Normal synthesis and expression of endothelial IIb/IIIa in Glanzmann's thrombasthenia

Glanzmann's thrombasthenia is a bleeding disorder, inherited in an autosomal recessive way and characterized by an absence or deficiency of the platelet glycoprotein (GP) IIb/IIIa complex. Recently, we and others demonstrated that cultured human umbilical vein endothelial cells synthesized a membrane protein complex similar to the platelet GP IIb/IIIa complex. In this article, we demonstrate that endothelial cells isolated from the umbilical vein of a newborn with Glanzmann's thrombasthenia, as compared with normal endothelial cells, show no difference in their ability to synthesize and express this GP IIb/IIIa complex. Our results indicate that Glanzmann's thrombasthenia is not accompanied by an "endotheliopathy."     

A humanised tissue‐engineered bone model allows species‐specific breast cancer‐related bone metastasis in vivo

Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer‐related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell–bone interactions. In this study, two established tissue‐engineered bone constructs (TEBCs) were applied to a breast cancer‐related metastasis model. A cylindrical medical‐grade polycaprolactone‐tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate‐coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA‐MB‐231, SUM1315, and MDA‐MB‐231BO breast cancer cells were cultured in polyethylene glycol‐based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer‐related bone metastasis seen in patients.     

Comparison of Porcine Epidemic Diarrhea Viruses from Germany and the United States, 2014

Since 2013, highly virulent porcine epidemic diarrhea virus has caused considerable economic losses in the United States. To determine the relation of US strains to those recently causing disease in Germany, we compared genomes and found that the strain from Germany is closely related to variants in the United States.     

High-dose chemoradiotherapy and autologous blood stem cell transplantation in multiple myeloma: results of a phase II trial involving 63 patients

Sixty-three patients with high tumor mass multiple myeloma were treated with high-dose chemotherapy and total body irradiation supported by autologous blood stem cell transplantation. After high-dose therapy, they were monitored for a median of 44 months. Seven patients died early from toxicity. All the other patients, including those whose disease was resistant to previous therapies, showed a tumor mass reduction. At 6 months postengraftment, 40 (71%) of the surviving patients had minimal residual disease and 11 (20%) were in apparent complete remission. During follow-up, 25 out of the 63 (39%) patients relapsed and 16 of these died; 31 (49%) had a sustained remission. The median overall and event-free survival times after transplantation were 59 and 43 months, respectively. The initial serum beta 2-microglobulin value (> or < 2.8 mg/L) and length of previous therapy (> or < 6 courses of chemotherapy) were the only significant prognostic factors. In all surviving patients, blood stem cell autograft provided satisfactory and sustained haematopoietic reconstitution most often within 15 days. High dose chemoradiotherapy followed by autologous blood stem cell transplantation is thus an important therapeutic option for young patients with aggressive multiple myeloma.     

Outcome of HIV-infected patients with invasive squamous-cell carcinoma of the anal canal in the era of highly active antiretroviral therapy

PURPOSE: Before the development of highly active antiretroviral therapy for the treatment of HIV infection, HIV patients diagnosed with invasive squamous-cell carcinoma of the anal canal carried a very poor prognosis. This study was designed to determine the outcome in a similar group of patients in the era of highly active antiretroviral therapy.METHODS: HIV-positive patients treated for invasive squamous-cell carcinoma of the anal canal at the University of Texas Medical Center affiliated hospitals from 1980 to 2001 were identified from operative data and cancer registries. We reviewed these records and collected data regarding age, CD4 count, highly active antiretroviral therapy, cancer treatment, complications, and survival. The patients were divided into two groups based on the presence or absence of highly active antiretroviral therapy and compared using a Kaplan-Meier approach.RESULTS: Fourteen patients with HIV and invasive squamous-cell carcinoma of the anal canal were identified. Six were in the prehighly active antiretroviral therapy group and eight in the highly active antiretroviral therapy group. All were considered for treatment with chemotherapy and radiation. In the prehighly active antiretroviral therapy group, one patient refused therapy and three were unable to complete the squamous-cell carcinoma therapy as planned because of complications. Four of eight highly active antiretroviral therapy patients were unable to complete the squamous-cell carcinoma therapy as planned. The prehighly active antiretroviral therapy patients had a mean age of 40 years and a mean CD4 count of 190 at the time of diagnosis. The highly active antiretroviral therapy patients had a mean age of 44 years and a mean CD4 count of 255 at the time of diagnosis. The 24-month survival was 17 percent in the prehighly active antiretroviral therapy group and 67 percent in the highly active antiretroviral therapy group (P = 0.0524). All six patients in the prehighly active antiretroviral therapy group died with active squamous-cell carcinoma vs. two in the highly active antiretroviral therapy group. Four of the remaining six patients had no evidence of active squamous-cell carcinoma at the last follow-up visit.CONCLUSIONS: A review of patients with HIV and invasive squamous-cell carcinoma of the anal canal suggests a trend toward a higher CD4 count at the time of diagnosis and improved survival in patients receiving highly active antiretroviral therapy. In this new era, HIV-positive patients should be on highly active antiretroviral therapy. If not, highly active antiretroviral therapy should be initiated, and standard multimodality therapies for invasive squamous-cell carcinoma of the anal canal are recommended.Read at the meeting of The American Society of Colon and Rectal Surgeons, New Orleans, Louisiana, June 21 to 26, 2003.     

Detection of genomic deletions of PKP2 in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease that predominantly affects the right ventricle and is associated with ventricular arrhythmias that may lead to sudden cardiac death. Mutations within at least seven separate genes have been identified to cause ARVC, however a genetic culprit remains elusive in approximately 50% of cases. Although negative genetic testing may be secondary to pathogenic mutations within undiscovered genes, an alternative explanation may be the presence of large deletions or duplications involving known genes. These large copy number variants may not be detected with standard clinical genetic testing which is presently limited to direct DNA sequencing. We describe two cases of ARVC possessing large deletions involving plakophilin‐2 (PKP2) identified with microarray analysis and/or multiplex ligation‐dependent probe amplification (MLPA) that would have been classified as genotype negative with standard clinical genetic testing. A deletion of the entire coding region of PKP2 excluding exon 1 was identified in patient 1 and his son. In patient 2, MLPA analysis of PKP2 revealed deletion of the entire gene with subsequent microarray analysis demonstrating a de novo 7.9 Mb deletion of chromosome 12p12.1p11.1. These findings support screening for large copy number variants in clinically suspected ARVC cases without clear disease causing mutations following initial sequencing analysis.     

Effect of shared care on blood pressure in patients with chronic kidney disease: a cluster randomised controlled trial

Background

Chronic kidney disease (CKD) is highly prevalent in patients with diabetes or hypertension in primary care. A shared care model could improve quality of care in these patients

Aim

To assess the effect of a shared care model in managing patients with CKD who also have diabetes or hypertension.

Design and setting

A cluster randomised controlled trial in nine general practices in The Netherlands.

Method

Five practices were allocated to the shared care model and four practices to usual care for 1 year. Primary outcome was the achievement of blood pressure targets (130/80 mmHg) and lowering of blood pressure in patients with diabetes mellitus or hypertension and an estimated glomerular filtration rate (eGFR)<60ml/min/1.73m².

Results

Data of 90 intervention and 74 control patients could be analysed. Blood pressure in the intervention group decreased with 8.1 (95% CI = 4.8 to 11.3)/1.1 (95% CI = −1.0 to 3.2) compared to −0.2 (95% CI = −3.8 to 3.3)/−0.5 (95% CI = −2.9 to 1.8) in the control group. Use of lipid-lowering drugs, angiotensin-system inhibitors and vitamin D was higher in the intervention group than in the control group (73% versus 51%, 81% versus 64%, and 15% versus 1%, respectively, [P = 0.004, P = 0.01, and P = 0.002]).

Conclusion

A shared care model between GP, nurse practitioner and nephrologist is beneficial in reducing systolic blood pressure in patients with CKD in primary care.     

Analysis of gene expression in wild‐type and Notch1 mutant retinal cells by single cell profiling

Results: To examine the molecular underpinnings of this observation, microarray analysis of single retinal cells from wild‐type or Notch1 conditional knockout retinas was performed. In situ hybridization was carried out to validate some of the findings. 相似文献   

RNAsnp: Efficient Detection of Local RNA Secondary Structure Changes Induced by SNPs

Structural characteristics are essential for the functioning of many noncoding RNAs and cis‐regulatory elements of mRNAs. SNPs may disrupt these structures, interfere with their molecular function, and hence cause a phenotypic effect. RNA folding algorithms can provide detailed insights into structural effects of SNPs. The global measures employed so far suffer from limited accuracy of folding programs on large RNAs and are computationally too demanding for genome‐wide applications. Here, we present a strategy that focuses on the local regions of maximal structural change between mutant and wild‐type. These local regions are approximated in a “screening mode” that is intended for genome‐wide applications. Furthermore, localized regions are identified as those with maximal discrepancy. The mutation effects are quantified in terms of empirical P values. To this end, the RNAsnp software uses extensive precomputed tables of the distribution of SNP effects as function of length and GC content. RNAsnp thus achieves both a noise reduction and speed‐up of several orders of magnitude over shuffling‐based approaches. On a data set comprising 501 SNPs associated with human‐inherited diseases, we predict 54 to have significant local structural effect in the untranslated region of mRNAs. RNAsnp is available at http://rth.dk/resources/rnasnp .