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Biomedical subjects

J Goldman

Publications and source records attributed to J Goldman.

At least 55 records · Page 3Linked to original sources
PubMed2000

A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation.

Busulfan has been previously only available in an oral formulation due to its poor water solubility. We report the results of a phase I study of multiple escalating doses of intravenous busulfan (Spartaject Busulfan, Orphan Europe, Paris, France) for myeloablation prior to stem cell transplantation (SCT) in 12 patients with chronic myeloid leukemia, acute myeloid leukemia or acute lymphocytic leukemia. One patient received allogeneic SCT; the other 11 patients received autologous SCT. The first six patients received i.v. busulfan diluted in 50 ml of 0.9% normal saline and the last six patients received busulfan in a 500-ml 5% dextrose solution. All patients experienced profound myelosuppression and all but one demonstrated hematopoietic engraftment. Toxicity was mild or moderate and there were no toxic deaths attributable to busulfan. Of note, there were no cases of veno-occlusive disease of the liver. Busulfan plasma concentrations were determined by gas chromatography with electron capture detection and showed little intrapatient variability. In most cases there was no significant difference between the first and last dose PK parameters. These data suggest that dose adjustment based on first dose PK data could allow uniformity of busulfan dosing for patients receiving SCT.

Acute Disease↗
PubMed2000

High-dose busulphan alone as cytoreduction before allogeneic or autologous stem cell transplantation for chronic myeloid leukaemia: a single-centre experience.

Transplant-related morbidity and mortality remain a major problem following stem cell transplantation (SCT). The use of high-dose single-agent busulphan before allogeneic or autologous SCT may be a reasonable compromise between maintaining cytoreductive efficacy and minimizing toxicity in patients with chronic myeloid leukaemia (CML). Seventy patients with CML have received busulphan as the only cytoreductive therapy before SCT on 79 occasions. The probability of survival of the 14 allogeneic recipients (all of whom were undergoing a second transplant from the original donor) was 78% at 5 years. Sixty-five autologous SCT were performed in 56 patients, of whom 40 were in late chronic phase. The actuarial 3-year post-autograft survival was 54% for these 56 first autografts. For patients in chronic phase, the 3-year survival was 76% compared with 30% at 2 years for those with advanced phase disease. Busulphan therapy was well tolerated, and except for mild mucositis little toxicity was experienced. None of these patients developed hepatic veno-occlusive disease (VOD). Nine patients (one allogeneic and eight autologous recipients) received several doses of an intravenous formulation of busulphan with very low toxicity. High-dose busulphan alone appears sufficient to provide adequate cytoreduction and immunosuppression in second allogeneic transplants and is also effective as cytoreduction before autologous SCT in patients with CML.

Adolescent↗
PubMed2000

A prospective trial of telepathology for intraoperative consultation (frozen sections).

Telepathology is a maturing technology that, for a variety of reasons, has not been widely deployed. In addition, clinical validation is relatively modest compared with accepted telemedicine applications such as teleradiology. A prototype telepathology system (Tele-Path(sm)) featuring high-resolution images selected from a remote microscope site has been developed at the University of Alabama at Birmingham (UAB). To validate the diagnostic efficacy of the system, a prospective study was undertaken of parallel diagnoses by conventional microscopy and telepathology with a remotely operated microscope. Slides from 99 intraoperative consultations from 29 tissue/ organ sites in the University of Alabama Hospitals by 9 academic pathologists were used in the study. Each microscopic and telepathology diagnosis was compared with the final diagnosis rendered by a referee pathologist. Diagnoses were classified as correct, false positive, or false negative or classification error. Of the 99 frozen sections evaluated, 3 cases were deferred. Of the remaining 96 cases, 2 received incorrect diagnoses in both the microscopic and telepathology arms of the study. Three errors occurred only in the telepathology arm. There was 1 false-positive diagnosis, 1 false-negative diagnosis, and 1 classification error. Statistical analysis indicated no significant difference between telepathology and conventional microscopy. Qualitative data indicated that the pathologists were generally satisfied with the performance of the system. Telepathology using this system paradigm is sufficiently accurate for real time utilization in a complex surgical environment. Telepathology therefore may be an effective model to support the surgical services of hospitals lacking full-time pathology coverage, resulting in full-time access to anatomic pathology services.

Diagnostic Errors↗
PubMed2000

Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease.

Hereditary canine spinal muscular atrophy (HCSMA) features rapidly progressive muscle weakness that affects muscles in an apparent proximal-to-distal gradient. In the medial gastrocnemius (MG) muscle of homozygous HCSMA animals, motor unit tetanic failure is apparent before the appearance of muscle weakness and appears to be presynaptic in origin. We determined whether structural changes in neuromuscular junctions or muscle fibers were apparent at times when tetanic failure is prevalent. We were surprised to observe that, at ages when motor unit tetanic failure is common, the structure of neuromuscular junctions and the appearance of muscle fibers in the MG muscle were indistinguishable from those of symptom-free animals. In contrast, in more proximal muscles, many neuromuscular junctions were disassembled, with some postsynaptic specializations only partially occupied by motor nerve terminals, and muscle fiber atrophy and degeneration were also apparent. These observations suggest that the motor unit tetanic failure observed in the MG muscle in homozygous animals is not due to synaptic degeneration or to pathological processes that affect muscle fibers directly. Together with previous physiological analyses, our results suggest that motor unit failure is due to failure of neuromuscular synaptic transmission that precedes nerve or muscle degeneration.

Animals↗
PubMed2000

Short Report: Engraftment of T-cell-depleted allogeneic haematopoietic stem cells using a reduced intensity conditioning regimen.

Graft-versus-host disease (GVHD) remains a significant complication in patients undergoing allogeneic stem cell transplantation (SCT) using a reduced intensity conditioning regimen. Although T-cell depletion (TCD) reduces the risk of GVHD after a myeloablative conditioning regimen, it is associated with an increased risk of graft failure. We have therefore examined whether TCD compromises engraftment using a fludarabine-based conditioning regimen. Fifteen patients have been transplanted using such a regimen of whom 13 underwent ex vivo TCD. All but one patient demonstrated durable engraftment and no patient receiving a TCD product developed severe GVHD. Thus, TCD may play a role in GvHD prophylaxis using such regimens.

Adult↗
PubMed1999

Identification of three HLA-A*0201-restricted cytotoxic T cell epitopes in the cytomegalovirus protein pp65 that are conserved between eight strains of the virus.

The Ag specificity of the CTL response against CMV is directed almost entirely to a single CMV tegument protein, the phosphoprotein pp65. We report the identification of three peptides derived from the protein pp65 that displayed a high or intermediate binding to HLA-A*0201 molecules, which were also able to induce an in vitro CTL response in peripheral blood lymphocytes from CMV seropositive individuals. The peptide-specific CTLs generated were capable of recognizing the naturally processed pp65 either presented by CMV-infected cells or by cells infected with an adenovirus construct expressing pp65 in an HLA-A*0201-restricted manner. Thus, we were able to demonstrate responses to subdominant CTL epitopes in CMV-pp65 that were not detected in polyclonal cultures obtained by conventional stimulations. We also found that the amino acid sequences of the three peptides identified as HLA-A*0201-restricted CTL epitopes were conserved among different wild-type strains of CMV obtained from renal transplant patients, an AIDS patient, and a congenitally infected infant, as well as three laboratory strains of the virus (AD169, Towne and Davis). These observations suggest that these pp65 CTL peptide epitopes could potentially be used as synthetic peptide vaccines or for other therapeutic strategies aimed at HLA-A*0201-positive individuals, who represent approximately 40% of the European Caucasoid population. However, strain variation must be taken in consideration when the search for CTL epitopes is extended to other HLA class I alleles, because these mutations may span potential CTL epitopes for other HLA molecules, as it is described in this study.

Antigen Presentation↗
PubMed1999

Leukoencephalopathy and raised brain lactate from heroin vapor inhalation ("chasing the dragon")

BACKGROUND: Inhalation of heated heroin vapor ("chasing the dragon"), which is gaining popularity among drug users seeking to avoid the risks of parenteral drug administration, can produce progressive spongiform leukoencephalopathy. METHODS: We studied the clinical phenotype and course, MRI, MRS, and brain pathology in the first American patients described with this syndrome. RESULTS: Two of the three heroin users studied inhaled heroin pyrolysate together daily over the course of 2 weeks. They developed ataxia, dysmetria, and dysarthria. Patient 1 progressed to an akinetic mute state with decorticate posture and subsequent spastic quadriparesis. Patient 2 developed a mild spastic quadriparesis and gait freezing. Patient 3 was asymptomatic following less heroin exposure. Brain MRI showed diffuse, symmetrical white matter hyperintensities in the cerebellum, posterior cerebrum, posterior limbs of the internal capsule, splenium of the corpus callosum, medial lemniscus, and lateral brainstem. MRS showed elevated lactate. Brain biopsy (Patient 1) showed white matter spongiform degeneration with relative sparing of U-fibers; electron microscopy revealed intramyelinic vacuolation with splitting of intraperiod lines. Progressive deterioration occurred in Patients 1 and 2 over 4 weeks. Both were treated with antioxidants including oral coenzyme Q, and clinical improvement occurred. Patient 1 recovered nearly completely over 24 months. Patient 2 improved, but developed a delayed-onset cerebellar hand tremor. Both still have white matter abnormalities on MRI and MRS. CONCLUSIONS: Elevated lactate in white matter and the possible response to antioxidants suggests mitochondrial dysfunction in progressive spongiform leukoencephalopathy following inhalation of heated heroin vapor.

Administration, Inhalation↗
PubMed1999

Intensive plasma exchange for severe autoimmune hemolytic anemia in a four-month-old infant.

We report the smallest infant (7.5 kg) to receive intensive plasma exchange (52 PEs) therapy as treatment of autoimmune hemolytic anemia (AIHA). PE temporarily reduces circulating autoantibody levels and can be an effective adjunctive therapy with corticosteroids and cytotoxic drugs or other immuno-suppressants. Although his clinical course was prolonged and complicated by cytomegalovirus infection with spontaneous perforation of his colon, his recovery was complete. He has remained healthy for more than 2 years. Because of his small size, calcium gluconate was added to replacement fluids and calcium levels closely monitored. The apheresis machine and tubing were routinely primed with red blood cells and FFP substituted for 5% human albumin during the second half of all procedures to maintain adequate levels of procoagulant. Our experience suggests that intensive PE is helpful in controlling severe AIHA and should be considered even for very small patients.

Adrenal Cortex Hormones↗
PubMed1999

Improvement of depression following transcranial magnetic stimulation.

Psychiatry as a field was transformed by the discovery and introduction of electroconvulsive therapy (ECT) as a treatment in the early part of this century. ECT demonstrated that depression was a disease of the brain and that it could be treated with a direct brain intervention. Psychiatry's evolution continued in 1958 with the discovery of the antidepressant activity of the monoamine oxidase inhibitors. Interestingly, although the area of neuropsychopharmacology has continued to advance, the realm of physical somatic interventions in psychiatry has lagged behind. With perhaps the exception of light therapy, there were no advances in somatic interventions in psychiatry. However, in 1985, Barker et al. developed a brief high intensity electromagnet capable of depolarizing cortical neurons, called transcranial magnetic stimulation (TMS). There has been much interest in the past 10 years in whether TMS might have antidepressant actions, similar to ECT but without causing a seizure and with no apparent cognitive side effects. This review examines the basic principles underlying TMS, and describes how TMS differs from electrical stimulation and the other uses of magnets.

Cerebral Cortex↗
PubMed1999

Donor lymphocyte infusions.

The infusion of lymphocytes from the original marrow donor (donor lymphocyte infusions [DLI]) is remarkably effective in treating chronic myeloid leukemia in relapse after allogeneic stem cell transplantation. DLI are less effective in acute leukemia and other hematologic tumors, but the use of interleukin-2 in conjunction with DLI after allograft may increase the response rate. The use of DLI to treat certain solid tumors is under investigation. In contrast, the value of donor lymphocytes for treating infectious complications post-transplant and graft failure has been established. The major drawback of DLI remains graft-versus-host disease, but novel regimens of administration and/or selective manipulation of donor cells prior to infusion have reduced its incidence. Further progresses in this area will help to establish the role of nonmyeloablative conditioning for allografting.

Bone Marrow Transplantation↗