Biomedical subjects
Publications and source records attributed to M Pless.
Sixty-one consecutive patients with locally advanced inoperable non-small-cell lung cancer were treated with chemoradiation with 60 Gy and concomitant daily low-dose cisplatin (6 mg/m(2)) in a single uninterrupted course. Toxicity was mild, 80% of patients were treated as outpatients. The median survival of 70 weeks compares favorably to the literature.
The predictive value of daily C-reactive protein (CRP) monitoring to distinguish causes of fever in neutropenic patients was studied retrospectively. A total of 143 fever episodes during 113 consecutive hospitalizations were studied in 71 patients who had been referred for chemotherapy or haemopoietic stem cell transplantation (HSCT). There were, on average, 1.3 fever episodes per hospital stay, attributed to: infection (55, 27 invasive bacterial, 5 fungal, 3 viral and 20 probable infections); acute graft vs host disease (GvHD) (20); drugs (22); transfusions (7); and not attributable (39). 130 (91%) fever episodes were accompanied by a rise in CRP, 6 (4%) episodes were fatal. Maximal CRP levels (CRPmax) and maximal temperature (Tmax) were higher in invasive bacterial infections than in aGvHD and higher in aGvHD than in drug- or transfusion-related fever (p < 0.0001). Temperature and CRP rose in parallel. A total of 16 patients developed grade II-IV aGvHD by day 11 (9-21) (median, range) after allogeneic HSCT. Acute GvHD was preceded by fever for 3 d (1-7), and by CRP increase for 5 d (0-15) (p < 0.0001). CRP monitoring may be useful to distinguish between causes of fever. Very high CRP levels tend to be associated with invasive bacterial infections. CRP is not an early warning sign. An increase in CRP and fever may precede other clinical manifestations of aGvHD.
A retrospective chart review was performed for identification of patients with isolated internuclear ophthalmoplegia (INO) postcardiac catheterization from two neuro-ophthalmology units. Of the 110 patients with a diagnosis of INO who were evaluated during the observation period, five patients (4.5%) demonstrated relatively isolated INO occurring in the perioperative period of a cardiac endovascular procedure. These five patients underwent diagnostic catheterization alone (three patients), balloon angioplasty (one patient), or stent placement (one patient). All patients improved, with resolution of diplopia in primary position after a mean period of 82 days. The occurrence of INO in the postcardiac catheterization setting is not uncommon, and it appears to be related to dorsal pontine ischemia. The pontomesencephalic medial longitudinal fasciculus is supplied by small-caliber perforating end-arteries from the basilar trunk, which increases selective vulnerability of this area. Cardiac catheterization may precipitate microemboli involving these vessels, leading to internuclear ophthalmoplegia.
OBJECTIVE: To determine whether the diagnostic sensitivity of bilateral temporal artery biopsy is superior to that of unilateral biopsy in cases of suspected temporal arteritis. MATERIALS AND METHODS: A retrospective analysis of the results of 60 bilateral temporal artery biopsies examined in an ophthalmic pathology laboratory. RESULTS: The histopathologic diagnosis in 13% of the biopsy pairs was discordant. There was a 5% chance of obtaining a positive biopsy result on the side opposite an initially negative biopsy result. CONCLUSIONS: Bilateral temporal artery biopsy is 5% more likely than unilateral biopsy to detect the characteristic histopathologic findings in patients with temporal arteritis.
Induction of pleurodesis offers benefit for patients with metastatic tumors and symptomatic malignant pleural effusions, but the best method for achieving this is still unknown. In this prospective, randomized comparison of two well-established pleurodesis procedures, 36 patients with malignant pleural effusions, expanded lungs after drainage, and expected survival of > 1 mo received either bleomycin instillation (60E) via a small-bore thoracostomy tube or thoracoscopic talc poudrage (5 g) under local anesthesia. Efficacy, safety, and cost could be evaluated for 32 treatments (17 bleomycin, 15 talc) in 31 patients. Recurrence rates of effusion with bleomycin and talc poudrage after 30 d were 41% and 13% (p = 0.12), respectively, those after 90 d were 59% and 13%, respectively (p = 0.01), and those after 180 d were 65% and 13% (p = 0.005), respectively. Neither procedure showed any major adverse effect, and both were equally well tolerated. Cost estimation favored thoracoscopic talc poudrage, both for the initial hospitalization and with regard to recurrences. In conclusion, thoracoscopic talc pleurodesis under local anesthesia is superior to bleomycin instillation for pleurodesis in cases of malignant pleural effusion.
The purpose of this study was to determine whether group motor skill intervention is an effective form of treatment when added to consultative services in 5- to 6-year-old children with developmental coordination disorder (DCD). An experimental group of DCD children (n = 17) was compared with a DCD control group without intervention (n = 20). The intervention was conducted once a week for 10 weeks. No significant differences between the groups in either Movement ABC motor test or the Movement ABC checklist were found before or after this intervention. When subgroups with different categories of motor difficulties were compared, significantly more children with borderline motor difficulties in the experimental group than in the control group had changed (improved) their category after intervention. It is concluded that children with definite motor difficulties do not benefit from this type of intervention. Future research should include comparison of well-defined subgroups of children with DCD.
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The potential of recombinant human (rh)Flt3 ligand (FL), alone or in combination with other recombinant growth factors, to mobilize peripheral blood precursor cells (PBPCs) was examined in an animal model. Adult outbred New Zealand White rabbits received subcutaneous injections daily for 14 days in a standardized protocol; whole blood cell counts and colony-forming unit-granulocyte/macrophage (CFU-GM) colonies were measured 3 times weekly during the injection period and for an additional observation period of 14 days. Two animals in each group were treated as follows: 200 or 500 microg/kg FL, 10 microg/kg granulocyte colony-stimulating factor (G-CSF), 10 or 75 microg/kg stem cell factor (SCF), 10 microg/kg G-CSF + 500 microg/kg FL, 10 microg/kg G-CSF + 75 microg/kg SCF + 500 microg/kg FL. Both G-CSF and FL induced a sustained and dose-dependent increase in the leukocyte count to a maximum of 5-fold. They were additive in combination, leading to a tenfold increase in white blood cell counts. No consistent pattern was observed for platelet counts or red blood cells. No toxic side effects were seen. Both G-CSF and FL mobilized CFU-GM in a dose-dependent fashion to a 59-fold increase for G-CSF and 116-fold for FL. Maximum mobilization occurred on day 4 with G-CSF and on day 11 with FL. G-CSF + FL in combination acted synergistically, inducing a 503-fold increase of CFU-GM over baseline. The addition of SCF to this combination did not alter leukocyte counts or CFU-GM mobilization. Our results indicate that FL is a potent and safe agent for the mobilization of PB-PCs and is synergistic with G-CSF.
Ectopic expression of the erythropoietin receptor (EpoR) in the interleukin-3 (IL-3)-dependent cell line Ba/F3 results in growth and partial erythroid differentiation in Epo. In contrast, introduction and activation of the interleukin-5 receptor (IL-5R) or of the granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) results in proliferation only. As this effect is specific to the EpoR, the role of its extracellular or cytoplasmic domain in differentiation was tested after construction of two chimeric receptors. One receptor contained the extracellular domain of EpoR fused to the endodomain of IL-3R beta-chain (E/beta), while the other contained the EpoR cytoplasmic region fused to the extracellular domain of GM-CSFR alpha-chain (GMER). Surprisingly, both receptors induced differentiation ruling out a strict specificity of the extracellular or cytoplasmic region of EpoR in this process. Instead the ability to signal differentiation correlated with structural features shared by the EpoR, GMER, and E/beta receptors. Dimerization of all three receptors results in the pairing of two signal transducing chains in the cytoplasm, in contrast to the mitogenic receptors IL-3R, IL-5R, GM-CSFR, which assemble as alphabeta heterodimers. Two new chimeric receptors that fulfilled the structural requirement exemplified by EpoR, but lacked any part of EpoR, were designed to consolidate this model. They consisted of the ectodomains of the GMR-alpha and IL-5R alpha, respectively, fused to the endodomain of IL-3R beta-chain. Both receptors were as effective as EpoR in signaling differentiation in response to their cognate ligand. Another property of receptors fulfilling these structural requirements is that they cause a marked delay in signal transducers and activators of transcription 5 (STAT5) activation on ligand stimulation. Taken together our studies show that structural assembly of receptors dictates their potential to signal erythroid differentiation in Ba/F3 cells, that differentiation can take place in the absence of Epo and that a delay in STAT5 activation is highly predictive of this process.
Cytokine receptors activate multiple signal transduction pathways, resulting in the induction of specific target genes. We have recently identified a hematopoietic cell-specific immediate-early gene, DUB-1, that encodes a growth-regulatory deubiquitinating enzyme. The DUB-1 gene contains a 112-bp enhancer element that is specifically induced by the beta c subunit of the interleukin-3 (IL-3) receptor. To investigate the mechanism of DUB-1 induction, we examined the effects of dominant-negative forms of JAK kinases, STAT transcription factors, and Raf-1 in transient transfection assays. In Ba/F3 cells, IL-3 induced a dose-dependent activation of DUB-1-luciferase (luc) and GAS-luc reporter constructs. A dominant-negative form of JAK2 (truncated at amino acid 829) inhibited the induction of DUB-1-luc and GAS-luc by IL-3. A dominant-negative form of STAT5 (truncated at amino acid 650) inhibited the induction of GAS-luc but not DUB-1-luc. A dominant-negative form of Raf-1 inhibited the induction of DUB-1-luc but had no effect on the induction of GAS-luc by IL-3. The requirement for JAK2 in the stimulation of the DUB-1 enhancer was further supported by the suppression of DUB-1 induction in Ba/F3 cells stably expressing the dominant-negative JAK2 polypeptide. We hypothesize that IL-3 activates a JAK2/Raf-1 signaling pathway that is required for DUB-1 induction and is independent of STAT5.
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OBJECTIVE: To describe patients with orbital apex masses involving the optic nerve who enjoyed spontaneous improvement in visual function without therapy. METHODS: A retrospective chart review of cases in an academic neuro-ophthalmology practice identified three cases of tumorous compression of the optic nerve in which there was spontaneous improvement in visual function. Each patient had undergone a full neuro-ophthalmologic evaluation, followed up with serial imaging. RESULTS: The first patient initially had a visual acuity of 2/200 and central visual field defects. Over a 4-year period, her visual acuity improved to 20/40 and her visual field expanded centrally. The second patient initially had a visual acuity of 20/40 and a cecocentral visual field defect. After a 4-year follow-up, her visual acuity had improved to 20/15 and her cecocentral defect had shrunk. The third patient had an initial visual acuity of 20/25, an afferent pupillary defect, and optic atrophy. Over a 2-year period she developed a paracentral scotoma and her visual acuity worsened to 20/30. In the next 2 years her visual acuity improved to 20/10 and her visual field normalized. CONCLUSIONS: In exceptional instances, visual dysfunction from tumorous compression of the optic nerve in the orbital apex may spontaneously improve. Clinicians who use the natural history of visual loss in differential diagnosis should be aware that spontaneous remission is compatible with the presence of tumor.
Cytokines regulate cell growth and differentiation by inducing the expression of specific target genes. We have recently isolated a cytokine-inducible, immediate-early cDNA, DUB-1, that encodes a deubiquitinating enzyme. The DUB-1 mRNA was specifically induced by the receptors for interleukin-3, granulocyte-macrophage colony-stimulating factor, and interleukin-5, suggesting a role for the beta common (betac subunit known to be shared by these receptors. In order to identify the mechanism of cytokine induction, we isolated a murine genomic clone for DUB-1 containing a functional promoter region. The DUB-1 gene contains two exons, and the nucleotide sequence of its coding region is identical to the sequence of DUB-1 cDNA. Various regions of the 5' flanking region of the DUB-1 gene were assayed for cytokine-inducible activity. An enhancer region that retains the beta c-specific inducible activity of the DUB-1 gene was identified. Enhancer activity was localized to a 112-bp fragment located 1.4 kb upstream from the ATG start codon. Gel mobility shift assays revealed two specific protein complexes that bound to this minimal enhancer region. One complex was induced by betac signaling, while the other was noninducible. Finally, the membrane-proximal region of human betac was required for DUB-1 induction. In conclusion, DUB-1 is the first example of an immediate-early gene that is induced by a specific subunit of a cytokine receptor. Further analysis of the DUB-1 enhancer element may reveal specific determinants of a betac-specific signaling pathway.
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A 39-year-old patient with severe aplastic anemia (AA), resistant to therapy, received recombinant human IL-3 (rhIL-3) on a phase I/II trial. During treatment she developed disseminated skin lesions, suggestive of vasculitis, and severe progressive peripheral neuropathy culminating in complete paralysis. She died 25 days after beginning treatment from profuse bleeding. On autopsy, evidence of vascular leaks with widespread bleeding and extensive hemorrhagic involvement of peripheral nerves was found. An additional feature was massive reactive erythrophagocytosis in lymph nodes, spleen and bone marrow. The coincidence between rhIL-3 administration and the dramatic events suggest a causal relation. As a possible pathogenic mechanism, an rhIL-3 induced excessive stimulation of macrophages and production of secondary cytokines such as tumor necrosis factor (TNF) is suggested. TNF is considered as a major factor in the development of both a vascular leak and reactive erythrophagocytosis. This case report can be regarded as an example of the possible unusual pathologic phenomena we may expect to see in the near future with increasing use of growth factors.
The radiologic investigation of the optic pathways has an integral part in the diagnostic evaluation of diverse lesions, such as inflammatory disease, vascular disorders, and benign and malignant tumors that afflict the optic pathways. These radiologic methods consist principally of computed tomography and magnetic resonance imaging, and, in vascular lesions, magnetic resonance angiography and conventional angiography.
The goal of this prospective randomized single-center study was the comparison of safety and efficacy of high-dose oral/intravenous fluconazole (400 mg daily) (group A) with oral nystatin plus miconazole inhalations (group B) in the prevention of fungal infections on a hemato-oncological isolation Ward. Of 157 patients admitted to the isolation ward during the study period only 90 (57%) were eligible for randomization; 22 (14%) had a fungal infection at admission. Of the 90 randomized patients, 89 were evaluable, 43 in group A and 46 in group B. The age, sex, diagnosis, planned therapy and risk factors for fungal infections at admission as well as the duration of neutropenia were in the same proportions in both groups. Oral thrush and mucocutaneous candidiasis were prevented in all patients of both groups, and 29 patients (32%: 17 in group A, 12 in group B) were discharged after successful prophylaxis (NS). Empiric amphotericin B was given according to predetermined criteria to 45 patients (51%: 23 group A, 22 group B; NS). Fluconazole significantly delayed the time before the start of intravenous amphotericin B. It was begun after a median of 10 days (0-45 days, range) of neutropenia below 0.5 x 10(9) granulocytes/l in group A and 7.5 days (0-26, range) in group B (P < 0.05). The duration of successful prophylaxis was significantly longer in group A (26 days median) than in group B (21 days, median) (P < 0.05). Systematic fungal infection was documented in 3 patients (1 group A, 2 group B; NS).
Mobilized peripheral blood precursor cells (PBPC) are used with increasing frequency to restore autologous hematopoiesis following high-dose radio-chemotherapy. The success of this method has aroused interest in the use of mobilized PBPC for allogeneic transplants. This approach would eliminate the need for marrow aspiration and general anesthesia. In this project we tested the feasibility of allogeneic histoincompatible PBPC transplants in rabbits. Adult outbred Red Burgundy rabbits were used as donors, histoincompatible New Zealand White rabbits of the opposite sex as recipients. One individual donor was used for one individual recipient. Conditioning consisted of 10 Gy total body irradiation (TBI). Donor animals were pre-treated with recombinant human granulocyte colony-stimulating factor (rh G-CSF) given s.c. at 10 micrograms/kg daily. Three schedules of PBPC collection and reinfusion were tested in 3 groups of animals, each consisting of 5 donor recipient pairs: (A) PBPC were collected either on days -2, -1 and 0, and infused at once after TBI on day 0; (B) collected and infused on days 0, +2, +4, +7, +9, and +11; (C) collected on 3 consecutive days, cryopreserved for 1 month and infused on day 0 followed by 3 fresh donations on days +4, +8 and +11. The median amount of blood processed from donor animals was 470 ml (312-602) containing about 10 x 10(8) (5-71 x 10(8)) nucleated cells. Recipient animals received a median of 2.7 x 10(8) cells/kg equivalent to 9.6 x 10(4) colony-forming units granulocyte-macrophages (CFU-GM)/kg (data derived from Group C of the animals).(ABSTRACT TRUNCATED AT 250 WORDS)