Successful correction of the human beta-thalassemia major phenotype using a lentiviral vector

beta-thalassemias are the most common single gene disorders and are potentially amenable to gene therapy. However, retroviral vectors carrying the human beta-globin cassette have been notoriously unstable. Recently, considerable progress has been made using lentiviral vectors, which stably transmit the beta-globin expression cassette. Thus far, mouse studies have shown correction of the beta-thalassemia intermedia phenotype and a partial, variable correction of beta-thalassemia major phenotype. We tested a lentiviral vector carrying the human beta-globin expression cassette flanked by a chromatin insulator in transfusion-dependent human thalassemia major, where it would be ultimately relevant. We demonstrated that the vector expressed normal amounts of human beta-globin in erythroid cells produced in in vitro cultures for unilineage erythroid differentiation. There was restoration of effective erythropoiesis and reversal of the abnormally elevated apoptosis that characterizes beta-thalassemia. The gene-corrected human beta-thalassemia progenitor cells were transplanted into immune-deficient mice, where they underwent normal erythroid differentiation, expressed normal levels of human beta-globin, and displayed normal effective erythropoiesis 3 to 4 months after xenotransplantation. Variability of beta-globin expression in erythroid colonies derived in vitro or from xenograft bone marrow was similar to that seen in normal controls. Our results show genetic modification of primitive progenitor cells with correction of the human thalassemia major phenotype.     

Safe motherhood in Pakistan

The maternal mortality ratio in Pakistan remains high at between 350 and 500 per 100,000 live births, while the neonatal mortality ratio is 50 per 1000 live births. This paper examines the trends in maternal and neonatal mortality in Pakistan and looks at why slow progress has been made in attempts to achieve safe motherhood. Despite numerous initiatives, it is uncertain whether Pakistan will achieve Millennium Development Goals 4 and 5 by 2015.     

The 'new genetics' and primary care: GPs' views on their role and their educational needs.

BACKGROUND: Given the limited specialist resources available to cope with the rising demand for genetic services, it has been proposed that at least some of these services are provided by primary care in the future. OBJECTIVE: We aimed to explore GPs' attitudes towards new developments in genetics, to establish the role they envisage for primary care and to clearly define the education, information and training needed to support them in this role. METHODS: We carried out a qualitative study with GPs using four focus groups (26 GPs) and 15 individual semi-structured interviews. RESULTS: GPs perceive genetics as an important and increasingly relevant topic for primary care. Views on the appropriate level of involvement for primary care are mixed. GPs currently lack the relevant knowledge and skills to manage patients concerned about their family history. Other potential barriers to increasing primary care involvement included the time and costs involved, and ethical and legal concerns. CONCLUSION: If primary care is to become more involved in the delivery of genetic services in the future, then a major educational effort is required to raise awareness of the potential scope and limitations of new developments.     

Qualification Requirements for Performing Neurointerventional Procedures: A Report of the Practice Guidelines Committee of the American Society of Neuroimaging and the Society of Vascular and Interventional Neurology

The aim of this document is to summarize the existing data derived from regulatory bodies, professional organizations, and clinical trials with direct pertinence to indications and qualifications required for performing neurointerventional procedures and provide recommendations regarding qualifications required for performing individual neurointerventional procedures. Recommendations are provided for performance of cerebral angiography, intra‐arterial thrombolysis, carotid angioplasty and stent placement, intracranial angioplasty and stent placement, and endovascular treatment of intracranial aneurysms and arteriovenous malformations.     

Cutting Balloon Angioplasty for Carotid In‐Stent Restenosis: Case Reports and Review of the Literature

Percutaneous stenting techniques are becoming more commonly used for treatment of carotid artery disease. One outcome of particular concern is in‐stent restenosis. Indications for treatment of in‐stent restenosis are not clearly defined. Use of traditional balloon angioplasty with or without stent placement is still considered the first option. Cutting balloon angioplasty has recently been used as an alternative treatment option for revascularization of in‐stent restenosis with higher procedural success rates and without the use of additional stents. We report our experience with cutting balloon angioplasty in treating 2 patients with carotid in‐stent restonosis, and review previous cases reported in the literature. A total of 16 patients have been treated with cutting balloon angioplasty. Among 11 patients for whom the clinical and angiographic information were available, 63% of patients were asymptomatic at the time of treatment, and more than 90% of patients showed either complete angiographic resolution or residual stenosis of less than 30%. Additional stent placement or angioplasty was required in only half of the patients, and 1 patient had recurrent stenosis. The review suggests that the procedure is safe and effective.     

Craniocerebral epidermoid and dermoid tumours: a review of 32 cases

Summary We reviewed 22 epidermoid and 10 dermoid tumours of the skull and brain from patients operated on consecutively at Henry Ford Hospital between 1975 and 1991.There were 19 intradural (16 epidermoid, 3 dermoid) and 13 extradural (6 epidermoid, 7 dermoid) lesions. The average age at presentation was 35 years for patients with epidermoids and 15 years for those with dermoids. Common clinical presentations for patients with intradural lesions included headache, visual deficits, and seizures, whereas patients with extradural lesions harbored asymptomatic scalp masses. All patients with intradural lesions were investigated with computed tomography (CT) and cerebral angiography, and 8 patients underwent magnetic resonance imaging (MRI).Total resection was possible in 12 (92%) of 13 extradural tumours, all with excellent outcomes. Eight (42%) of the intradural tumours were completely resected.Overall, with the intradural tumours we had good to excellent results in 17 patients (90%), poor results in 1 (5%), and 1 death (5%). Re-operation was needed in 5 intradural recurrences (26%) with deterioration in only one patient's neurologic status postoperatively.From a review of ours and others' data, we conclude that 1) these tumours have an insidious onset despite significant size and mass effect as demonstrated by imaging studies; 2) CT, angiography, and particularly MRI help to define the extent of subarachnoid tumour spread and involvement of neurovascular structures, thus permitting better surgical planning; 3) a significant number of intradural tumours are difficult to excise because of their adherence to neurovascular structures, and thus are related to higher morbidity and mortality; and 4) because of extremely slow growth, complete tumour resection should not be the goal at the risk of injury to neurovascular structures.     

Diphosphoryl lipid A derived from lipopolysaccharide (LPS) of Rhodopseudomonas sphaeroides inhibits activation of 70Z/3 cells by LPS.

Diphosphoryl lipid A derived from nontoxic lipopolysaccharide (LPS) of Rhodopseudomonas sphaeroides ATCC 17023 did not stimulate the murine pre-B cell line 70Z/3 to synthesize surface immunoglobulin or kappa mRNA. However, it effectively blocked Escherichia coli LPS-induced activation of 70Z/3 cells in a concentration-dependent manner. This inhibition was specific only to cells activated by LPS, since it did not inhibit activation of 70Z/3 cells by gamma interferon. Maximal inhibitory effect occurred when the antagonist was added within 2 h before adding the LPS. These results strongly suggested that R. sphaeroides diphosphoryl lipid A is competing with E. coli LPS for physiological lipid A receptors on the 70Z/3 cells.     

Prenatal detection and progression of right coronary artery to right ventricle fistula.

Prenatal diagnosis of a congenital coronary artery fistula between the right coronary artery and right ventricle was made by colour Doppler echocardiography at 20 weeks of gestation. Its progression was monitored by serial echocardiography throughout pregnancy and postnatally.