibril abnormalities, but biopsies from the clinically inconspicuous daughters showed only ultrastructural alterations of collagen fibrils. These findings are inconclusive regarding the diagnosis of PXE in the daughters. Predictive or preclinical diagnosis of incurable, late-onset disorders creates complex social, ethical, and legal problems which call for special management strategies.

Clinical variability of Larsen syndrome: diagnosis in a father after sonographic detection of a severely affected fetus.

Larsen syndrome shows a broad spectrum of clinical manifestation ranging from a lethal form of the disorder to a mild clinical expression with absence of major diagnostic features. Here we show that even intrafamilial manifestation may vary extremely to the point that Larsen syndrome in a father has been diagnosed only by typical sonographic features in an affected fetus.

Phenotypic variation and genetic heterogeneity in Léri-Weill syndrome.

Léri-Weill syndrome (LWS) or dyschondrosteosis represents a short stature syndrome characterised by the mesomelic shortening of the forearms and lower legs and by bilateral Madelung deformity of the wrists. Recently, mutations in the pseudoautosomal homeobox gene SHOX have been shown to be causative for this disorder. This gene has previously been described as the short stature gene implicated in Turner syndrome (TS). We studied 32 Léri-Weill patients from 18 different German and Dutch families and present clinical, radiological and molecular data. Phenotypic inter- and intrafamilial heterogeneity is a frequent finding in LWS, and phenotypic manifestations are generally more severe in females. In males, muscular hypertrophy is a frequent finding. To test for SHOX mutations we used FISH, Southern blot and SSCP analysis as well as long-range PCR and sequencing. We identified (sub)microscopic deletions encompassing the SHOX gene region in 10 out of 18 families investigated. Deletion sizes varied between 100 kb and 9 Mb and did not correlate with the severity of the phenotype. We did not detect SHOX mutations in almost half (41%) the LWS families studied, which suggests different genetic etiologies.

Ellis-van Creveld syndrome: examination at 15 weeks' gestation.

In 1940, Ellis and van Creveld defined a syndrome they referred to as chondro-ectodermal dysplasia. This autosomal recessive condition, now usually referred to as Ellis-van Creveld syndrome (EVC), comprises bilateral postaxial polydactyly, a chondrodysplasia, characterized by shortness of limbs, and ectodermal dysplasia. Congenital heart defects are also common. There are many reports in medical literature describing affected newborns and even, older children. Here, we report the clinical, radiological and histological findings in a 15-week-old affected fetus. The diagnosis of Ellis-van Creveld syndrome in this fetus is based on a positive family history (an affected sib) and shortness of long bones as well as hexadactyly diagnosed by prenatal ultrasonography. On post-mortem examination, bilateral postaxial hexadactyly and symmetrical shortness of the long bones was noted. Histologically, there was too short a zone of cartilagineous columns in the metaphyses, a reduced number of chondrocytes and an irregularly structured spongiosa within the ossification zone. In addition, the fetus was found to have an atrio-ventricular canal. This heart defect is presumably rare in this syndrome. Other characteristic features such as small and dysplastic nails, sparse hair and abnormalities of the teeth were, of course, not yet present in this early developmental stage. In addition to EVC, the fetus had a 47,XXY chromosome constitution.

Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation.

We have observed over 25 different mutations in the diastrophic dysplasia sulphate transporter gene (DTDST) in association with the recessive disorders achondrogenesis 1B, atelosteogenesis 2, and diastrophic dysplasia. The c862t (R279W) transition is the most common mutation in non-Finnish patients, but in these disorders it is usually combined with other DTDST mutations. We had not seen a case of homozygosity for c862t (R279W) until we analysed DNA from a 36 year old male with tall-normal stature (180 cm) who asked for genetic counselling for suspected multiple epiphyseal dysplasia. He was treated for club foot and hip dysplasia at birth. Skeletal changes consistent with multiple epiphyseal dysplasia, with the peculiar finding of a double layered patella, were recognised during childhood. Cleft palate, swelling of the ear pinna, and hitch hiker thumb were absent. He was found to be homozygous, and both healthy parents heterozygous, for the R279W mutation in DTDST, and his fibroblasts showed a sulphate incorporation defect typical of DTDST disorders. Counselling was given for a recessive disorder, thereby considerably reducing the probability of affected offspring. Multiple epiphyseal dysplasia is more frequently caused by dominant mutations in the COMP (EDM1, McKusick 132400) and COL9A2 genes (EDM2, McKusick 600204). A few other patients and families with features similar to our proband have been described previously and considered to have autosomal recessive MED (EDM4, McKusick 226900). This observation confirms the existence of this entity and assigns it to the phenotypic spectrum associated with mutations at the DTDST locus.

Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.

Greig cephalopolysyndactyly syndrome, characterized by craniofacial and limb anomalies (GCPS; MIM 175700), previously has been demonstrated to be associated with translocations as well as point mutations affecting one allele of the zinc finger gene GLI3. In addition to GCPS, Pallister-Hall syndrome (PHS; MIM 146510) and post-axial polydactyly type A (PAP-A; MIM 174200), two other disorders of human development, are caused by GLI3 mutations. In order to gain more insight into the mutational spectrum associated with a single phenotype, we report here the extension of the GLI3 mutation analysis to 24 new GCPS cases. We report the identification of 15 novel mutations present in one of the patient's GLI3 alleles. The mutations map throughout the coding gene regions. The majority are truncating mutations (nine of 15) that engender prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. Two missense and two splicing mutations mapping within the zinc finger motifs presumably also interfere with DNA binding. The five mutations identified within the protein regions C-terminal to the zinc fingers putatively affect additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to two adjacent independent domains (TA(1)and TA(2)) in the C-terminal third of GLI3. Since these are the only functional domains affected by three C-terminally truncating mutations, we postulate that GCPS may be due either to haploinsufficiency resulting from the complete loss of one gene copy or to functional haploinsufficiency related to compromised properties of this transcription factor such as DNA binding and transactivation.

Addition of a small curvature reduces power losses across total cavopulmonary connections.

BACKGROUND: In the Fontan circulation the vis a tergo for lung perfusion is limited. The hypothesis of this in vitro study was that energy dissipation at the common cavopulmonary connection can be reduced by the addition of caval curvature. METHODS: Two Perspex models were analyzed, the commonly used crosslike cavopulmonary connection (model 1) and a modified curved configuration (model 2). Pressures and flows across the connections were measured simultaneously at various caval and pulmonary artery flow splits and resistances. Mixing of inferior and superior caval fluid was evaluated. RESULTS: Caval pressure oscillations occurred in model 1 only. Curvature reduced power losses in all settings significantly (alpha = 0.05), most successfully at adult caval flow ratios and at high flow rates. At equal pulmonary resistances pulmonary flow was balanced in both models. The inferior caval fluid is preferably directed to the right lung in model 2 predominantly for caval flow conditions in younger patients. CONCLUSIONS: Our data show that the modified curved cavopulmonary connection is hydrodynamically advantageous but might impair caval fluid mixing in younger children.

Superior hydrodynamics of a modified cavopulmonary connection for the Norwood operation.

BACKGROUND: In the Fontan circulation, energy consumption at the cavopulmonary connection is crucial. Our hypothesis was that a modification of the standard Norwood variant of cavopulmonary connection with an extended anastomosis would improve hydrodynamics. METHODS: The in vitro hydrodynamics of two different Perspex glass models resembling the Norwood variant of cavopulmonary connection (model I) and the modification (model II) were analyzed in a mock circulation at nonpulsatile flows of 2 to 5 L/min to simulate rest and exercise. The pulmonary flow split was varied to imitate varying lung resistances. Inferior-to-superior caval flow ratio and size of models were increased to simulate growth. RESULTS: The pulmonary flow was preferentially directed to the left lung in model I and was better balanced in model II. Power losses increased exponentially with total flow in both models and were markedly higher in model I. These differences were attenuated in the larger models. Anastomotic turbulences were larger in model I. Power losses in both models were relatively insensitive to changes in pulmonary flow split. CONCLUSIONS: The proposed modification of the Norwood variant of cavopulmonary connection seems to be hydrodynamically advantageous and warrants further evaluation.

Prenatal diagnosis of a lethal multiple pterygium syndrome type II. Case report.

Advances in ultrasound technology and sonographer's experience lead to the description of many rare syndromes and malformations through prenatal diagnosis. Diaphragmatic hernia is a rather common malformation but can be an indicator of different syndromes. We report the prenatal diagnosis of lethal multiple pterygium syndrome type II which has been established in the 34th week of pregnancy. The sonographically detectable symptoms consisted of polyhydramnios, hygroma colli, diaphragmatic hernia, scoliosis, short forearms, hypokinesia of the fetus and pterygia over the large joints. Labour was induced in the 34th week of pregnancy; the neonate died shortly after vaginal delivery as a result of the pulmonary hypoplasia. A multidisciplinary approach in prenatal assessment may help to clarify difficult diagnostic problems and may be of direct benefit for the pregnant patient.

Intracellular pharmacokinetics of anthracyclines in human leukemia cells: correlation of DNA-binding with apoptotic cell death.

Anthracyclines are major components of the most therapeutical strategies in hematological oncology. These drugs are not directly cytotoxic but induce apoptosis. Due to their lipophilicity, anthracyclines are rapidly distributed in myeloid and lymphatic leukemia cells. Within 20 min after treatment, daunorubicin and idarubicin are found to intercalate into DNA. Shortly after treatment, DNA damage occurs and increases within 3 hours. Apoptosis can be monitored 12-24 hours after treatment, at this timepoint the majority of DNA strand breaks have already been repaired. A statistically highly significant linear correlation could be established between the DNA binding rate of anthracyclines and the resulting cell death. This indicates that DNA binding is a prerequisite for the induction of apoptosis. With respect to cellular resistance mechanisms, 2 different pharmacodynamic phases can be distinguished: intracellular distribution and cellular reaction. The endpoint of the "distribution phase" is marked by the DNA intercalation of the anthracyclines. Cellular resistance mechanisms which decrease the DNA binding include membrane transport mechanisms and vesicular trapping of the drugs. The "reaction phase" might be disturbed by complex antiapoptotic mechanisms. The assessment of DNA binding in malignant cells during or shortly after treatment with anthracyclines might be a useful tool to distinguish cellular resistance mechanisms.