The Role of von Willebrand Factor in Microvascular Surgery in Severely Injured Patients.

Microvascular anastomosis has become a standard surgical technique for reconstruction because of increasing possibilities, indications, and clinical success regarding the survival of the flaps. However, the main dreaded complications exist in thrombosis. Leaving surgical complications aside, systemic problems like disorder of the coagulation-fibrinolysis system are a significant cause of graft loss usually being unrecognized. Reports exist describing a hypercoagulable state with clotting activation and inhibition of fibrinolysis after trauma and delayed surgery considering the secondary homeostasis. In this clinical case, a patient had a large soft tissue defect at the temporal side of the head after severe trauma. After some days of primary stabilization, reconstruction using a free microvascular latissimus dorsi flap was performed. Multiple revisions of the arterial and venous branches had to be performed intraoperatively due to insufficient flap perfusion. After 24 hours, definitive flap loss occurred due to multiple thrombosis in the arterial and venous branches. Postoperative comprehensive coagulation analysis revealed a distinct activation of primary hemostasis with massively increased von Willebrand factor parameters and factor VIII activity as well as acetylsalicylic acid resistance contributing to thrombotic occlusion. In severely injured patients, comprehensive preoperative determination of the coagulation status (especially those of the primary hemostasis) is indispensable before performing free flap reconstruction surgeries to reduce the risk of microvascular flap loss.

Relapsing polychondritis: a chameleon among orphan diseases.

Relapsing polychondritis (RPC) is a rare disease with recurrent episodes of inflammation of cartilage tissue leading to fibrosis and organ damage. Despite unknown etiology, there is some evidence of a genetic predisposition. The clinical presentation is heterogeneous and an association with other autoimmune disorders such as rheumatoid arthritis or different forms of vasculitis has been described. All organ systems containing cartilage can be affected, such as ear, nose, joints, trachea, aorta, and coronary arteries. Given the broad spectrum of potential manifestations, a variety of medical specialists may be involved in the management of RPC patients. As establishing the diagnosis of RPC may be difficult, an interdisciplinary approach may be preferable. Treatment options include glucocorticoids, dapsone, disease-modifying antirheumatic drugs, and biologics. Prognosis is as heterogeneous as the clinical picture, depending on the severity of organ damage. In this paper we give an overview of the current knowledge with regard to pathogenesis, clinical picture, diagnosis, and therapy of RPC.

Strong PSMA Radioligand Uptake by Rectal Carcinoma: Who Put the "S" in PSMA?

We present a case of a 71-year-old patient with newly diagnosed rectal adenocarcinoma and hepatic metastases. Restaging after chemotherapy revealed a good response of the rectal primary while liver metastases were progressive. As the patient also had a history of prostate cancer, a Ga-PSMA-HBED-CC PET/CT scan was performed to noninvasively further assess hepatic metastases. However, a definite differentiation between tumor entities was not possible because not only the liver metastases but also the rectal primary showed radioligand uptake (moderate and strong, respectively). Consecutive liver biopsy revealed a poorly differentiated adenocarcinoma of intestinal origin.

Regulation of the Rac GTPase pathway by the multifunctional Rho GEF Pebble is essential for mesoderm migration in the Drosophila gastrula.

The Drosophila guanine nucleotide exchange factor Pebble (Pbl) is essential for cytokinesis and cell migration during gastrulation. In dividing cells, Pbl promotes Rho1 activation at the cell cortex, leading to formation of the contractile actin-myosin ring. The role of Pbl in fibroblast growth factor-triggered mesoderm spreading during gastrulation is less well understood and its targets and subcellular localization are unknown. To address these issues we performed a domain-function study in the embryo. We show that Pbl is localized to the nucleus and the cell cortex in migrating mesoderm cells and found that, in addition to the PH domain, the conserved C-terminal tail of the protein is crucial for cortical localization. Moreover, we show that the Rac pathway plays an essential role during mesoderm migration. Genetic and biochemical interactions indicate that during mesoderm migration, Pbl functions by activating a Rac-dependent pathway. Furthermore, gain-of-function and rescue experiments suggest an important regulatory role of the C-terminal tail of Pbl for the selective activation of Rho1-versus Rac-dependent pathways.

Augmentation index and large-artery remodeling in patients with longstanding rheumatoid arthritis compared with healthy controls.

OBJECTIVE: There is growing evidence of premature atherosclerosis in patients with rheumatoid arthritis (RA), leading to a higher rate of cardiovascular events than in the general population. The augmentation index (AIx), a marker of arterial stiffness, is an indicator of vascular function. The aim of the study was as follows: (1) to investigate whether AIx is increased in RA patients without traditional cardiovascular risk factors and (2) to evaluate whether there is an interrelationship with large artery remodeling as ascertained by carotid ultrasound. METHODS: Thirty-six RA patients (age, 46.4 +/- 7.7 years; 31 female) were recruited. Patients were eligible for analysis if they had no traditional cardiovascular risk factors. AIx was assessed noninvasively during pulse wave analyses. For large artery remodeling the intima-media thickness (IMT) was measured in both common carotid arteries with ultrasound. Results were compared with 36 age- and sex-matched controls. RESULTS: AIx was statistically significantly higher in RA patients as compared with controls (27.4 +/- 9.4% versus 18.4 +/- 9.0%; P < 0.001). In addition, IMT was significantly higher in RA patients (0.73 +/- 0.16 mm versus 0.65 +/- 0.12 mm; P = 0.01). In RA patients there was a positive correlation between IMT and AIx (r[IMT; AIx] = 0.45; P = 0.008). CONCLUSION: AIx, a marker of arterial stiffness, as well as IMT, a marker of large-artery remodeling, are increased in RA patients without traditional cardiovascular risk factors. Measuring AIx might assist in better assessing the increased cardiovascular risk in RA patients.

Hierarchy of nonhomologous end-joining, single-strand annealing and gene conversion at site-directed DNA double-strand breaks.

In mammalian cells, DNA double-strand breaks (DSBs) are repaired by three pathways, nonhomologous end-joining (NHEJ), gene conversion (GC) and single-strand annealing (SSA). These pathways are distinct with regard to repair efficiency and mutagenic potential and must be tightly controlled to preserve viability and genomic stability. Here, we employed chromosomal reporter constructs to characterize the hierarchy of NHEJ, GC and SSA at a single I-SceI-induced DSB in Chinese hamster ovary cells. We discovered that the use of GC and SSA was increased by 6- to 8-fold upon loss of Ku80 function, suggesting that NHEJ is dominant over the other two pathways. However, NHEJ efficiency was not altered if GC was impaired by Rad51 knockdown. Interestingly, when SSA was made available as an alternative mode for DSB repair, loss of Rad51 function led to an increase in SSA activity at the expense of NHEJ, implying that Rad51 may indirectly promote NHEJ by limiting SSA. We conclude that a repair hierarchy exists to limit the access of the most mutagenic mechanism, SSA, to the break site. Furthermore, the cellular choice of repair pathways is reversible and can be influenced at the level of effector proteins such as Ku80 or Rad51.

The Wiskott-Aldrich syndrome protein (WASP) is essential for myoblast fusion in Drosophila.

In higher organisms, mononucleated myoblasts fuse to form multinucleated myotubes. During this process, myoblasts undergo specific changes in cell morphology and cytoarchitecture. Previously, we have shown that the actin regulator Kette (Hem-2/Nap-1) is essential for myoblast fusion. In this study, we describe the role of the evolutionary conserved Wiskott-Aldrich syndrome protein that serves as a regulator for the Arp2/3 complex for myoblast fusion. By screening an EMS mutagenesis collection, we discovered a new wasp allele that does not complete fusion during myogenesis. Interestingly, this new wasp3D3-035 allele is characterized by a disruption of fusion after precursor formation. The molecular lesion in this wasp allele leads to a stop codon preventing translation of the CA domain. Usually, the WASP protein exerts its function through the Arp2/3-interacting CA domain. Accordingly, a waspDeltaCA that is expressed in a wild-type background acts as dominant-negative during the fusion process. Furthermore, we show that the myoblast fusion phenotype of kette mutant embryos can be suppressed by reducing the gene dose of wasp3D3-035. Thus, Kette antagonizes WASP function during myoblast fusion.

Congenital glioblastoma multiforme with abnormal vascularity presenting as intracranial hemorrhage in prenatal ultrasound.

BACKGROUND: A rare case of a congenital brain neoplasm with intratumoral massive hemorrhage suggested by prenatal ultrasound examination in a 32-week gestational age male fetus is reported. The child died shortly after birth due to cardiorespiratory insufficiency. METHODS: Autopsy disclosed a large well-delimited tumor with a sponge-like appearance due to high vascularization, which involved nearly the whole left cerebral hemisphere and led to marked hydrocephalus by secondary aqueductal stenosis. Histological and immunohistochemical examination confirmed the diagnosis of a malignant glioma with features of a glioblastoma multiforme (GBM) matching well with previous findings in primary pediatric GBMs. FINDINGS: The present case demonstrates that malignant congenital neoplasms should be considered in the differential diagnosis of fetal intracranial hemorrhage.

The RhoGEF Pebble is required for cell shape changes during cell migration triggered by the Drosophila FGF receptor Heartless.

The FGF receptor Heartless (HTL) is required for mesodermal cell migration in the Drosophila gastrula. We show that mesoderm cells undergo different phases of specific cell shape changes during mesoderm migration. During the migratory phase, the cells adhere to the basal surface of the ectoderm and exhibit extensive protrusive activity. HTL is required for the protrusive activity of the mesoderm cells. Moreover, the early phenotype of htl mutants suggests that HTL is required for the adhesion of mesoderm cells to the ectoderm. In a genetic screen we identified pebble (pbl) as a novel gene required for mesoderm migration. pbl encodes a guanyl nucleotide exchange factor (GEF) for RHO1 and is known as an essential regulator of cytokinesis. We show that the function of PBL in cell migration is independent of the function of PBL in cytokinesis. Although RHO1 acts as a substrate for PBL in cytokinesis, compromising RHO1 function in the mesoderm does not block cell migration. These data suggest that the function of PBL in cell migration might be mediated through a pathway distinct from RHO1. This idea is supported by allele-specific differences in the expressivity of the cytokinesis and cell migration phenotypes of different pbl mutants. We show that PBL is autonomously required in the mesoderm for cell migration. Like HTL, PBL is required for early cell shape changes during mesoderm migration. Expression of a constitutively active form of HTL is unable to rescue the early cellular defects in pbl mutants, suggesting that PBL is required for the ability of HTL to trigger these cell shape changes. These results provide evidence for a novel function of the Rho-GEF PBL in HTL-dependent mesodermal cell migration.