Haemopoietic growth factors.

Haemopoietic growth factors are involved in the production of the various blood cells from progenitors in the bone marrow, making them useful in a range of clinical situations. The genes for several of them have been cloned and their production engineered by recombinant technology, making them widely available. Myeloid growth factors are used to support patients in the aftermath of chemotherapy and bone marrow transplantation and have potential application in the treatment of infectious diseases. Erythropoietin is widely used for patients with anaemia due to failure of marrow production, having established its effectiveness in chronic renal failure. Thrombopoietin has recently been described and may provide a means to alleviate thrombocytopenia. Current indications and areas of recent reappraisal are addressed in this review.     

von Willebrand factor as a marker of endothelial cell activation following BMT.

Endothelial cell activation may play a role in thrombotic complications of BMT such as hepatic veno-occlusive disease (VOD), right atrial line thrombosis and microangiopathic haemolysis. To assess this, von Willebrand factor antigen (vWF:ag) was measured in 72 patients (25 allografts, 46 autografts and one syngeneic) during the first 6 weeks post-transplant. There was a significant rise in vWF:ag in both allografts and autografts but a greater increase was seen in the allografts. The changes in vWF:ag did not correlate with changes in C reactive protein showing that this was not merely an acute phase response. vWF multimers were normal in a subgroup of uncomplicated transplants showing that there was no large scale endothelial cell disruption. Patients with VOD did not have changes in vWF:ag that were consistently different from uncomplicated controls. Three of four patients who developed line thrombosis had higher levels of vWF:ag compared with control groups; multimeric structure of the vWF was again normal. These results show that there is endothelial cell activation post-BMT and that this is greater in allografts compared with autografts, thus suggesting a possible mechanism for the higher incidence of VOD in this group. There were no useful predictive markers of VOD or thrombosis in individual patients.     

Drug effects on an effortful operant: pentobarbital and amphetamine

The behavioral effects of amphetamine and pentobarbital depend upon the conditions maintaining behavior. For example, amphetamine usually decreases the rate of operant behavior maintained by fixed ratio schedules while pentobarbital either increases it or leaves it unaffected. However, when considerable exertion is required, as in situations that require endurance, amphetamine tends to enhance performance while barbiturates degrade it. These differences complicate predictions of the effects of these two drugs on effortful operants. The present experiment was designed to characterize effortful responding behaviorally and pharmacologically. Cebus monkeys were trained to operate a lever by flexing their arms and extending their legs; this response exerted a force approximating their body weight. This operant was maintained by a multiple fixed ratio fixed interval (Mult FR FI) schedule. The two schedules maintained dramatically different response patterns. The FR schedule maintained vigorous, high rate responding characterized by a narrow IRT distribution centered at 0.5 sec. The FI schedule maintained very low overall rates of responding characterized by a variable IRT distribution with a median of 1.5 to 2 sec. Despite very low rates of responding during the FI component, no consistent rate increases appeared after amphetamine, and 0.3 mg/kg eliminated responding altogether. Pentobarbital increased overall rate but also shifted the interresponse time (IRT) distribution toward longer IRTs. The increase in overall rate arose from an earlier onset of responding during the FI component and occurred simultaneously with response slowing. The present studies do not support suggestions of a generalized enhancement of effortful performance by amphetamine or a generalized degradation by pentobarbital.     

Mutations in different functional domains of the human muscle acetylcholine receptor alpha subunit in patients with the slow-channel congenital myasthenic syndrome

Congenital myasthenic syndromes are a group of rare genetic disorders that compromise neuromuscular transmission. A subset of these disorders, the slow-channel congenital myasthenic syndrome (SCCMS), is dominantly inherited and has been shown to involve mutations within the muscle acetylcholine receptor (AChR). We have identified three new SCCMS mutations and a further familial case of the alpha G153S mutation. Single channel recordings from wild-type and mutant human AChR expressed in Xenopus oocytes demonstrate that each mutation prolongs channel activation episodes. The novel mutations alpha V156M, alpha T254I and alpha S269I are in different functional domains of the AChR alpha subunit. Whereas alpha T254I is in the pore-lining region, like five of six previously reported SCCMS mutations, alpha S269I and alpha V156M are in extracellular domains. alpha S269I lies within the short extracellular sequence between M2 and M3, and identifies a new region of muscle AChR involved in ACh binding/channel gating. alpha V156M, although located close to alpha G153S which has been shown to increase ACh binding affinity, appears to alter channel function through a different molecular mechanism. Our results demonstrate heterogeneity in the SCCMS, indicate new regions of the AChR involved in ACh binding/channel gating and highlight the potential role of mutations outside the pore-lining regions in altering channel function in other ion channel disorders.      

Amyloid deposits in lymph nodes: A morphologic and immunohistochemical study

In a series of approximately 80,000 lymph nodes, amyloid deposition was found in 18; 12 of those nodes were selected, on the basis of availability of specimens, for investigation by immunohistochemical typing to identify the protein of origin and by correlation with morphologic criteria and clinical information. Four patterns of amyloid deposition were identified: lymph node vessel involvement, follicular deposition, diffuse deposition, and a combination of follicular and diffuse deposition. All cases were classified immunohistochemically with the amyloid type-specific antisera anti-AA, anti-A lambda, anti-A kappa, anti-ASc1, and anti-AF. Immunoglobulin-derived protein (AL) in lymph nodes was found in every case of isolated amyloidosis, lymphoplasmacytic/lymphoplasmacytoid immunocytoma, plasmacytoma, and idiopathic amyloidosis. Among the cases of AL amyloidosis were nine of A lambda and one of the A kappa type. AA protein was present in two cases of reactive systemic amyloidosis. There was no useful morphologic correlation with the immunohistochemically identified amyloid types.     

Colorectal polyps in an Australian population. A histological and immunohistochemical study

The histology and immunohistochemistry of 896 polyps and other focal epithelial abnormalities detected macroscopically in 86 surgical resections from patients with colorectal adenocarcinoma and benign bowel disorders were studied. The lesions identified included 177 adenomas, 387 hyperplastic (metaplastic) polyps, and 202 non-neoplastic polyps designated 'focal cryptal hyperplasia'. Numbers of both neoplastic and non-neoplastic polyps were significantly increased in resections for carcinoma, with 72 per cent of all polyps in right and 10 per cent in left hemicolectomy specimens being neoplastic. Thirty per cent of adenomas were less than 2 mm in diameter and 6 per cent larger than 10 mm. Observations on polyp size, number, distribution, histological appearance, and antigenic composition suggested that focal cryptal hyperplasia evolves into the hyperplastic polyp. In doing so, there is loss of expression of a tissue specific antigen. Hyperplastic polyps were significantly larger in colons with adenoma than in those without.     

Involvement of antioxidant enzymes in multiple-drug resistance in a human T-lymphoblastic leukemia-cell line which over-expresses p-glycoprotein

We have compared the specific activities of Cu/Zn superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in a vinblastine sensitive human T-lymphoblastic cell line (CCRF-CEM) and its multiple drug resistant (MDR) counterpart cell line (CEM/VLB100), which over-expresses P-glycoprotein (PGP). We have found that the specific activity Cu/Zn SOD was consistently 38% increased in CEM/VLB100 cells compared with CCRF-CEM cells. In contrast, the activities of CAT and GSH-Px were similar in the two cell lines. These results suggest that MDR in CEM/VLB100 is a complicated phenotype which not only involves a PGP mechanism, but also a SOD protection mechanism against drug-mediated O2.- cytotoxicity.