Pancreatic Acinar Cell Carcinoma: A Multi-institutional Study

Introduction  The presentation and outcome of patients with acinar cell carcinoma (ACC) of the pancreas compared to the more common ductal cell adenocarcinoma (DCA) may be distinct. This study combines the experience with ACC from multiple academic institutions to better understand its natural history and outcomes. Methods  This study is a multi-institutional retrospective review of patients with ACC. Results  Between 1988 and 2008, 17 patients were identified with pathologically confirmed ACC. Median age at presentation was 59 years. Common presenting symptoms were abdominal pain (60%), back pain (50%), and weight loss (45%). Fifteen patients underwent 16 operations: pancreaticoduodenectomy (nine), distal pancreatectomy (four), and exploratory laparotomy (three). Mean tumor size was 5.3 cm. American Joint Commission on Cancer tumor stages were stage I (two), stage II (eight), stage III (four), and stage IV (three). Overall, 1- and 5-year survival rates were 88% and 50%, respectively. In resected cases (13), 1- and 5-year survival rates were 92% and 53%, respectively. Median survival in resected cases was 61 months. This is in contrast to 1,608 patients with ductal cell adenocarcinoma who underwent resection identified from recent literature reports where the average median survival was only 24 months. There was no discernable difference in the outcomes of patients with ACC between United States and Germany patients. Conclusion  Acinar cell carcinoma of the pancreas is rare and appears to have a presentation and outcome distinct from the more common pancreatic DCA. Based upon these data, the outcome of patients with ACC is superior to that of DCA. Jesus M. Matos and C. Max Schmidt contributed equally to this work. This paper was presented at the Society for Surgery of the Alimentary Tract (SSAT) in San Diego, California in May 2008.     

Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: a novel perspective for seizure control

Cell therapies based on focal delivery of the inhibitory neuromodulator adenosine were previously shown to provide potent seizure suppression in animal models of epilepsy. However, hitherto used therapeutic cells were derived from rodents and thus not suitable for clinical applications. Autologous patient-derived adenosine-releasing cell implants would constitute a major therapeutic advance to avoid both xenotransplantation and immunosuppression. Here we describe a novel approach based on lentiviral RNAi mediated downregulation of adenosine kinase (ADK), the major adenosine-removing enzyme, in human mesenchymal stem cells (hMSCs), which would be compatible with autologous cell grafting in patients. Following lentiviral transduction of hMSCs with anti-ADK miRNA expression cassettes we demonstrate up to 80% downregulation of ADK and a concentration of 8.5 ng adenosine per ml of medium after incubating 10(5) cells for 8 h. hMSCs with a knockdown of ADK or cells expressing a scrambled control sequence were transplanted into hippocampi of mice 1 week prior to the intraamygdaloid injection of kainic acid (KA). While mice with control implants expressing a scrambled miRNA sequence or sham treated control animals were characterized by KA-induced status epilepticus and subsequent CA3 neuronal cell loss, animals with therapeutic ADK knockdown implants displayed a 35% reduction in seizure duration and 65% reduction in CA3 neuronal cell loss, when analyzed 24 h after KA-injection. We conclude that lentiviral expression of anti-ADK miRNA constitutes a versatile tool to generate therapeutically effective adenosine releasing hMSCs, thus representing a model system to generate patient identical autologous adult stem cell grafts.     

Muller cells are living optical fibers in the vertebrate retina

Although biological cells are mostly transparent, they are phase objects that differ in shape and refractive index. Any image that is projected through layers of randomly oriented cells will normally be distorted by refraction, reflection, and scattering. Counterintuitively, the retina of the vertebrate eye is inverted with respect to its optical function and light must pass through several tissue layers before reaching the light-detecting photoreceptor cells. Here we report on the specific optical properties of glial cells present in the retina, which might contribute to optimize this apparently unfavorable situation. We investigated intact retinal tissue and individual Müller cells, which are radial glial cells spanning the entire retinal thickness. Müller cells have an extended funnel shape, a higher refractive index than their surrounding tissue, and are oriented along the direction of light propagation. Transmission and reflection confocal microscopy of retinal tissue in vitro and in vivo showed that these cells provide a low-scattering passage for light from the retinal surface to the photoreceptor cells. Using a modified dual-beam laser trap we could also demonstrate that individual Müller cells act as optical fibers. Furthermore, their parallel array in the retina is reminiscent of fiberoptic plates used for low-distortion image transfer. Thus, Müller cells seem to mediate the image transfer through the vertebrate retina with minimal distortion and low loss. This finding elucidates a fundamental feature of the inverted retina as an optical system and ascribes a new function to glial cells.     

Prion detection by an amyloid seeding assay

Polymerization of recombinant prion protein (recPrP), which was produced in bacteria, into amyloid fibers was accompanied by the acquisition of prion infectivity. We report here that partially purified preparations of prions seed the polymerization of recPrP into amyloid as detected by a fluorescence shift in the dye Thioflavin T. Our amyloid seeding assay (ASA) detected PrP^Sc, the sole component of the prion, in brain samples from humans with sporadic Creutzfeldt–Jakob disease, as well as in rodents with experimental prion disease. The ASA detected a variety of prion strains passaged in both mice and hamsters. The sensitivity of the ASA varied with strain type; for hamster Sc237 prions, the limit of detection was ≈1 fg. Some prion strains consist largely of protease-sensitive PrP^Sc (sPrP^Sc), and these strains were readily detected by ASA. Our studies show that the ASA provides an alternative methodology for detecting both sPrP^Sc and protease-resistant PrP^Sc that does not rely on protease digestion or immunodetection.     

Complementarity determining regions of an anti-prion protein scFv fragment orchestrate conformation specificity and antiprion activity

The prion protein, PrP, exists in several stable conformations, with the presence of one conformation, PrP(Sc), associated with transmissible neurodegenerative diseases. Targeting PrP by high-affinity ligands has been proven to be an effective way of preventing peripheral prion infections. Here, we have generated bacterially expressed single chain fragments of the variable domains (scFv) of a monoclonal antibody in Escherichia coli, originally raised against purified PrP(Sc) that recognizes both PrP(C) and PrP(Sc). This scFv fragment had a dissociation constant (K(D)) with recombinant PrP of 2 nM and cleared prions in ScN2a cells at 4 nM, as demonstrated by a mouse prion bioassay. A peptide corresponding to the complementarity determining region 3 of the heavy chain (CDR3H) selectively bound PrP(Sc) but had lost antiprion activity. However, synthesis and application of an improved peptide mimicking side chain topology of CDR3H while exhibiting increased protease resistance, a retro-inverso d-peptide of CDR3H, still bound PrP(Sc) and reinstated antiprion activity. We conclude that (1) scFvW226 is so far the smallest polypeptide with bioassay confirmed antiprion activity, and (2) differential conformation specificity and bioactivity can be regulated by orchestrating the participation of different CDRs.     

Radiometric dating of the type-site for Homo heidelbergensis at Mauer, Germany

The Mauer mandible, holotype of Homo heidelbergensis, was found in 1907 in fluvial sands deposited by the Neckar River 10 km southeast of Heidelberg, Germany. The fossil is an important key to understanding early human occupation of Europe north of the Alps. Given the associated mammal fauna and the geological context, the find layer has been placed in the early Middle Pleistocene, but confirmatory chronometric evidence has hitherto been missing. Here we show that two independent techniques, the combined electron spin resonance/U-series method used with mammal teeth and infrared radiofluorescence applied to sand grains, date the type-site of Homo heidelbergensis at Mauer to 609 ± 40 ka. This result demonstrates that the mandible is the oldest hominin fossil reported to date from central and northern Europe and raises questions concerning the phyletic relationship of Homo heidelbergensis to more ancient populations documented from southern Europe and in Africa. We address the paleoanthropological significance of the Mauer jaw in light of this dating evidence.     

Dobrava-Belgrade Virus Spillover Infections, Germany

We present the molecular identification of Apodemus agrarius (striped field mouse) as reservoir host of the Dobrava-Belgrade virus (DOBV) lineage DOBV-Aa in 3 federal states of Germany. Phylogenetic analyses provided evidence for multiple spillover of DOBV-Aa to A. flavicollis, a crucial prerequisite for host switch and genetic reassortment.     

Versorgungswirklichkeit bei osteoporosebedingten Frakturen in der deutschen Unfallchirurgie

The implementation of clinical pathways has a proven positive effect on the diagnostic workup and initiation of therapy in osteoporotic fracture patients. Unlike in most countries, fracture care in Germany is provided by so-called trauma surgeons. Therefore, it is essential to focus on the trauma surgeon for correct diagnostic workup and therapy initiation after a fragility fracture. A questionnaire was mailed to 409 departments of traumatology inquiring about the existence of a standardized clinical pathway for diagnosis and treatment of patients with fragility fractures. One of the central issues of the survey was whether those pathways comply with national guidelines. Only institutions that stated that they followed a clinical pathway were analyzed. 80% of institutions took part in our survey, 35% of which reported following a defined clinical pathway. Diagnostic workup is in concordance with the national guidelines in 30%, and therapy is guideline-based in 51%, with 12% basing both diagnostic workup and therapy on the guidelines. Thus, the vast majority of German traumatology departments do not follow national guidelines regarding osteoporosis diagnostics and therapy in patients with fragility fractures, leading to a great opportunity to improve fragility fracture care by means of both education and interdisciplinary cooperation.