Serum ferritin level is one of the most commonly requested investigations in both primary and secondary care. Whilst low serum ferritin levels invariably indicate reduced iron stores, raised serum ferritin levels can be due to multiple different aetiologies, including iron overload, inflammation, liver or renal disease, malignancy, and the recently described metabolic syndrome. A key test in the further investigation of an unexpected raised serum ferritin is the serum transferrin saturation. This guideline reviews the investigation and management of a raised serum ferritin level. The investigation and management of genetic haemochromatosis is not dealt with however and is the subject of a separate guideline.

SummaryIn Paroxysmal nocturnal haemoglobinuria (PNH), pregnancy is associated with increased maternal and foetal complications to such an extent that the condition has been considered relatively contra-indicated in PNH. Eculizumab has revolutionized the treatment of PNH. We evaluate its use in pregnancy to date. We report on seven patients exposed to eculizumab at different stages of pregnancy including the first two patients to receive the drug from conception to delivery. There was no evidence of complement blockade from cord blood samples taken at delivery. Eculizumab appears safe to use in this setting and is likely to prevent many of the complications usually observed.

The human protein ABC7 belongs to the adenosine triphosphate-binding cassette transporter superfamily, and its yeast orthologue, Atm1p, plays a central role in the maturation of cytosolic iron-sulfur (Fe/S) cluster-containing proteins. Previously, a missense mutation in the human ABC7 gene was shown to be the defect in members of a family affected with X-linked sideroblastic anemia with cerebellar ataxia (XLSA/A). Here, the promoter region and the intron/exon structure of the human ABC7 gene were characterized, and the function of wild-type and mutant ABC7 in cytosolic Fe/S protein maturation was analyzed. The gene contains 16 exons, all with intron/exon boundaries following the AG/GT rule. A single missense mutation was found in exon 10 of the ABC7gene in 2 affected brothers with XLSA/A. The mutation was a G-to-A transition at nucleotide 1305 of the full-length cDNA, resulting in a charge inversion caused by the substitution of lysine for glutamate at residue 433 C-terminal to the putative sixth transmembrane domain of ABC7. Expression of normal ABC7 almost fully complemented the defect in the maturation of cytosolic Fe/S proteins in a yeast strain in which the ATM1 gene had been deleted (Δatm1 cells). Thus, ABC7 is a functional orthologue of Atm1p. In contrast, the expression of mutated ABC7 (E433K) or Atm1p (D398K) proteins in Δatm1 cells led to a low efficiency of cytosolic Fe/S protein maturation. These data demonstrate that both the molecular defect in XLSA/A and the impaired maturation of a cytosolic Fe/S protein result from an ABC7 mutation in the reported family.

Summary:suppression. Finally, culture conditions may be developed which could be applied to gene transduction protocols. We have previously demonstrated that CD34 + cells, Most investigators initiate stem/progenitor cell expansion selected from peripheral blood progenitor cells (PBPC), with CD34 + cells purified by positive selection since these can be expanded in ex vivo culture and can be infused cells appear to be superior to unselected material. In in tandem with unmanipulated PBPC with little or no addition, up to a 4.0 log depletion of contaminating tumour toxicity. In this study, four patients (two non-Hodgkin's cells can be obtained using CD34 selected starting populymphoma (NHL), two multiple myeloma (MM)) lations. 7 A recent study suggested that any remaining received myeloablative conditioning prior to stem cell tumour cells do not increase in number during ex vivo rescue using ex vivo expanded cells alone. The two expansion, and this may represent a further purging patients with NHL received cyclophosphamide and total effect. 8,9 The first clinical studies using progenitor cells body irradiation (CY/TBI) and the two patients with expanded ex vivo have now been reported. 5,6,10,11 In only MM, busulphan and melphalan (Bu/M). One case one of these studies, in a small number of patients, stem received an inadequate CFU-GM dose, despite expancell rescue was performed using only the expanded cells, sion, and in one case the expanded cells were contamiwithout unmanipulated 'back-up'. 5 Brugger et al 5 expanded nated. No definitive conclusions may therefore be drawn one tenth of a standard peripheral blood progenitor cell concerning engraftment in these two cases. However, (PBPC) product prior to infusion. Six patients were transthe other two cases received high doses of committed planted with expanded cells only, and five of six experiprogenitors. Following infusion of the expanded enced rapid engraftment following high-dose, but nonmaterial, all four patients failed to show sustained myeloablative, chemotherapy. The remaining patient died neutrophil engraftment and none showed evidence of prior to the anticipated time of engraftment. platelet engraftment. Back-up, unmanipulated PBPC In our previous study, we established the safety and were therefore infused on days 14, 34, 32 and 28 and feasibility of transfusing CD34 + cells which had been selecsubsequently all four cases achieved satisfactory ted from cryopreserved PBPC and then expanded ex vivo. 6 engraftment of both neutrophils and platelets. In conTen patients received у20 × 10 4 CFU-GM/kg unmanipclusion, we feel that, CD34 + cells, expanded ex vivo using ulated PBPC in addition to an aliquot of expanded cells the conditions described in this report, may not provide (range 33-279 × 10 4 CFU-GM/kg). There were no toxic durable engraftment following fully myeloablative effects from the progenitor cells which had been generated conditioning.ex vivo. 6 Keywords: ex vivo expansion; CD34 positive; PBPC;The primary objective of this second study was to det...

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In the past five years 12 patients have been identified presenting with chronic duodenal ulcer (DU) disease and with no evidence of current or recent Helicobacter pylori (H pylori) infection. Four of them were taking regular non-steroidal anti inflammatory agents, one was subsequently found to have Crohn's disease of the duodenum, and one to have the Zollinger-Ellison syndrome. The remaining six patients with idiopathic DU disease were remarkable for their absence of the A1 blood antigen gene. Detailed studies of gastric function were performed in these six patients and compared with H pylon positive patients with DU and with healthy volunteers. The median integrated gastrin response in the patients with idiopathic DU (2810 (range 750-8750) ng/l min) was similar to that of the H pylori positive patients with DU (3355 (550-8725)) and higher than that of the H pylon negative healthy volunteers (560 (225-1125)). The median peak acid output in the patients with idiopathic DU (37 mmol/h, range 17-52) was similar to that of the H pylon positive patients with DU (40 (15-57)) and higher than that ofthe non-ulcer controls (22 (16-29)). The median percentage of a liquid meal retained in the stomach at 60 minutes was less in the patients with idiopathic DU (23 (15-33)) than in Hpyloni negative healthy volunteers (34 (30-53) p<0-01). The median percentage of a solid meal retained at 60 minutes was less in the patients with idiopathic DU (54 (9-83)) than in either H pylon negative healthy volunteers (87 (49-95) p<001) or H pylon positive patients with DU (79 (51-100) p<0-01). In conclusion, three abnormalities of gastric function are prevalent in patients with H pylon negative idiopathic DU disease -hypergastrinaemia, increased acid secretion, and the one feature distinguishing them from H pylon positive patients with DU -rapid gastric emptying of both liquids and solids. Each of these abnormalities will increase the exposure of the duodenal mucosa to acid and thus explain its ulceration. The absence of the blood group A1 antigen gene is consistent with a genetic basis for the disturbed gastric function linked to the ABO blood group antigen genes. (Gut 1993; 34: 762-768) More than 95% of patients with chronic duo-

These data demonstrate that CD34 cells can successfully be selected from cryopreserved material, expanded ex vivo on a large scale, and safely reinfused following myeloablative conditioning regimens.

X-linked sideroblastic anemia (XLSA) is caused by mutations of the erythroid-specific 6-aminolevulinate synthase gene (ALAS2) resulting in deficient heme synthesis. The characteristic hypochromic, microcytic anemia typically becomes manifest in the first three decades of life. Hematologic response to pyridoxine is variable and rarely complete. We report two unrelated cases of highly pyridoxine-responsive XLSA in geriatric patients previously diagnosed with refractory anemia and ringed sideroblasts. A previously unaffected 77-yr-old male and an 81-yr-old female were each found to have developed severe hypochromic, microcytic anemia with ringed sideroblasts in the bone marrow, which responded dramatically to pyridoxine with normalization of hemoglobin values. Sequence analysis identified an A to C transversion in exon 7 (K299Q) of the ALAS2 gene in the male proband and his daughter. In the female proband a