Characterizing Mechanical Heterogeneity in Cardiovascular Cells

Most tissue-level mechanical models assume homogeneous mechanical properties within a single cell type. However, measurements of cellular mechanical properties show large variability in whole-cell mechanical properties between cells from a single population. This heterogeneity has been observed in many cell populations and with several measurement techniques but the sources are not yet fully understood. Cell mechanical properties are directly related to the composition and organization of the cytoskeleton, which is physically coupled to neighboring cells through adherens junctions and to underlying matrix scaffolds through focal adhesion complexes. As such, we believe that this high level of heterogeneity can be attributed to varying local microenvironment conditions throughout the sample. To test this hypothesis, cardiomyocytes and vascular smooth muscle cells were cultured under several conditions that limited the variability in their microenvironment. First, cells were cultured on aligned collagen and fibronectin matrices (more uniform extracellular matrix). Next, cell-cell and cell-matrix interactions were limited by using antibodies to N-cadherin and integrin beta1. Finally, these experiments were replicated on gels and under tension conditions to more closely mimic the native cellular microenvironment. Under each of these conditions, cellular viscoelastic mechanical properties were characterized through AFM testing and cellular structure was analyzed through immunofluorescence imaging. The results of these studies provide insights from a basic science prospective about the impact of the cellular microenvironment on cell behavior. Additionally, researchers may use these results to consider heterogeneity in the cellular microenvironment in vivo, especially in disease conditions where there is often elevated disorganization, and incorporate realistic levels of cellular heterogeneity in tissue-level mechanical models. Such models may help to better understand tissue behavior in both health and disease

GDNF Secreting Human Neural Progenitor Cells Protect Dying Motor Neurons, but Not Their Projection to Muscle, in a Rat Model of Familial ALS

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by rapid loss of muscle control and eventual paralysis due to the death of large motor neurons in the brain and spinal cord. Growth factors such as glial cell line derived neurotrophic factor (GDNF) are known to protect motor neurons from damage in a range of models. However, penetrance through the blood brain barrier and delivery to the spinal cord remains a serious challenge. Although there may be a primary dysfunction in the motor neuron itself, there is also increasing evidence that excitotoxicity due to glial dysfunction plays a crucial role in disease progression. Clearly it would be of great interest if wild type glial cells could ameliorate motor neuron loss in these models, perhaps in combination with the release of growth factors such as GDNF.Human neural progenitor cells can be expanded in culture for long periods and survive transplantation into the adult rodent central nervous system, in some cases making large numbers of GFAP positive astrocytes. They can also be genetically modified to release GDNF (hNPC(GDNF)) and thus act as long-term 'mini pumps' in specific regions of the rodent and primate brain. In the current study we genetically modified human neural stem cells to release GDNF and transplanted them into the spinal cord of rats over-expressing mutant SOD1 (SOD1(G93A)). Following unilateral transplantation into the spinal cord of SOD1(G93A) rats there was robust cellular migration into degenerating areas, efficient delivery of GDNF and remarkable preservation of motor neurons at early and end stages of the disease within chimeric regions. The progenitors retained immature markers, and those not secreting GDNF had no effect on motor neuron survival. Interestingly, this robust motor neuron survival was not accompanied by continued innervation of muscle end plates and thus resulted in no improvement in ipsilateral limb use.The potential to maintain dying motor neurons by delivering GDNF using neural progenitor cells represents a novel and powerful treatment strategy for ALS. While this approach represents a unique way to prevent motor neuron loss, our data also suggest that additional strategies may also be required for maintenance of neuromuscular connections and full functional recovery. However, simply maintaining motor neurons in patients would be the first step of a therapeutic advance for this devastating and incurable disease, while future strategies focus on the maintenance of the neuromuscular junction

Endogenous Endotoxin Participates in Causing a Panenteric Inflammatory Ileus After Colonic Surgery

Colonic surgery frequently results in the panenteric development of postoperative dysmotility. The present study focuses on distant inflammatory events within the small intestinal muscularis after surgical manipulation of the colon and investigates the role of gut derived bacterial products in causing smooth muscle dysfunction

Treatment of necrotizing pancreatitis

Item does not contain fulltextAcute pancreatitis is a common and potentially lethal disease. It is associated with significant morbidity and consumes enormous health care resources. Over the last 2 decades, the treatment of acute pancreatitis has undergone fundamental changes based on new conceptual insights and evidence from clinical studies. The majority of patients with necrotizing pancreatitis have sterile necrosis, which can be successfully treated conservatively. Emphasis of conservative treatment is on supportive measures and prevention of infection of necrosis and other complications. Patients with infected necrosis generally need to undergo an intervention, which has shifted from primary open necrosectomy in an early disease stage to a step-up approach, starting with catheter drainage if needed, followed by minimally invasive surgical or endoscopic necrosectomy once peripancreatic collections have sufficiently demarcated. This review provides an overview of current standards for conservative and invasive treatment of necrotizing pancreatitis