Generation of a Novel In Vitro Model to Study Endothelial Dysfunction from Atherothrombotic Specimens

Cardiovascular Drugs and Therapy - Endothelial dysfunction is central to the pathogenesis of acute coronary syndrome. The study of diseased endothelium is very challenging due to inherent...     

The diagnosis of Gestational Diabetes Mellitus and its impact on In Vitro Fertilization pregnancies. A pilot study

BackgroundIn Vitro Fertilization (IVF) is increasingly becoming a necessary mode of reproduction. This high risk group is prone to Gestational Diabetes Mellitus (GDM) which further exposes these pregnancies to an increased risk of adverse outcomes. In light of the limited data in the current literature, further investigation is needed regarding the time of GDM diagnosis in IVF pregnancies as well as the outcome of IVF pregnancies complicated by GDM.MethodsIn this three center pilot cross sectional study, the data of 101 singleton IVF pregnancies complicated by GDM were analyzed. Prompt GDM diagnosis in IVF pregnancies was accomplished by self-blood glucose monitoring (SMBG) from the first antenatal visit and confirmed by an OGTT. To evaluate pregnancy outcome, maternal and fetal complications in the 101 GDM IVF group was compared to 101 IVF as well as 101 spontaneous conceptions (SC). The three groups were matched by age. The effect of demographic and glycemic parameters on the outcome of GDM IVF pregnancies was investigated.ResultsGDM diagnosis was made before the 24th week in 37.6% of the GDM IVF group. The week of delivery was earlier for the GDM IVF group (37 ± 1.7) relative to the IVF (37.9 ± 0.9, p < 0.001) and the SC group (38.1 ± 0.8, p < 0.001). GDM IVF pregnancies exhibited greater preeclampsia rates and 84.8% underwent caesarian section. No significant difference regarding LGA and SGA birth weights was found. Complications of GDM IVF pregnancies were associated with the 1-h postprandial BG (r = 0.267, p = 0.007).ConclusionGDM screening in IVF pregnancies may be considered earlier than the 24th week. IVF pregnancies affected by GDM are prone to increased maternal and fetal complications which are associated with 1-h postprandial BG.     

Effects of medroxyprogesterone and estradiol on the recovery of spermatogenesis in irradiated rats

Suppression of intratesticular testosterone (ITT) levels is required for spermatogenic recovery in rats after irradiation, but maintenance of peripheral testosterone (T) levels is important for many male functions. Considering the preservation of peripheral T while suppressing ITT, we tested the effects of a combination of a progestin, medroxyprogesterone acetate (MPA), plus T on spermatogenic recovery after irradiation, and compared its effects to those of T alone or T combined with estradiol (E2). Rats were given testicular irradiation (6 Gy) and treated during wk 3-7 after irradiation with MPA + T, or the individual steroids with or without GnRH antagonist (GnRH-ant), or GnRH-ant alone, or T + E2. Whereas GnRH-ant alone stimulated differentiation in 55% of tubules 13 wk after irradiation compared with 0% in irradiated-only rats, the addition of MPA reduced the percentage of tubules showing differentiation to 18%. However, T or MPA alone or the combination of the two induced germ cell differentiation in only 2-4% of tubules. In contrast, E2 stimulated differentiation in 88% of tubules, and T combined with E2 still resulted in differentiation in 30% of tubules. Although both MPA and E2 suppressed ITT levels to approximately 2% of control (2 ng/g testis), MPA was a less effective stimulator of spermatogenic recovery than E2 or GnRH-ant alone. MPA's function as a weak androgen was likely responsible for inhibiting spermatogenic recovery, as was the case for all other tested androgens. Thus, for clinical protection or restoration of spermatogenesis after radiation or chemotherapy by suppressing T production, MPA, at least in the doses used in the present study, is suboptimal. The combination of an estrogen with T appears to be most effective for stimulating such recovery.     

Risk factors for pneumonia in the intubated patient

The information gathered here helps to explain why risk factors in the development of VAP vary from series to series. It also explains why different investigators have found opposite effects when evaluating the antibiotics. Antibiotic therapy has a bimodal effect in the development of VAP. Antibiotics protect against pneumonia development within the first days of MV, especially against types caused by endogenous flora, but they are responsible for selection of a set of resistant pathogens that are associated with significant attributable mortality, such as P aeruginosa and MRSA. These observations suggest that risk factors vary depending on the exposure to risk (ie, length of stay or MV). This variable should be considered when stratifying patients for risk factor analysis and also in the design of clinical trials for VAP prophylaxis.     

MT1-MMP collagenolytic activity is regulated through association with tetraspanin CD151 in primary endothelial cells

MT1-MMP plays a key role in endothelial function, as underscored by the angiogenic defects found in MT1-MMP deficient mice. We have studied the molecular interactions that underlie the functional regulation of MT1-MMP. At lateral endothelial cell junctions, MT1-MMP colocalizes with tetraspanin CD151 (Tspan 24) and its associated partner alpha3beta1 integrin. Biochemical and FRET analyses show that MT1-MMP, through its hemopexin domain, associates tightly with CD151, thus forming alpha3beta1 integrin/CD151/MT1-MMP ternary complexes. siRNA knockdown of HUVEC CD151 expression enhanced MT1-MMP-mediated activation of MMP2, and the same activation was seen in ex vivo lung endothelial cells isolated from CD151-deficient mice. However, analysis of collagen degradation in these experimental models revealed a diminished MT1-MMP enzymatic activity in confined areas around the cell periphery. CD151 knockdown affected both MT1-MMP subcellular localization and its inclusion into detergent-resistant membrane domains, and prevented biochemical association of the metalloproteinase with the integrin alpha3beta1. These data provide evidence for a novel regulatory role of tetraspanin microdomains on the collagenolytic activity of MT1-MMP and indicate that CD151 is a key regulator of MT1-MMP in endothelial homeostasis.     

Phase I/II dose escalation study of recombinant human interleukin-11 following ifosfamide, carboplatin and etoposide in children, adolescents and young adults with solid tumours or lymphoma: a clinical, haematological and biological study

Thrombocytopenia remains the major dose-limiting toxicity of myelosuppressive chemotherapy in children with solid tumours. Recombinant human interleukin-11 (rhIL-11) has been approved by the Food and Drug Administration as treatment for adults with solid tumours and lymphomas with severe chemotherapy-induced thrombocytopenia. We conducted a phase I/II trial of rhIL-11 following ifosfamide, carboplatin and etoposide (ICE) chemotherapy in children with solid tumours or lymphomas. Patients received ifosfamide 1800 mg/m(2)/d for 5 d, carboplatin 400 mg/m(2)/d for 2 d and etoposide 100 mg/m(2)/d for 5 d with rhIL-11 subcutaneous (s.c.) at 25-125 microg/kg/d on days 6-33. Forty-seven patients with median age 10.5 years (range, 0.7-26 years) were studied. Median days to absolute neutrophil count >/=0.5 x 10(9)/l, platelet count >/=50 x 10(9)/l and platelet transfusions were 23, 18, 18, 16.5 and 18.5, 21, 20, 18 and 3, 3, 4, and 2 d at doses 25, 50, 75 and 100 Schulteg/kg respectively. There was a dose-dependent increase in C(max) (7.6-25.5 ng/ml), AUC(0-rho) (57-209 ng.h/ml) and T(1/2) (4-8.2 h) respectively. There was a 4% incidence of anti-IL-11 antibody formation. Clinically important adverse events to rhIL-11 were papilloedema and periosteal bone formation. In summary, rhIL-11 was well tolerated at doses of 相似文献   

A “false positive” octreoscan in ileal Crohn’s disease

We present a case report of a patient with a suspicious ileal carcinoid tumour. Clinical examination as well as computer tomograghy （CT） scan suggested a tumour. Octeotride scan showed uptake in the same bowel loop reported as pathological in CT. The patient underwent surgery and biopsy which reported Crohn’s disease （CD）. The interest in the case is due to the fact that this is, to the best of our knowledge, the second report of Crohn’sdisease as a cause of false positive octeotride scan. Unfortunately, no somatostatin recptors could be found in the sample, so further studies should be performed.     

Ultrastructural Changes of Mitochondria in the Cultivated Skin Fibroblasts of Patients with Point Mutations in Mitochondrial DNA

Mitochondrial disorders represent a heterogeneous group of multisystem diseases with extreme variability in clinical phenotype. The diagnosis of mitochondrial disorders relies heavily on extensive biochemical and molecular analyses combined with morphological studies including electron microscopy. Although muscle is the tissue of choice for electron microscopic studies, the authors investigated cultivated human skin fibroblasts (HSF) harboring 3 different pathologic mtDNA mutations: 3243A > G, 8344A > G, 8993T > G. They addressed to the possibility of whether mtDNA mutations influence mitochondrial morphology in HSF and if ultrastructural changes of mitochondria may be used for differential diagnostics of mitochondrial disorders caused by mtDNA mutations. Ultrastructural analysis of patients' HSF revealed a heterogeneous mixture of mainly abnormal, partially swelling mitochondria with unusual and sparse cristae. The most characteristic cristal abnormalities were heterogeneity in size and shapes or their absence. Typical filamentous and branched mitochondria with numerous cristae as appeared in control HSF were almost not observed. In all lines of cultured HSF with various mtDNA mutations, similar ultrastructural abnormalities and severely changed mitochondrial interior were found, although no alterations in function and amount of OXPHOS were detected by routinely used biochemical methods in two lines of cultured HSF. This highlights the importance of morphological analysis, even in cultured fibroblasts, in diagnostics of mitochondrial disorders.     

Low RKIP expression associates with poor prognosis in bladder cancer patients

Urothelial bladder cancer (UBC) is a heterogeneous type of disease. It is urgent to screen biomarkers of tumour aggressiveness in order to clarify the clinical behaviour and to personalize therapy in UBC patients. Raf kinase inhibitory protein (RKIP) is a metastasis suppressor, and its downregulation is associated with metastatic events in an increasing number of solid tumours. We evaluated the clinical and prognostic significance of RKIP expression in patients with high risk of progression UBC. Using immunohistochemistry, we determined RKIP expression levels in a series of 81 patients with high-grade pT1/pTis or muscle-invasive UBC. Staining of CD31 and D2-40 was used to assess blood and lymphatic vessels, in order to distinguish between blood and lymphatic vessel invasion (LVI). We found that 90 % of pT1/pTis tumours, 94 % of non-muscle invasive papillary tumours and 76 % of the cases without LVI occurrence expressed RKIP in >10 % of cells. In this group, we observed a subgroup of tumours (42 %) in which the tumour centre was significantly more intensely stained than the invasion front. This heterogeneous pattern was observed in 63 % of the cases with LVI. Low RKIP expression was associated with poorer 5-year disease-free and overall survival rates, and remained as an independent prognostic factor for disease-free survival. Loss of RKIP expression may be an important prognostic factor for patients with high risk of progression bladder cancer.