ON HOOKWORM ANEMIA: (APLASTIC ANEMIA IN HOOKWORM DISEASE)

We have discussed three types or stages of blood changes in hookworm disease.Attention is directed to a severe irreversible aplastic anemia which occurs not infrequently in hookworm disease. The pathogenesis is obscure, but we believe thatit is due to bone marrow exhaustion following continuous blood loss in the presenceof various factors, including dietary deficiency.

The symptomatology, hematologic and bone marrow findings are described.

     

The importance of accurate dosage of topical agents: a method of estimating involved area and application to calcipotriol treatment failures

Little attention is given to accurate dosage of topical medication which is a potential source of side-effects and treatment failure. There are studies on the dosage for 'sparing' application relevant to topical steroids but not for 'liberal' application. Though calcipotriol is a first line topical treatment for psoriasis, approximately one-third of patients do not respond adequately. The aims of the present study were to define liberal dosage, to develop a method of calculation of area of involved skin and to evaluate the efficacy of calcipotriol in optimized liberal dosages, based on preliminary studies, in calcipotriol treatment failures. Weight/unit area of ointment and cream base, constituting liberal application, was determined in six normal volunteers. The area of psoriatic involvement in 24 calcipotriol non-responders was estimated by a 'fill-up' method and a modified 'hand' method. The results of the two methods were similar (Pearson correlation coefficient 0.68, P < 0.0001) but the 'hand' method proved easier in use and was the preferred method for the rest of the study. The patients applied calcipotriol at their accustomed rates for at least 2 weeks and then at the calculated liberal rates, using cream in the morning and ointment at night, for 4 weeks. The efficacy measures were Psoriasis Area and Severity Index (PASI) (primary measure), a four-point efficacy score and a visual analogue scale. As a result of the preliminary study and the actual amounts used by the patients in the psoriasis treatment study reported below, liberal application has been defined as 50 g/m2 per application for ointment base and 40 g/m2 per application for cream. At this dosage, an average individual would use approximately 100 g of medication/week to treat 10% of the body surface. During the 4-week treatment study, the psoriasis patients used an average of 39 g (SD 17 g)/m2 per application of cream and 52 g (SD 13 g)/m2 per application of ointment. All efficacy measures showed marked improvement (P < 0.0001). The frequency distribution of the PASI reduction defined responsive (70% of patients) and poorly responsive groups (30%), with mean PASI reduction of 60% and 17%, respectively.     

An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: further evidence for SMN as the primary SMA-determining gene

The gene for autosomal recessive spinal muscular atrophy (SMA) has been mapped to 5q12 in a region that contains repeated markers and genes. Three cDNAs that detect deletions in SMA patients have been reported. One of these, the survival motor neuron (SMN) cDNA, is encoded by two genes (SMNT and SMNC) which are distinguished by base changes in exons 7 and 8. Exon 7 of the SMNT gene is not detectable in approximately 95% of SMA cases, due either to deletion or sequence conversion. There is limited information on the mutations in SMA patients that have detectable SMNT, these are critical for confirmation of SMNT as the SMA gene. Using SSCP analysis of the SMN exons we screened our SMA patients that possess at least one intact SMNT allele for mutations in SMNT. We identified one type I SMA patient with an 11 bp duplication in exon 6 which causes a frameshift and premature termination of the deduced SMNT protein. Dosage and SSCP analysis of SMNT in this family indicated that the father contributed a SMNT-deleted allele to the affected child whereas the mother passed on the 11 bp exon 6 duplication SMNT allele. Analysis of RNA by RT-PCR conclusively demonstrated that the 11 bp duplication is associated with the SMNT locus and not SMNC. This mutation provides strong support for SMN as the SMA-determining gene and indicates that disruption of SMNT on its own is sufficient to produce a severe type I SMA phenotype.      

Heterogeneity of autosomal dominant osteopetrosis

A review of the radiographs of 26 patients with autosomal dominant osteopetrosis disclosed two distinct and strictly family-related radiographic types. Both types had universal osteosclerosis. In type 1 the most striking finding was pronounced sclerosis of the cranial vault while the spine was almost unaffected. In type 2 the sclerosis of the skull was most pronounced at the base, the vertebrae always had end-plate thickening, and in the pelvis the iliac wings contained convex arcs of sclerotic bone. Age and sex distribution did not differ between the types. Autosomal dominant osteopetrosis may be a heterogeneous group of inherited bone disorders.     

Aggregated low density lipoprotein induces tissue factor by inhibiting sphingomyelinase activity in human vascular smooth muscle cells

Summary. Background: Our previous results demonstrated that aggregated low density lipoprotein (agLDL) induces tissue factor (TF) expression and activation through Rho A translocation in human vascular smooth muscle cells (VSMC). We also previously demonstrated that membrane sphingomyelin (SM) content is higher in agLDL‐exposed VSMC than in control cells. The main enzymes regulating cellular SM content are the family of sphingomyelinases (Smases) that hydrolize SM to phosphorylcholine and ceramide (CER). Objectives: We wished to investigate whether agLDL has the ability to modulate acidic‐ (A‐) and neutral (N‐) Smase activity and whether or not this effect is related to the upregulatory effect of agLDL on Rho A translocation and TF activation in human VSMC. Methods and Results: By measuring generated [¹⁴C]‐phosphorylcholine, we found that agLDL significantly decreased A‐Smase and specially N‐Smase activity. Pharmacological Smase inhibitors increased Rho A and TF. Specific loss‐of‐function of A‐Smase or N‐Smase 1 (N1‐Smase) by siRNA treatment (500 nmol L^?1, 12 hours) dramatically increased membrane Rho A protein levels (5‐ and 3‐fold, respectively). Concomitantly, TF protein expression and TF procoagulant activity were also increased. Inhibition of A‐Smase or N‐Smase activity by agLDL, siRNA‐anti A‐ or N1‐Smase or pharmacological treatment significantly increased the SM content of vascular cells. The inhibition of SM synthesis by fumonisin B₁ (FB₁) prevented the upregulatory effect of agLDL on TF. Conclusions: These results demonstrate that inhibition of both A‐ and N1‐Smase might explain the upregulatory effect of agLDL on TF activation, and suggest that this effect is related, at least in part, to membrane SM enrichment.     

Immunoglobulin and T cell receptor gene rearrangements in human lymphoma and leukemia

DNA samples from blood leukocytes or tumor biopsies of 45 patients with phenotypic B or T cell neoplasms were analyzed for rearrangements of the immunoglobulin (Ig) or T cell receptor (TCR) genes by Southern blot hybridization analysis. Rearrangements of the Ig heavy chain joining region genes (JH) were present in DNA from each of 28 B cell lymphomas and leukemias; 14 of 21 of these tumors also had rearrangements of the Ig kappa light chain joining (JK) or deleting element (KDel) genes. Conversely, 16 of 17 T cell lymphomas and leukemias had rearranged TCR beta chain genes. One B cell and one T cell tumor had rearrangements of both Ig and TCR genes. There was a strong correlation between the rearrangements of specific genes and the immunophenotype of the tumor: JH rearrangement without TCR beta chain rearrangement occurred only in B cell tumors; TCR beta chain rearrangement with or without JH rearrangement occurred only in T cell tumors, with one exception; and JK and KDel rearrangements were found only in B cell tumors. Thus, rearrangements of the Ig heavy and light chain genes and the TCR beta chain genes were found to be highly sensitive markers of monoclonal human lymphomas and lymphoid leukemias, with the type of gene rearrangements well correlated with the cell lineage of these neoplasms.