Aluminium speciation in cerebrospinal fluid of acutely aluminium-intoxicated dialysis patients before and after desferrioxamine treatment; a step in the understanding of the element's neurotoxicity

Background: The association between aluminium and dialysis encephalopathy and deterioration of the neurological state during desferrioxamine treatment of dialysis patients is well established. At present little is known about the speciation and the mechanisms underlying the element's neurotoxicity. Methods. Aluminium speciation was performed in cerebrospinal fluid samples of acutely aluminium-intoxicated dialysis patients using a recently developed high-performance liquid chromatographic/electro-thermal atomic absorption spectrometric hybrid method. Results: Baseline cerebrospinal fluid aluminium levels of samples taken shortly after the intoxication were low but elevated (5.0±2.0 &mgr;g/l, n=3) as compared to subjects with normal renal function (<1 &mgr;g/l). In contrast to the situation noted in serum and to the iron speciation in cerebrospinal fluid, aluminium was not bound to transferrin but appeared as two distinct compounds, the main fraction eluting at the elution volume of aluminium citrate/silicate. The second compound was not identified. Forty-four hours after desferrioxamine administration the cerebrospinal fluid aluminium levels had increased up to a concentration of 10.3±2.5 &mgr;g/l (n=3). This was accompanied by a change in the speciation profile with aluminium appearing at the elution volume of aluminoxamine. Conclusion: Our findings may contribute to a better understanding of the neurotoxic effects of aluminium and its desferrioxamine chelate in dialysis patients.     

Xenogeneic bone marrow transplantation: II. Porcine-specific growth factors enhance porcine bone marrow engraftment in an in vitro primate microenvironment

Abstract: Establishment of mixed bone marrow chimerism in pig-to-primate transplantation, as a means of inducing specific immune tolerance, will require that both immune and nonimmune barriers be overcome. As a preliminary step in evaluating nonimmune barriers in this system, we have developed an in vitro model of engraftment in which long-term culture of porcine bone marrow-derived hematopoietic cells is supported on preformed primate bone marrow stromal layers. In the absence of cytokine supplementation, primate stromal cells were unable to support long-term porcine hematopoiesis in these cultures. Supplementation with porcine Steel Factor was required for long-term maintenance of hematopoietic progenitor cell content and total hematopoietic activity. Addition of porcine IL-3, in combination with porcine Steel Factor, increased long-term progenitor cell content and hematopoietic activity on primate stroma to levels comparable to that obtained in cultures on porcine stroma. The combination of porcine GM-CSF and Steel Factor increased progenitor cell content and hematopoietic activity early in the cultures, but had little effect in long-term cultures. The Steel Factor and IL-3 combination was species-specific in its action in these cultures, as the corresponding human cytokines were unable to effectively support long-term porcine hematopoiesis. Likewise, the combination of porcine cytokines had only minimal effects on long-term bone marrow culture of primate CD34+ cells I on primate stroma.     

Missense mutations in codon 225 of ornithine transcarbamylase (OTC) result in decreased amounts of OTC protein: A hypothesis on the molecular mechanism of the OTC deficiency

Mutations P225L and P225R were identified in codon 225 of the gene for ornithine transcarbamylase (OTC) in two patients with the neonatal form of OTC deficiency. The mutations occur at a CpG dinucleotide and eliminate a unique MspI restriction site in exon 7 of the OTC gene. They do not alter existing splice sites or create new sites, as judged from the nucleotide sequence. Both mutations are associated with undetectable levels of OTC antigen in liver homogenates, and with either complete lack of OTC activity (P225R mutation) or very small residual activity (0.15% of normal in the P225L mutation). The residual activity observed with P225L exhibits normal pH dependence, little or no increases in the Km values for ornithine and carbamoyl phosphate and normal stability at either 37°C or, in the presence of 0.66 mol/L urea, at 0°C. The latter conditions were used to examine whether the P225L mutation favours dissociation of the active OTC trimer. Given the normal stability and lack of tendency to dissociation of the mutant enzyme, it appears likely that the dramatic reduction in the level of OTC protein is due to inefficient conversion of the mutant OTC precursor polypeptide (pOTC) into the correctly localized, appropriately folded, mature enzyme trimer, suggesting degradation of pOTC in transit to the mitochondria.     

Impact of a region-wide approach to improving systems for heart attack care: the West Midlands thrombolysis project.

OBJECTIVE: To describe changes in delay to administration of thrombolytic therapy associated with a region-wide audit. DESIGN: Observational study of patients admitted with suspected myocardial infarction (MI) based on continuous audit. SUBJECTS: 18877 patients admitted to 23 hospitals with suspected MI between April 1995 and March 1998. RESULTS: Of 11232 patients with a discharge diagnosis of definite MI, 8802 (46.6%) received thrombolytic therapy during hospitalisation, with 5155 patients eligible for treatment on admission to hospital on the basis of established indications. Call-to-needle time for those eligible for treatment on admission fell from median 105 min in the first year of the project to 85 min in year 3 (P<0.001), and door-to-needle time fell from 45 to 35 min (P<0.001). Forty percent of eligible patients were treated within the then current national standard of 90 min from time of call for help, with nearly 49% in the final year and 20% being treated within the new national standard of 60 min, by the third year. CONCLUSION: The proportion of eligible patients receiving thrombolysis within 1 h of the call for help doubled during the 3-year project but the majority of patients still wait longer than 60-min 'call-to-needle'. New systems to reduce delays to administration of thrombolysis to within 60 min of call for help are required, including consideration of pre-hospital treatment.     

International primary care classifications: the effect of fifteen years of evolution.

To better understand the development of primary care classifications over the past 15 years, 10 primary care databases have been retrospectively analysed using the structure of the International Classification of Primary Care (ICPC) as the basis. All datasets were based on routine data collection using different classification systems by several family physicians during all encounters with their patients over considerable periods of time, in most cases one year. The prevalences or the rates of the available diagnostic--and reason for encounter--classes were distributed over four frequencies. With a few exceptions the distribution of diagnostic labels referring to common diseases is surprisingly similar. The use of ICPC however results in a quantum leap in the use of symptom and complaint diagnoses. Because of this shift primary care physicians now have available a classification with 400 diagnostic classes used with a prevalence of > or = 1/1000 patient-years or per 1000 visiting patients per year. The classification of reasons for encounter allows the physician to identify over 300 reasons for encounter used > or = 1/1000 patient years or per 1000 visiting patients per year. Family physicians have been successful in the development of new primary care classifications. Rag bag rubrics which are the result of the structure of ICPC are used relatively often and deserve more attention from primary care taxonomers.