Identification and characterization of DNA imbalances in neuroblastoma by high-resolution oligonucleotide array comparative genomic hybridization

Neuroblastoma (NB) is a pediatric tumor characterized by high genetic heterogeneity. Although the prognostic significance of some genomic abnormalities (i.e., MYCN amplification, 1p loss, and 17q gain) is recognized, genes that are involved in chromosome rearrangements remain largely unknown. Considerable progress has been made over the last years in characterizing DNA abnormalities by metaphase comparative genomic hybridization (mCGH) and array CGH (aCGH). Here we report a pilot study of 5 localized and 12 disseminated NB by 44,000 and of 4 out of 17 cases by 244,000 oligonucleotide aCGH. Localized tumors were predominantly characterized by losses of whole chromosomes 3, 4, 10, and 16, and gains of 6, 7, 8, 13, 17, 18, and 20, whereas disseminated tumors showed several structural aberrations including 17q gain and 3p and 11q losses. Characterization of chromosome 2p in MYCN-amplified NB revealed several structural rearrangements with regions of gain interspersed among sites of amplification, indicating that the MYCN amplicon may encompass several genes. The high-resolution zooming in chromosomal aberrant regions detected several micro-deletions and micro-amplifications in the NB genome. Our results indicate that the increased sensitivity of the aCGH also allows the identification of DNA aberrations in challenging samples (i.e., NB showing tissue and genetic heterogeneity).     

Therapeutic benefit of treatment with anti-thymocyte globulin and latent TGF-beta1 in the MRL/lpr lupus mouse model

The pathogenesis of systemic lupus erythematosus is believed to involve defects in regulatory T cell (Treg) activity and abnormal activation of B and T lymphocytes. The purpose of this study was to test the therapeutic potential of rabbit anti-mouse thymocyte globulin (ATG), a lymphocyte-depleting agent, in conjunction with transforming growth factor (TGF)-beta1, a factor involved in the induction and expansion of Tregs. MRL/lpr mice with active disease were treated with ATG followed by a 12-day course of latent TGF-beta1 during the period of lymphocyte repopulation. Treatment with ATG + latent TGF-beta1 synergistically inhibited the progression of proteinuria and albuminuria and provided a significant improvement in long-term survival. This therapeutic benefit correlated histologically with reduced glomerular pathology and protein cast formation. The mechanism of action did not involve suppression of autoantibody formation but may involve the activity of CD4(+)CD25(+)FoxP3(+) Tregs, which were found to be induced by ATG + TGF-beta1 treatment in vitro.     

Accidental outbreak of non-bacterial food poisoning

Background: Troops deployed in isolated garrisons face erratic supply of rations. At times they resort to use of locally grown plants without knowledge of local flora, resulting in accidental food poisoning.     

Rescue of wild-type E-cadherin expression from nonsense-mutated cancer cells by a suppressor-tRNA

Hereditary diffuse gastric cancer (HDGC) syndrome, although rare, is highly penetrant at an early age, and is severe and incurable because of ineffective screening tools and therapy. Approximately 45% of HDGC families carry germline CDH1/E-cadherin alterations, 20% of which are nonsense leading to premature protein truncation. Prophylactic gastrectomy is the only recommended approach for all asymptomatic CDH1 mutation carriers. Suppressor-tRNAs can replace premature stop codons (PTCs) with a cognate amino acid, inducing readthrough and generating full-length proteins. The use of suppressor-tRNAs in HDGC patients could therefore constitute a less invasive therapeutic option for nonsense mutation carriers, delaying the development of gastric cancer. Our analysis revealed that 23/108 (21.3%) of E-cadherin-mutant families carried nonsense mutations that could be potentially corrected by eight suppressor-tRNAs, and arginine was the most frequently affected amino acid. Using site-directed mutagenesis, we developed an arginine suppressor-tRNA vector to correct one HDGC nonsense mutation. E-cadherin- deficient cell lines were transfected with plasmids carrying simultaneously the suppressor-tRNA and wild-type or mutant CDH1 mini-genes. RT-PCR, western blot, immunofluorescence, flow cytometry and proximity ligation assay (PLA) were used to establish the model, and monitor mRNA and protein expression and function recovery from CDH1 vectors. Cells expressing a CDH1 mini-gene, carrying a nonsense mutation and the suppressor-tRNA, recovered full-length E-cadherin expression and its correct localization and incorporation into the adhesion complex. This is the first demonstration of functional recovery of a mutated causative gene in hereditary cancer by cognate amino acid replacement with suppressor-tRNAs. Of the HDGC families, 21.3% are candidates for correction with suppressor-tRNAs to potentially delay cancer onset.     

Atopic eczema: Its social and financial costs

Atopic dermatitis is a disorder with considerable social and financial costs. A recent Australian study indicates that the family stress related to the care of a child with moderate or severe atopic dermatitis is significantly greater than that of care of children with insulin-dependent diabetes mellitus. The factors contributing to family stress include: sleep deprivation; loss of employment; time taken for care of atopic dermatitis; and financial costs. An estimate of the yearly financial costs for a family and community (which includes medical, hospital, direct costs of treatments and indirect costs from loss of employment), range from $A1142 per child per year with mild atopic dermatitis, to $A6099 per year for a child with severe atopic dermatitis. As the current prevalence of atopic dermatitis in Australia is 10-15%, this indicates a considerable financial burden on the community. It is possible that appropriate interventions directed to reducing trigger factors, may produce worthwhile savings, in addition to benefits for the individuals and families. Atopic dermatitis should not be regarded as a minor skin disorder but as a condition which has the potential to be a major handicap involving considerable personal, social and financial consequences both for the family and for the community.     

Analysis of t(15;17) chromosomal breakpoint sequences in therapy‐related versus de novo acute promyelocytic leukemia: Association of DNA breaks with specific DNA motifs at PML and RARA loci

We compared genomic breakpoints at the PML and RARA loci in 23 patients with therapy‐related acute promyelocytic leukemia (t‐APL) and 25 de novo APL cases.Eighteen of 23 t‐APL cases received the topoisomerase II poison mitoxantrone for their primary disorder. DNA breaks were clustered in a previously reported 8 bp “hot spot” region of PML corresponding to a preferred site of mitoxantrone‐induced DNA topoisomerase II‐mediated cleavage in 39% of t‐APL occurring in patients exposed to this agent and in none of the cases arising de novo (P = 0.007). As to RARA breakpoints, clustering in a 3′ region of intron 2 (region B) was found in 65% of t‐APL and 28% of de novo APL patients, respectively. Scan statistics revealed significant clustering of RARA breakpoints in region B in t‐APL cases (P = 0.001) as compared to de novo APL (P = 1). Furthermore, ～300 bp downstream of RARA region B contained a sequence highly homologous to a topoisomerase II consensus sequence. Biased distribution of DNA breakpoints at both PML and RARA loci suggest the existence of different pathogenetic mechanisms in t‐APL as compared with de novo APL. © 2010 Wiley‐Liss, Inc.     

Total Pectoral Implantation: A New Technique for Implantation of Transvenous Defibrillator Lead Systems and Implantable Cardioverter Defibrillator

We describe a new approach to tolal pectoral implantation of cardioverter defibrillators with an endocardial defibrillation lead system. Endocardial lead configuration used was an FDA approved right atrial-superior vena cavo defibriliation spring electrode, right ventricular bipolar sensing electrode, and a pectoral patch. Endocardial leads were implanted via a cephalic or an axillary venesection. Pectoral patch was placed in a sabmuscular position. In case of failure to obtain satisfactory thresholds, a small intercostal thoracofomy was performed via fhe same skin incision and patch placed over the epicardium instead of submuscular position and used with Ihe right atrial spring electrode. The device was implanted in the pectoral region, submuscularly, over the patch. Sixteen consecutive patients underwent this approach. With a submascular patch, adequate defibrillation thresholds (< 15 joules [J]) were obtained in 14 (87.5%) patients. In the other two, defibrillation thresholds of ≤ 15) were obtained with a epicardial patch. Pectoral implantation of the device was feasible in all 16 patients and none needed repositioning. Average postimplant hospital stay was 5 days. During follow-up period (average 5 months), none of the patients reported any major local symptoms and no problems have been encountered in device interrogation. Thus, total pectoral implantation of the cardioverter defibrillator including the patch, leads, and the device is feasible. Furthermore, in case of foilure to obtain adequate defibrillotjon thresholds with submuscular patch, an epicardial patch can easily be implanted and allows 100% successful defibrillation at energy levels of ≤ 15 J with right atrial patch configuration.     

Is the influence of nurse care practices and nursing home organization understood? A qualitative study

palacios-ceña d., cachón-pérez j.m., gómez-pérez d., gómez-calero c., brea-rivero m. & fernández-de-las-peñas c. (2012) Journal of Nursing Management
Is the influence of nurse care practices and nursing home organization understood? A qualitative study Aim To describe residents’ experience of nursing home organization and nursing care practices in a region of Spain. Background Nursing home organization, nursing practices and rules within the institution may all influence residents’ daily living and their perception on the quality of care provided. Design A qualitative approach was conducted, using purposeful and theoretical sampling. Data were collected from nursing home residents, following unstructured and semi-structured interviews, researcher field notes and residents’ personal diaries and letters. Giorgi analysis was conducted. Results Two main themes emerged. (1) ‘Following nursing home rules’. Norms may be seen as boundaries, especially for those residents who were independent before admission. (2) ‘Prioritizing nursing care in residents’. Prioritizing the nursing care may limit the autonomy of residents because it does not meet their preferences and needs. Conclusion Understanding the meaning of nursing home organization and nursing care practices with nursing home residents might provide deeper insight into their expectations. Implications for nursing management Nursing staff should have greater involvement in the nursing home organization, as well as in prioritizing the care provision based on resident’s needs and preferences.