Intensive retreatment of adults and children with acute lymphoblastic leukemia.

Twenty-three patients (16 adults) failing their first or subsequent (n = 8) intensive treatment for de novo acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia lymphoid blast phase (n = 2) were managed with protocol POG 8201, originally introduced in relapsed ALL of childhood. In this programme, a four-drug induction phase is followed by early consolidation with teniposide-cytarabine, intrathecal chemotherapy, continuation weekly chemotherapy alternating teniposide-cytarabine with vincristine-cyclophosphamide, and periodic reinduction courses. Fourteen adults and five children with ALL achieved a complete response (CR) (86 per cent). The highest response rate (100 per cent) was obtained in 12 patients treated at first relapse after an initial CR of greater than 18 months (p = 0.07). Median duration of CR was 8 months in adults and 11 months in children. A longer than previous one CR (inversion) was obtained in four cases. Four ALL patients were successfully transplanted from a matched sibling after 3-11 months from achievement of CR. Median overall survival in adults with ALL was 11 months, significantly longer than for 40 comparable cases treated intensively but without rotational continuation therapy in previous years (p less than 0.001). This regimen is applicable to adults with relapsed ALL, where prolongation of survival may allow time for effective salvage with bone marrow transplantation.     

Renal effect of anti-hypertensive drugs depends on sodium diet in the excision remnant kidney model.

Angiotensin converting enzyme inhibitors (ACEI) are believed to protect remnant kidney, but all previous studies used the ligation model which causes severe hypertension, and very few have compared drugs in rats having similar control of blood pressure (BP). We compared rats with uremia obtained by 70% excision of total renal mass, a model which causes mild, late hypertension. Study I compared the effects of enalapril (E), cicletanine (C) and placebo (P) in uremic (U) rats fed a 0.50% (normal-high) Na diet. Study II compared the effects of E, C, P, and guanfacine (G) in U rats fed a diet restricted to 0.25% Na (normal-low). In study I, UP rats developed progressive hypertension (140, 146, 160 and 166 mm Hg at 3, 6, 9 and 12 weeks), proteinuria (240 mg/day at 9 and 12 weeks) which were not affected by E or C. The occurrence of end-stage renal disease (ESRD) led to the sacrifice of all rats after three months. All three groups had similar severe renal lesions (over 25% sclerosed glomeruli in 5 of 10 UP, 9 of 14 UE, 7 of 14 UC rats, with huge cystic tubular dilatations). In study II, rats could be sacrificed later (6 months) and had evidence of less severe renal disease. All the drugs tested prevented hypertension throughout the study (P less than 0.001), with lowest values in UE rats. E and G, but not C, reduced proteinuria. Renal damage was reduced with E and G, but not with C, despite similar BP in C and G rats. Thus, in contrast with what was obtained in the ligation model, ACEI affected neither the BP nor the renal lesions of rats made uremic by renal excision and fed a 0.50% Na diet. Moderate Na restriction improved the consequences of nephron loss and restored the anti-hypertensive effect of drugs. However, these drugs had a different effect on renal preservation: it was dramatic with E, good with G, and undetectable with C.     

Collagen-chondroitin sulfate-based PLLA-SAIB-coated rhBMP-2 delivery system for bone repair

Bone morphogenetic proteins (BMPs) are osteoinductive proteins used intensively in clinical investigations involving various bone-related treatments. Owing to their high potential in new bone formation they require local application at the treatment site. For this purpose various controlled delivery systems with BMPs as the excipients have been prepared in recent years. Focusing on this clinical need a disc-shaped BMP carrier was designed as a local delivery system using soluble collagen and chondroitin sulfate. In situ release studies carried out with a model protein (FITC-labeled Protein A) presented a very high rate of release; with most of the protein content being released within 24 h. This rate could be decreased by providing a poly(L-lactide) (PLLA) and sucrose acetate isobutyrate-based (SAIB-based) coat around the release system, applied after BMP loading. In this way, it was possible to extend the release period from 24 h to about 12 days. In situ release of BMP from the same carriers, as quantitated using an ELISA kit, was even slower, with 50% of the protein being released in 15 days. In order to be able to secure the BMP delivery system at the bone defect site and to provide support a mesh knitted using Vicryl sutures and bonded with poly(L-lactide-co-glycolide) (PLGA) was tested in in vivo. Two time periods, 1 and 3 weeks, were used to evaluate the healing process. Osteoinduction by the BMP carrier system was assessed by histology-based bone scoring and X-ray examinations. PLLA-SAIB-coated collagen discs containing BMP presented good biocompatibility and optimum osteogenic stimulation. Structural changes in histological micrographs at week 1 indicated dose-dependent periosteal ossification. At the end of week 3 histological findings with both BMP (1 and 2 microg) doses were almost the same.     

Differential distribution of aldolase A and C in the human central nervous system

We have analyzed the distribution of aldolase A and C mRNAs and proteins in various areas of the human brain using Northern blot analyses and immunohistochemistry. Aldolase A mRNA expression was higher than aldolase C mRNA expression in all areas of the brain examined. Aldolase C mRNA expression was highest in the cerebellum. Aldolase C protein was present in well-delimited regions of the CNS, and was distributed in stripes in the Purkinje cell layer of the cerebellum, in the inferior olives and in the sensory neurons of the posterior horn of the spinal cord. The novel finding of aldolase C in well-delimited cell compartments of the human cerebellum and in several other areas of the CNS lends weight to the hypothesis that this protein exerts other functions (e.g. sensory transmission) besides those characteristic of a glycolytic enzyme.     

Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1.

We report the identification of mutations in lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) genes in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17. Linkage disequilibrium analysis of six families affected by NCIE permitted us to reduce a recently reported interval of 8.4 cM on chromosome 17p13.1 to a 600 kb region around the marker D17S1796, which contains LOX genes. LOX products have long been implicated in skin disorders. Two point mutations and one deletion were found in ALOXE3 and three point mutations were found in ALOX12B in these consanguineous families from the Mediterranean basin. ALOXE3 and ALOX12B are two genes which are physically linked and functionally related. They are separated by 38 kb, have one more exon than the other LOX genes and are mainly expressed in epithelial cells including keratinocytes. Although the main substrate(s) of the two enzymes is (are) still unknown, the products of ALOX12B obtained in experimental systems have been demonstrated to be of R-chirality. It seems likely that the product of one of these enzymes may be the substrate of the other, and that they belong to the same metabolic pathway.     

Intracranial tuberculomas in a child: regression on the CT scan under conservative therapy

The case of a four-year-old boy is reported in whom the diagnosis of multiple cerebral and cerebellar focal tuberculous infections ("tuberculomas") was made. The diagnosis was based on a positive skin test, a history of contact, typical x-ray findings in the lung, CSF findings, and CT scan. The patient was treated during a three-year-period with antituberculous therapy. Sequential CT scans showed a relatively slow modification of the lesions, during a period of at least eighteen months, and thereafter their almost complete regression.     

Increased sodium requirement following early postnatal surgical correction of congenital uropathies in infants

Serum electrolyte equilibrium and plasma aldosterone concentrations were monitored in 19 infants who had severe obstructive uropathy or grade 5 vesico-ureteral reflux and were undergoing surgical correction in the first 2 months of life. Before surgery high plasma aldosterone levels were observed in 8 patients, but serum sodium and potassium concentrations were normal. Plasma concentrations of aldosterone were elevated in all patients during the week following surgery and 7 patients developed severe hyponatraemia, hyperkalaemia and weight loss despite very high plasma aldosterone concentrations. As a consequence 5 infants were infused with sodium chloride (4 mEq/kg per day) before and for 36h after surgery; this prevented metabolic imbalance. We conclude that infants undergoing surgical correction of uropathies may require a high sodium intake to maintain electrolyte balance and adequate growth.