Hair cell re-growth

Hair cell loss is usually a function of age, noise, ototoxic drugs and genetics. Therapeutic strategies fall into two categories: protection and regeneration. Protective methods include targeted application of growth factors and other agents to promote cell survival, and systemic application of drugs to prevent activation of programmed cell death. These strategies are related to treatments that cause predictable damage, such as the use of aminoglycoside antibiotics. The challenge of hair cell regeneration is more difficult. Instead of preventing cell loss, we must consider methods of stimulating cell division and hair cell differentiation from existing cells. We need to know much more about the molecular mechanisms that govern these processes so that we can identify potential targets for specific drugs or gene therapies. One method of approaching the issue is to combine in vitro models of developing hair cells with genomic and proteomic technologies. The benefits of hair cell re-growth may not be limited to full replacement of pre-existing cells. Surrogate hair cells may help to maintain cochlear innervation, even if they do not detect sound, and this property could be harnessed to improve the performance of cochlear implants.     

Differences in the Carboxy-Terminal (Putative Phospholipid Binding) Domains of Clostridium perfringens and Clostridium bifermentans Phospholipases C Influence the Hemolytic and Lethal Properties of These Enzymes

The phospholipases C of C. perfringens (alpha-toxin) and C. bifermentans (Cbp) show >50% amino acid homology but differ in their hemolytic and toxic properties. We report here the purification and characterisation of alpha-toxin and Cbp. The phospholipase C activity of alpha-toxin and Cbp was similar when tested with phosphatidylcholine in egg yolk or in liposomes. However, the hemolytic activity of alpha-toxin was more than 100-fold that of Cbp. To investigate whether differences in the carboxy-terminal domains of these proteins were responsible for differences in the hemolytic and toxic properties, a hybrid protein (NbiCalpha) was constructed comprising the N domain of Cbp and the C domain of alpha-toxin. The hemolytic activity of NbiCalpha was 10-fold that of Cbp, and the hybrid enzyme was toxic. These results confirm that the C-terminal domain of these proteins confers different properties on the enzymatically active N-terminal domain of these proteins.     

Localization of glycoconjugates recognized by the HNK-1 antibody in mouse and chick embryos during early neural development

The monoclonal antibody HNK-1 recognizes a carbohydrate epitope present on a host of glycoconjugates which include the glycoproteins neural cell adhesion molecules (N-CAM) myelin-associated glycoprotein and ependymins, and two glycolipids. Other antibodies, including NC-1, L2 and IgM paraproteins from neuropathy patients share similar binding specificity to the same or related sulfated glucuronyl-containing antigen (SGA). To further investigate its possible significance in early development, the distribution of SGA was studied in the head region of early developing chick (S13-S18) and mouse (E8.5-E11.5) embryos by immunocytochemistry. A striking species difference was found in the apparent distribution of immunodetectable SGA. In chick, migrating neural crest cells and their related cell types were heavily stained by HNK-1; whereas no stain was detectable on mouse neural crest cells at comparable stages, except perhaps in a restricted area adjacent to the otic placode and immediately adjacent to the neural tube. Within the developing CNS, the distribution of SGA was similar in both species. It was first expressed on neuroepithelial cells prior to axonal outgrowth, and was distributed in a continuous zone along the entire lateral walls of the early neural tube. Little or no SGA was detectable along most of the floor and roof plates. SGA appeared during this same period in the lateral basal lamina and within the adjacent mesenchyme and nearby cells. SGA was particularly evident on neuroepithelial endfeet at this stage. Early developing longitudinal axons were subsequently found to grow in association with the endfeet of SGA-positive neuroepithelial cells. These findings, in conjunction with previous studies, suggest that SGA is associated as a marker, and perhaps functionally, with the organization of early neuronal settling and axonal growth patterns within the developing vertebrate CNS.     

选择性κ阿片激动剂K-Ⅱ与U-50488的药理作用比较

K-Ⅱ系k阿片激动剂U-50488的同类物。通过部分离体和整体实验比较了K-Ⅱ与U-50488的药理作用。实验发现,K-Ⅱ抑制电刺激兔输精管收缩的IC₅₀值为0.42 nmol/L,U-50488为26.5 nmol/L;K-Ⅱ抑制小鼠运动功能(横筛法)的ED₅₀值为1.7 mg/g,U-50488为15.3 mg/kg;K-Ⅱ的小鼠LD₅₀值为152.5 mg/kg,U-50488为118.4 mg/g;K-Ⅱ明显降低小鼠自发活动的作用比U-50488强5倍。结果表明,K-Ⅱ是一个药理作用较U-50488强的k受体激动剂。     

Novel quantitative echocardiographic parameters in acute PE

Background The tricuspid annular plane systolic excursion (TAPSE) and the right ventricular performance index (RVPI) are quantitative measurements that are valid predictors of clinical outcomes in CHF, MI, PAH, and chronic pulmonary disease. We sought to measure TAPSE and RVPI in patients diagnosed with acute pulmonary embolism (APE) to assess for correlation with known predictors of clinical outcomes. Methods Patients admitted with APE had echocardiograms performed within 24 h of diagnosis and B-type natriuretic peptide (BNP) drawn on admission. Serial troponins were measured for the first 48 h of the hospital stay, and clinical course was followed until discharge. Results A total of 29 patients were enrolled in the study. Compared to those with a normal study, significantly more patients with an abnormal TAPSE had an elevated BNP (60% vs. 5%; P = 0.004) and troponin (50% vs. 11.1%; P = 0.042). The mean TAPSE was 22.3 mm when BNP was normal and 17.4 mm when elevated (P = 0.003). TAPSE values were significantly lower in patients with abnormal RV function by echocardiogram graded by a blinded cardiologist (17.6 mm vs. 21.7 mm; P = 0.03). Both TAPSE and RVPI correlated significantly with septal flattening, RVEDD, and RVEDD/LVEDD by echo. Conclusions TAPSE has good correlation with surrogate markers for morbidity and mortality in APE, and both TAPSE and RVPI seem to perform as well as the standard echo parameters used to assess RV function. Both are objective and easy to measure, and therefore warrant prospective study in larger patient groups, with assessment of clinical outcomes.     

Enhancement of swine progenitor chimerism in mixed swine/human bone marrow cultures with swine cytokines.

OBJECTIVE: The induction of transplantation tolerance across xenogeneic barriers by bone marrow transplantation holds great promise, but engraftment of xenogeneic stem cells has been difficult to achieve. Part of this difficulty is due to species-specific differences in regulatory cytokines and elements of the stromal microenvironment, which we studied here. MATERIALS AND METHODS: We developed a system where fresh bone marrow cells from swine and human are cultured on human bone marrow stroma in order to study these limiting factors in a clinically relevant species combination. RESULTS: We report here the ability of recombinant swine interleukin (IL)-3 and c-kit ligand (KL) to specifically enhance swine hematopoietic chimerism in this system. In the absence of exogenous swine cytokines, there were about half as many swine progenitors as human progenitors at 1, 2, and 4 weeks of culture. When used alone, swine IL-3 led to a notable but transient increase in the relative ratio of swine progenitors, while addition of swine KL increased the ratio of swine progenitors only modestly and only at later time points. In contrast, when swine IL-3 and KL were added together, there was a two- to fourfold increase in the ratio of swine to human progenitors at all times tested. CONCLUSION: These data demonstrate that both swine IL-3 and KL are needed for prolonged enhancement of swine progenitor chimerism under these conditions, and suggest that the species specificity of either one or both of these cytokines may represent an important barrier to prolonged engraftment of swine bone marrow in humans.     

Failure to awaken after general anaesthesia secondary to paradoxical venous embolus

A patient is presented who failed to regain consciousness after an apparently uneventful nine-hour revision of a total hip replacement. There were no clinically important haemodynamic changes during the operation, and oxygen saturation, capnography and acid base balance were normal throughout. Postop CT of the head showed a large left MCA infarct with midline shift. At autopsy, the patient was found to have a previously unsuspected patent foramen ovale, and a venous embolus in the left internal carotid artery, which probably had originated from the periprostatic venous plexus with a large infarct in the distribution of the left anterior and middle cerebral arteries. The authors conclude that massive paradoxical venous emboli can occur during surgery with minimal haemodynamic changes.