The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update

Diamond-Blackfan Anemia (DBA) is characterized by a defect of erythroid progenitors and, clinically, by anemia and malformations. DBA exhibits an autosomal dominant pattern of inheritance with incomplete penetrance. Currently nine genes, all encoding ribosomal proteins (RP), have been found mutated in approximately 50% of patients. Experimental evidence supports the hypothesis that DBA is primarily the result of defective ribosome synthesis. By means of a large collaboration among six centers, we report here a mutation update that includes nine genes and 220 distinct mutations, 56 of which are new. The DBA Mutation Database now includes data from 355 patients. Of those where inheritance has been examined, 125 patients carry a de novo mutation and 72 an inherited mutation. Mutagenesis may be ascribed to slippage in 65.5% of indels, whereas CpG dinucleotides are involved in 23% of transitions. Using bioinformatic tools we show that gene conversion mechanism is not common in RP genes mutagenesis, notwithstanding the abundance of RP pseudogenes. Genotype-phenotype analysis reveals that malformations are more frequently associated with mutations in RPL5 and RPL11 than in the other genes. All currently reported DBA mutations together with their functional and clinical data are included in the DBA Mutation Database.     

Pathogenic BRCA1 mutations may be necessary but not sufficient for tissue genomic heterogeneity: Deep sequencing data from ovarian cancer patients

Background

Tissue genomic heterogeneity (t-HET) in patients with epithelial ovarian cancer (OVCA) is related to tissue plasticity, i.e., flexibility to adapt to adverse molecular environments. Here, we interrogated the presence and clinical relevance of OVCA t-HET.

Electrosurgical bipolar vessel sealing for vaginal hysterectomies

Background

Vascular clamping of the uterine vessels and the ovarian and broad ligaments during vaginal hysterectomies is more difficult than in traditional abdominal hysterectomies. We aimed to assess the efficacy of electrosurgical bipolar vessel sealing systems (EBVS) as an adequate alternative to traditional suturing that could facilitate the accomplishment of securing the vascular pedicles.

Methods

We searched MEDLINE (1966–2013), Scopus (2004–2013), POPLINE (1973–2013), Cochrane Central (1999–2013) and Google Scholar (2004–2013) search engines, along with reference lists from all included studies.

Results

Eight randomized trials were selected, including 772 patients. We found that operative duration did not differ significantly among women treated with EBVS and those treated with traditional suture ligation (MD ?16.86, 95 % CI ?34.77, 1.05). Intraoperative blood loss on the other hand was significantly lower in the EBVS-treated group (MD ?49.47, 95 % CI ?67.60, ?31.35). There were no significant differences in intraoperative complication rates (OR 0.96, 95 % CI 0.46, 2.01), major postoperative complication rates (OR 0.61, 95 % CI 0.29, 1.32) or minor complications (OR 1.63, 95 % CI 0.67, 3.92).

Conclusion

Our meta-analysis showed that EBVS seem to produce less intraoperative blood loss during vascular clamping, without significantly lowering intraoperative time or complication rate. However, the heterogeneity of included studies preclude firm conclusions. Future studies examine consistently their safety, and cost-effectiveness, and whether the application of such units will enhance the rates of vaginal hysterectomies.     

5-HYDROXYTRYPTAMINE-INDUCED CONTRACTION OF THE MARMOSET AORTA IS MEDIATED BY A 5-HT1-LIKE RECEPTOR

1. 5-Hydroxytryptamine (5-HT) exerts both contractile and relaxant effects in the marmoset isolated aorta, actions that are unaffected by the 5-HT₂ antagonist ketanserin. The aim of the present study was to define the receptors mediating the contractile activity of 5-HT in the marmoset aorta.
2. Contractile responses were elicited in aortic rings that were either: (i) precontracted submaximally with the thromboxane A₂ agonist U44069 in order to amplify the responses; or (ii) exposed to N ^ω-nitro- L -arginine (100 μmol/L) plus LY 53857 (0.1 μmol/L; a 5-HT₂ receptor antagonist shown previously to inhibit relaxation). The effect of 5-HT on adenosine 3',5'-cyclic monophosphate (cAMP) formation was also investigated.
3. The effects of agonists and antagonists comprised: (i) agonist potencies in the order 5-carboxamidotryptamine > 5-HT > sumatriptan > 8-hydroxy-2-(di- n -propylamino)tetralin; (ii) inhibition of contractile action of 5-HT by the 5-HT_1D antagonist GR 127935; (iii) a contractile response to methysergide; (iv) a lack of effect of tropisetron, an antagonist of 5-HT₃ and 5-HT₄ receptors; and (v) inhibition of forskolin-stimulated cAMP formation by 5-HT (in the presence of LY 53857), indicative of negative coupling to adenylate cyclase.
4. The above effects fulfil the criteria for a 5-HT₁-like receptor. In view of the previous finding that this contractile response is insensitive to ketanserin, it is concluded that the contractile effects of 5-HT in the marmoset aorta are mediated exclusively by a 5-HT₁-like receptor.     

Bilateral renal artery stenting in a patient with Leriche syndrome

Stenting for renal artery stenosis is well described in the literature. Bilateral renal artery stenting is not such a common procedure, however it is quite rare in patients with Leriche syndrome, as is the case we present.     

Ethical issues in non-heart-beating donation

A shortage of organ donors and the large number of patients desperately waiting for kidney transplant have led to the search for new sources of transplantable organs. The waiting list has grown at an alarming rate resulting in increased waiting times and deaths. The introduction of non heart beating (NHB) donation programmes generates a lot of ethical issues. How should death of a patient be defined in the case of NHB donation? Is there a strict separation of responsibilities of the medical teams in the different phases of the procedure (patient treatment and actual donation)? How should consent be obtained? Is sufficient respect and care given to the patient and his family? How is the viability of the organs assessed and how should the organs be allocated? We believe that it is very important to debate these issues and to try to outline an ethical framework for NHB donation that can enjoy the widest possible community support.     

The Diamond Blackfan Anemia Registry: tool for investigating the epidemiology and biology of Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is a heterogeneous genetic disorder characterized by red cell aplasia and congenital anomalies. One of what appears to be multiple DBA genes has been cloned. Affected individuals in the same family may vary dramatically as to the degree of anemia, response to corticosteroids, and the presence of congenital anomalies. The epidemiology of DBA has been gleaned largely from literature reviews. This approach is limited because of the two-fold disadvantage of the reporting bias inherent in the literature and the lack of an active patient database. The Diamond Blackfan Anemia Registry of North America (DBAR) is designed to overcome these disadvantages to study the epidemiology and biology of DBA. The DBAR is a comprehensive database of patients with DBA who are enrolled after informed consent is obtained. Identification of patients is made through outreach to pediatric and adult hematologists and the Diamond Blackfan Anemia Foundation. The patients and/or their families complete a detailed questionnaire. A review of medical records and telephone interviews are performed to complete and clarify the information provided. To date, 354 patients have been enrolled in the DBAR. Using this database, important epidemiologic, clinical, and laboratory observations have been made with regard to the clinical presentation, the inheritance of DBA, the genetics of congenital malformations, the therapeutic outcome, including the efficacy of hematopoietic stem cell transplantation, and the recognition of DBA as a cancer predisposition syndrome. In particular, the database is an essential substrate for DBA gene discovery.