Glutamate in neurologic diseases

Excitotoxicity has been implicated as a mechanism of neuronal death in acute and chronic neurologic diseases. Cerebral ischemia, head and spinal cord injury, and prolonged seizure activity are associated with excessive release of glutamate into the extracellular space and subsequent neurotoxicity. Accumulating evidence suggests that impairment of intracellular energy metabolism increases neuronal vulnerability to glutamate which, even when present at physiologic concentrations, can damage neurons. This mechanism of slow excitotoxicity may be involved in neuronal death in chronic neurodegenerative diseases such as the mitochondrial encephalomyopathies, Huntington's disease, spinocerebellar degeneration syndromes, and motor neuron diseases. If so, glutamate antagonists in combination with agents that selectively inhibit the multiple steps downstream of the excitotoxic cascade or help improve intracellular energy metabolism may slow the neurodegenerative process and offer a therapeutic approach to treat these disorders.     

Neonatal immune neutropenia following the administration of intravenous immune globulin

Liver flukes Fasciola hepatica and Fasciola gigantica are polymorphic and vary morphologically depending upon the host being parasitized. It is known also that mixed infection occurs where both species are present. A technique involving protein separation was used to distinguish the 2 species. Isoelectric focusing of soluble proteins was performed on polyacrylamide gels using whole-body proteins from adult flukes. Although many bands appeared common to both species and some were shared with host tissues, the banding patterns could be used to distinguish 1 species from the other. Soluble protein isoelectric focusing is simple, reproducible, and has very good resolution. It seems well suited to the differentiation of the 2 fluke species.     

Intravenous immunoglobulin as sole therapy for systemic vasculitis

High-dose, pooled, i.v. immunoglobulin (IVIg) is a potential, alternative treatment for Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) which has shown promise in the treatment of refractory disease when administered with continuing immunosuppression. This study of six new patients with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis and early disease, without threatened vital organ function, examined the therapeutic response to treatment with IVIg alone. IVIg was well tolerated and all six patients had early reductions in disease activity. Four entered full, clinical remission which lasted for at least 1 yr, while in two the responses were partial and transient, and they subsequently required conventional treatment. After 16-48 months of follow-up, two of the four patients in full remission relapsed, but the other two have remained well.     

Passive immune globulin therapy in the SIV/macaque model: early intervention can alter disease profile

In this study, we investigated the impact of recombinant interleukin-2 (rIL-2) after high dose chemotherapy and autologous bone marrow transplantation (ABMT) in 25 patients with refractory or relapsed Hodgkin's disease (HD) (11 patients) and non Hodgkin's lymphoma (NHL) (14 patients). 48% of patients had resistant disease, 84% achieved complete remission after ABMT. rIL-2 was started at a median of 54 days post-transplant and consisted of a first cycle of 5 days followed by 4 cycles of 2 days every other week. Patients received a mean of 160 x 10(6) IU/m2 rIL-2 and hematological toxicity was moderate and transient. None of the 5 evaluable patients with measurable disease responded to rIL-2. After a 5 year median follow-up, the probability of survival and DFS is 72% (HD: 73% and NHL: 70%, p = NS) and 45% (HD: 36% and NHL: 48%, p = NS) respectively. These somewhat encouraging results warrant further evaluation of rIL-2 after ABMT in controlled studies, especially in NHL patients stratified for previous chemosensitivity.     

Progressive vaccinia treated with ribavirin and vaccinia immune globulin

A 67-year-old man with metastatic melanoma and chronic lymphocytic leukemia was inadvertently given a vaccinia melanoma oncolysate vaccination. He developed progressive vaccinia at the site of inoculation. The lesion started to heal only when he was treated with ribavirin. Vaccinia immune globulin was administered and appeared to help control the initial lesion and limit the development of satellite lesions.     

Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature

Over the past decade, intravenous immune globulin therapy (IVIG) has gained widespread use for a variety of clinical disorders. IVIG treatment is associated with a number of complications, including acute renal failure (ARF). Although the cause of IVIG-associated ARF is unknown, it may be related to the stabilizing agent used in the IVIG preparation. The development and resolution of ARF is typically rapid, but is some cases recovery may be delayed and require renal replacement therapy. In such patients, recurrence of ARF may be avoided by selection of a preparation with a different stabilizing agent. Two cases of IVIG-induced ARF are described, and all reported cases are analyzed to assess the probable mechanism of renal injury.     

Prevention of hepatitis type B with specific immune serum globulin

In order to evaluate the preventive value of specific immune serum globulin against hepatitis type B, we have used this immune globulin in required doses in 12 patients (10 with AU antigen negative and 2 with AU antigen positive) with chronic renal failure who required maintenance hemodialysis for a period of 15 months, and we were able to prevent hepatitis type B in our dialysis patients.     

Towards gene therapy for renal diseases

The rationale of the somatic gene therapy is the correction of diseases at the most fundamental level. Ideal gene therapy should be achieved by the replacement of the wrong gene sequence of genome with correct one. However, the gene technology to date is yet immature so as to correct the wrong gene sequence in vivo. Potentially, the present technology of gene transfer may provide: 1) correction of cellular dysfunction by expressing the deficient gene; 2) addition of new function for a cell by transferring an exogenous gene; 3) inhibition of unfavorable action of a cell by introducing a counteracting gene. In nephrology, the gene transfer targeted kidney has been challenged at the experimental level. HVJ-liposome method and recombinant adenovirus allow gene transfer to the particular cells in kidney in vivo. Ex vivo gene transfer using mesangial cells and macrophages are another option. Transplant kidney is also a good material for genetic engineering. The potential application of gene transfer is enormous while the therapeutic application have just begun to explored. We have been devoted to HVJ-liposome mediated gene transfer to the kidney and successfully demonstrated the suppression of the extracellular matrix accumulation of the glomeruli in the experimental glomerulonephritis through inhibition of the TGF-beta action by antisense oligonucleotides or soluble type receptor chimera for TGF-beta. We also applied this technology to the inhibition of interstitial fibrosis in unilateral ureter obstruction model. The new HVJ-liposome method improved in lipid composition allows gene transfer to tubulointerstitial fibroblast by retrograde approach from ureter. In consequence, introduced TGF-beta antisense suppressed the TGF-beta mRNA in concomitant with ameliorating interstitial fibrosis. We believe that the gene transfer technique will become common strategy to study the molecular aspect of the renal diseases and will be possibly applicable to molecular intervention in nephrology.     

Intravenous theophylline therapy: nomogram guidelines

We evolved a nomogram for guiding and standardizing intravenous theophylline therapy in hospitalized patients. It provides rapid calculation of a loading dose based on body weight and previous therapy and a maintenance infusion rate related to three categories of expected metabolic activity. The guidelines were prospectively used in the treatment of 72 patients, mainly in a respiratory care unit. The nomogram was successfully used to attain near-steady-state serum concentrations in the therapeutic range of 8 to 20 mg/litre in 72% of patients, with only two patients outside of the range of 5 to 25 mg/litre. These guidelines facilitate initial theophylline dosage in older patients with liver and cardiac disease and provide a rational basis for interpreting serum concentration measurements and adjustment of drug therapy.     

Intravenous immunoglobulin therapy for recurrent spontaneous abortion: a meta-analysis

The aim of this paper was to identify the mechanism/s responsible of the antimetastatic effect of a single low dose of cyclophosphamide (Cy), previously demonstrated by us in the rat lymphoma LTACB. No direct cytotoxic antimetastatic activity of Cy could be proved. In vitro treatment of L-TACB cells with mafosfamide did not alter their invasiveness or their motility. The adoptive transfer of splenocytes from Cy-treated tumor-bearing rats, together with L-TACB cells inhibited their metastatic growth. The single low dose Cy treatment of T-immunodeficient nude mice did not show the antimetastatic effect on L-TACB observed in immunocompetent mice. An inhibition of the metastatic ability due to immunomodulation by Cy is proposed.     

Intravenous gammaglobulin has no advantages over oral corticosteroids as primary therapy for adults with immune thrombocytopenia: a prospective randomized clinical trial

Symptomatic immune thrombocytopenia in adults is potentially lethal, and, when conventionally treated with oral corticosteroid agents, approximately two thirds of patients will have some response in platelet count, but this is seldom durable. Since cytotoxic drugs are of limited benefit at this stage, splenectomy becomes necessary in 70% of patients. Intravenous gammaglobulin has been advocated as an alternative to prednisone as the primary form of treatment. A prospective, randomized comparison was carried out between oral prednisone (1 mg/kg/day; group 1; n = 17), high-dose intravenous gammaglobulin (400 mg/kg on days 1 through 5; group 2; n = 13), or a combination of both agents given on the same schedule (group 3; n = 13). The groups were well matched clinically and hematologically. No mortality occurred after initiating therapy, but one patient experienced a cerebrovascular accident. Response, defined as a platelet count greater than 50 x 10(9)/L, was achieved in 82%, 54%, and 92% of patients in groups 1, 2, and 3, respectively, but was only significant between groups 2 and 3 (P = 0.0365). The median times to peak platelet counts were 8.5 days (range 7 to 21 days), 7 (range 5 to 10 days), and 7 (range 3 to 23 days), respectively. Although there was a trend in favor of the steroid-administered groups, relapse was not significantly different, which occurred at a median of 184, 32, and 76 days, respectively, nor was the average time to splenectomy different at 339, 59, and 98 days, respectively. At a minimum of 2 years of follow-up, 5 of 17 in group 1, 2 of 13 in group 2, and 1 of 13 in group 3 had achieved platelet counts of greater than 100 x 10(9)/L and, therefore, did not require splenectomy. In contrast, where this indication was present for failure to respond, 8 of 12 (67%) in group 1, 4 of 8 (50%) in group 2, and 9 of 12 (75%) in group 3 remain in complete remission. Significantly more patients in group 2 than group 3 experienced a relapse (P = 0.0365). It is concluded that in previously untreated adults with symptomatic immune thrombocytopenia, gammaglobulin offers no advantage over conventional corticosteroid administration as the primary form of therapy. Additionally, more intense immunosuppression, resulting from the use of both agents combined, is no better than single agent corticosteroid agents and appears to be an unnecessary and unwarranted expense.