Bone marrow mesenchymal stem cells undergo nemosis and induce keratinocyte wound healing utilizing the HGF/c-Met/PI3K pathway

We previously showed cell–cell contacts of human dermal fibroblasts to induce expression of the hepatocyte growth factor/scatter factor (HGF) in a process designated as nemosis. Now we report on nemosis initiation in bone marrow mesenchymal stem cells (BMSCs). Because BMSCs are being used increasingly in cell transplantation therapy we aimed to demonstrate a functional effect and benefit of BMSC nemosis for wound healing. Nemotic and monolayer cells were used to stimulate HaCaT keratinocyte migration in a scratch-wound healing assay. Both indicators of nemosis, HGF production and cyclooxygenase-2 expression, were induced in BMSC spheroids. When compared with a similar amount of cells as monolayer, nemotic cells induced keratinocyte in vitro scratch-wound healing in a concentration-dependent manner. The HGF receptor, c-Met, was rapidly phosphorylated in the nemosis-stimulated keratinocytes. Nemosis-induced in vitro scratch-wound healing was inhibited by an HGF-neutralizing antibody as well as the small molecule c-Met inhibitor, SU11274. HGF-induced in vitro scratch-wound healing was inhibited by PI3K inhibitors, wortmannin and LY294002, while LY303511, an inactive structural analogue of LY294002, had no effect. Inhibitors of the mitogen-activated protein kinases MEK/ERK1/2 (PD98059 and U0126), and p38 (SB203580) attenuated HGF-induced keratinocyte in vitro scratch-wound healing. We conclude that nemosis of BMSCs can induce keratinocyte in vitro scratch-wound healing, and that in this effect signaling via HGF/c-Met is involved.     

急性重度毒蕈中毒性肝炎抢救成功1例

1　病例报告　男 ,16岁 .误食毒蕈后出现恶心 ,呕吐伴有腹痛、腹泻 4d,每日大便 4～ 12次 ,为稀水便 ,有心慌、气短、发热 ,在当地医院以“毒蕈中毒”救治 ,症状无缓解 ,为进一步治疗于 2 0 0 0 - 0 8- 31转入我院 .查体 :T37.8℃ ,P110次·min-1 ,R18次·min-1 ,BP14/ 9k Pa.全身皮肤黄染 ,巩膜重度黄染 ,心肺无阳性体征 .腹平坦 ,上腹部有压痛 ,肌紧张及反跳痛 ,肝脾未触及 ,肝区有叩击痛 ,移动性浊音阳性 .入院后患者出现烦躁 ,意识不清 ,心率时快时慢 ,血压不稳定 .肝功 :T- BIL 2 5 4.1μmol· L-1 ,D- BIL 16 9.5 μmol· L-1 …     

An antibody that facilitates hematopoietic engraftment recognizes CD44

Pretreatment of recipients with the monoclonal antibody (MoAb) S5 facilitates engraftment of bone marrow from mismatched, unrelated donors in the canine transplantation model. In the direct comparisons reported here, the S5 glycoprotein (gp) was found to have structural homology to CD44 that in humans has been implicated in adhesive interactions of one type of effector cell, the lymphocyte. The S5 antigen and gp90Hermes-1 exhibited codistribution on canine peripheral blood cells. Both S5 and Hermes-1 (anti-CD44) MoAbs recognized 90-Kd species in radioimmune precipitations of 125I surface-labeled canine peripheral blood lymphocytes and bone marrow cells. Competitive antibody binding experiments showed that the epitope detected by S5 was distinct from that bound by Hermes-1 but overlapped with those defined by two other known anti-CD44 reagents, IM7 and Hutch-1. Sequential immunoprecipitation with S5 and Hermes-1 indicated that the two antibodies recognize the same or overlapping subsets of membrane gps. Tryptic digestion of S5 and anti-CD44 immunoprecipitates generated two major iodinated peptides of 27 and 35 Kd in both cases, a further indication of structural homology. Similarly, after N-glycanase digestion, S5 and CD44 immunoprecipitates were resolved to a single 68- Kd species. These findings suggest that CD44-mediated adhesive events may affect the fate of transplanted hematopoietic cells. The previous implications of this gp in T-lymphocyte activation and lymphocyte adhesion to endothelium thus provide useful paradigms to analyze its function in the bone marrow transplant setting.     

Tricuspid annulus motion and mitral annulus motion: Anatomical intimacy causing a good correlation?

BACKGROUND:

Echocardiographic evaluation of the heart and its function, especially left ventricular systolic function, has great clinical importance. Systolic function can be measured using several methods, such as the amplitude of motion of the left atrioventricular plane (mitral annulus motion [MAM]) toward the apex during systole. Similarly, right ventricular systolic function can be measured using the motion of the right atrioventricular plane (tricuspid annulus motion [TAM]) toward the apex during systole.

OBJECTIVES:

Because the mitral and tricuspid annuli are situated close to each other in the fibrous skeleton between both ventricles and atria, one might think that a decrease in the amplitude of MAM would be followed by a decrease in the amplitude of TAM. The present study was developed to determinine if this anatomical intimacy causes a good correlation between the amplitudes of TAM and MAM.

METHODS:

Nineteen healthy subjects and 103 consecutive patients were included in the study and examined using echocardiography. The amplitudes of TAM and MAM were measured and the correlation between the amplitudes was calculated.

RESULTS:

In the 103 consecutive patients, a significant but relatively weak positive correlation was found between TAM and MAM amplitudes (Pearson’s correlation coefficient [r]=0.58; P<0.001). In the 19 healthy subjects, no significant correlation was found.

CONCLUSIONS:

Despite the anatomical intimacy of the annuli, the correlation between the amplitudes of TAM and MAM in consecutive patients was rather weak, and there was no correlation in healthy subjects. These findings could be due to anatomical and physiological differences between the right and left ventricles.     

Précising definitions as a way to combat overdiagnosis

Roughly, overdiagnosis (ODx) occurs when people are harmed by receiving diagnoses (often accompanied by interventions) that do not benefit them, usually because the diagnosed conditions do not pose a threat to their health. ODx is a theoretical as well as a practical problem as it relates to definitions of disease. Elsewhere, it has been argued that disease is a vague concept and that this vagueness may contribute to ODx. In response, we develop a stipulative or précising definition of disease, for the specific purpose of decreasing or preventing ODx. We call this disease_ODx, aimed at distinguishing cases where it would be beneficial to identify (and treat the condition) from those where diagnosis is more likely to harm than benefit. A preliminary definition of disease_ODx is that X is a disease_ODx iff there is dysfunction that has a significant risk of causing severe harm. This paper examines the 3 concepts in this definition, using a naturalistic account of function, a Feinbergian account of comparative harm, and a probabilistic understanding of risk. We then test the utility of this approach using examples of clinical conditions that are currently overdiagnosed.     

Nutrient-specific modulation of gastric mechanosensitivity in patients with functional dyspepsia

Intraduodenal lipid infusion induces symptoms and increases sensitivity to gastric distension in patients with functional dyspepsia. To test whether these effects are specific for lipid, we compared the effects of intraduodenal infusions of either lipid or glucose on symptoms and gastric sensory and motor responses to gastric distension. Eighteen dyspeptic patients and nine controls were studied. The stomach was distended with a flaccid bag during isocaloric infusions (1 kcal/ml) of saline and either 10% Intralipid (nine patients) or 26.7% glucose (nine patients) into the duodenum. Dyspeptic symptoms and sensory thresholds for epigastric fullness and discomfort were assessed. Gastric pressure profiles during distensions were similar during lipid and glucose infusions in patients and controls, but both were significantly lower than during saline infusion. Lower volumes were required to induce fullness and discomfort in the patients compared with the controls. In the controls, the threshold volumes required to induce fullness and discomfort were greater during infusion of lipid and glucose than during saline infusion, but in the patients, the threshold volumes were increased during glucose infusion but further reduced during lipid infusion. Moreover, in the patients, nausea was more common during lipid than glucose infusion and did not occur during saline. The controls did not experience any symptoms during any infusion. In conclusion, intraduodenal lipid but not glucose sensitizes the stomach to distension in patients with functional dyspepsia but not in controls.