Decreased collagenase production by regional fibroblasts cultured from skin of a patient with connective tissue nevi of the collagen type

A 10-yr-old female presented with cerebriform tumors covering the plantar surfaces of both feet. Histologically, the lesions consisted of thick collagen fibers and the content of collagen per surface area of skin was increased about 8-fold. Examination of the collagen by SDS-polyacrylamide gel electrophoresis, after limited pepsin proteolysis, showed that the lesions consisted almost exclusively of type I collagen, the predominant collagen type in human skin. Thus, a diagnosis of connective tissue nevi of the collagen type was made. Fibroblast cultures were established from the affected and normal-appearing areas of the skin, and examined for the rate of collagen synthesis, production of collagenase and growth kinetics of the cells. Cell cultures derived from the lesion and from control skin synthesized procollagen at the same rate and in a normal type I/type III procollagen ratio. However, the production of enzymatically active and immunologically detectable collagenase was reduced by 70-82% in the cultures derived from the lesion as compared to controls (p less than 0.005). Fibroblasts derived from the lesions also displayed a mean population doubling time of 1.17 +/- 0.08 days compared to 1.83 +/- 0.24 and 1.92 +/- 0.09 days for control cell strains and cells derived from normal skin of the patient, respectively (p less than 0.025). These results suggest that the excessive deposition of collagen in this case may have resulted from decreased local degradation of collagen. Enhanced proliferative capacity of the regional fibroblasts may have contributed to the accumulation of collagen in these lesions.     

Insulin sensitivity and blood pressure in black and white children

Although insulin sensitivity is correlated with high blood pressure in adults, it is unclear whether such a relationship exists in children across ethnic groups. Therefore, the aims of the study were to establish (1) if body composition and insulin sensitivity were related to blood pressure in children, and (2) if any differences in blood pressure between white and black children were explained by body composition and/or insulin sensitivity. Insulin sensitivity and the acute insulin response were established by the minimal model and body composition by dual-energy X-ray absorptiometry. Blood pressure was recorded in the supine position. Body composition, fasting insulin (P<0.01), and the acute insulin response (P<0.05) were positively related to systolic blood pressure but not to diastolic blood pressure, and insulin sensitivity (P<0.001) was negatively related to systolic blood pressure but not to diastolic blood pressure. Insulin sensitivity was negatively associated with systolic and diastolic blood pressure after adjustment for body composition (P<0.01). Black children had higher systolic (110+/-9.2 versus 105+/-8.5 mm Hg, P=0.01) and diastolic (59+/-7.0 versus 54+/-8.0 mm Hg, P<0.01) blood pressure than did white children. The ethnic difference in blood pressure was not explained by body composition, fasting insulin, acute insulin response, or insulin sensitivity. In conclusion, the relationship between insulin sensitivity and systolic blood pressure is evident early in life. Black ethnicity and low insulin sensitivity contribute independently to higher blood pressure in children.     

The Plasmodium falciparum eIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle

Melatonin and its indoles derivatives are central in the synchronization of malaria parasites. In this research, we discovered that melatonin is unable to increase the parasitemia in the human malaria Plasmodium falciparum that lacks the kinase PfeIK1. The PfeIK1 knockout strain is a valuable tool in the screening of indol-related compound that blocks the melatonin effect in wild-type (WT) parasite development. The assays were performed by using flow cytometry with simultaneous labeling for mitochondria viability with MitoTracker Deep Red and nucleus staining with SYBR Green. We found that Melatotosil leads to an increase in parasitemia in P. falciparum and blocks melatonin effect in the WT parasite. Using microscopy imaging system, we found that Melatotosil at 500 nM is able to induce cytosolic calcium rise in transgenic PfGCaMP3 parasites. On the contrary, the compound Triptiofen blocks P. falciparum cell cycle with IC₅₀ 9.76 µM ± 0.6, inhibits melatonin action, and does not lead to a cytosolic calcium rise in PfGCaMP3 parasites. We also found that the synthetic indol-related compounds arrested parasite cycle for PfeIK1 knockout and (WT) P. falciparum (3D7) in 72 hours culture assays with the IC₅₀ values slighting lower for the WT strain. We concluded that the kinase PfeIK1 is central for melatonin downstream signaling pathways involved in parasite cell cycle progression. More importantly, the indol-related compounds block its cycle as an upstream essential mechanism for parasite survival. Our data clearly show that this class of compounds emerge as an alternative for the problem of resistance with the classical antimalarials.     

Early measles vaccination in bone marrow transplant recipients

Measles vaccination has been recommended after the second year following bone marrow transplant (BMT) in patients not receiving immunosuppressive drugs. During a measles outbreak, we vaccinated all patients after the first year of transplant, and conducted a prospective trial to evaluate safety, effectiveness and sustained immunity after early vaccination. Patients received attenuated virus vaccine between 9 and 18 months after BMT. A total of 51 patients were evaluated and 27 of them (52.9%) were receiving immunosuppressive drugs. Only mild adverse reactions were noted. Nine patients (17.6%) were susceptible (IgG< or =100 mIU/ml) at vaccination, and all seroconverted. In those immune at vaccination, a four-fold increase in measles IgG titers was found in one of 34 patients (2.9%) with specific IgG> or =200 mIU/ml compared to 14 of 17 (82.3%) with IgG<200 mIU/ml (P< 0.0001). Sustained immunity after 24 months was more likely to occur in patients with specific IgG levels< or =200 or > or =500 mIU/mL (83.4 and 100%, respectively) in comparison to patients with 200相似文献   

Hyperbranched Polyglycerol Is an Efficacious and Biocompatible Novel Osmotic Agent in a Rodent Model of Peritoneal Dialysis

♦ Objectives: To enhance the effectiveness of peritoneal dialysis (PD), new biocompatible PD solutions may be needed. The present study was designed to test the efficacy and biocompatibility of hyperbranched polyglycerol (HPG)—a nontoxic, nonimmunogenic water-soluble polyether polymer—in PD.♦ Methods: Adult Sprague-Dawley rats were instilled with 30 mL HPG solution (molecular weight 3 kDa; 2.5% - 15%) or control glucose PD solution (2.5% Dianeal: Baxter Healthcare Corporation, Deerfield, IL, USA), and intraperitoneal fluid was recovered after 4 hours. Peritoneal injury and cellular infiltration were determined by histologic and flow cytometric analysis. Human peritoneal mesothelial cells were assessed for viability in vitro after 3 hours of PD fluid exposure.♦ Results: The 15% HPG solution achieved a 4-hour dose-related ultrafiltration up to 43.33 ± 5.24 mL and a dose-related urea clearance up to 39.17 ± 5.21 mL, results that were superior to those with control PD solution (p < 0.05). The dialysate-to-plasma (D/P) ratios of urea with 7.5% and 15% HPG solution were not statistically different from those with control PD solution. Compared with fluid recovered from the control group, fluid recovered from the HPG group contained proportionally fewer neutrophils (3.63% ± 0.87% vs 9.31% ± 2.89%, p < 0.0001). Detachment of mesothelial cells positive for human bone marrow endothelial protein 1 did not increase in the HPG group compared with the stain control (p = 0.1832), but it was elevated in the control PD solution group (1.62% ± 0.68% vs 0.41% ± 0.31%, p = 0.0031). Peritoneal biopsies from animals in the HPG PD group, compared with those from control PD animals, demonstrated less neutrophilic infiltration and reduced thickness. Human peritoneal mesothelial cell survival after HPG exposure was superior in vitro (p < 0.0001, 7.5% HPG vs control; p < 0.01, 15% HPG vs control). Exposure to glucose PD solution induced cytoplasmic vacuolation and caspase 3-independent necrotic cell death that was not seen with HPG solution.♦ Conclusions: Our novel HPG PD solution demonstrated effective ultrafiltration and waste removal with reduced peritoneal injury in a rodent model of PD.Key words: Peritoneal dialysis solution, biocompatibility, hyperbranched polyglycerol, preclinical studyPeritoneal dialysis (PD) is a simple and safe renal replacement therapy (1-4) that currently constitutes 0% - 70% of national dialysis programs worldwide (5). To date, glucose remains the most common osmotic agent in commercial PD solutions, although other osmotic agents such as amino acids and glucose polymer (icodextrin) are available. A high level of glucose in PD solution has been documented to be associated with many systemic and locoregional health complications for PD patients. Daily exposure to glucose can cause hyperglycemia, hyperinsulinemia, obesity, and exacerbation of diabetes mellitus (6). Moreover, long-term exposure to glucose and glucose degradation products has been shown to directly damage the peritoneal membrane, leading to abnormal mesothelial transformation, maladaptive angiogenesis, and ultrafiltration (UF) failure (7-9). Thus, PD may become less effective over time or lead to metabolic complications that are not favorable over the long term, thereby adversely affecting both PD duration and mortality. New biocompatible PD solutions that address some of these unwanted complications are needed.Hyperbranched polyglycerol (HPG) is a compact, branched, and highly water-soluble polyether polymer (Figure 1) synthesized by single-step, multi-branching, ring-opening polymerization of glycidol under slow monomer addition (10). Hyperbranched polyglycerol can be precisely synthesized over a wide range of molecular weights and is chemically stable as a narrow distributed polymer in aqueous solution (11-13). It is highly hydrophilic and water-soluble (>400 mg/mL), with a very low intrinsic viscosity (4 - 7 mL g^-1), and therefore large amounts of the polymer can easily be dissolved in water (13,14). It also has multiple hydroxyl groups per molecule of polymer and exists at physiologic pH in aqueous solution (14). In experimental studies, we demonstrated that HPG and its derivative molecules are highly blood-compatible, nonimmunogenic, and nontoxic (14-17). Unlike other polymers, HPG has been shown to have very limited organ accumulation after intravenous injection (14,18). It does not activate the platelet, coagulation, or complement systems (14). Taken together, these properties make HPG a promising candidate for use as an osmotic agent in PD.Open in a separate windowFigure 1— Chemical structure of hyperbranched polyglycerol.