PubMed Health⌕ Search

Biomedical subjects

J Pringle

Publications and source records attributed to J Pringle.

At least 37 records · Page 2Linked to original sources
PubMed1994

Doxorubicin and cisplatin with granulocyte colony-stimulating factor as adjuvant chemotherapy for osteosarcoma: phase II trial of the European Osteosarcoma Intergroup.

PURPOSE: This report describes the toxicity and feasibility of administering doxorubicin (DOX) and cisplatin (CDDP) at 2-week intervals with granulocyte colony-stimulating factor (G-CSF) to patients with osteosarcoma and the compatibility of this regimen with endoprosthetic surgery performed after three cycles. PATIENTS AND METHODS: Twenty-four patients with biopsy-proven osteosarcoma were treated with three preoperative cycles of DOX 25 mg/m2/d on days 1 to 3 and CDDP 100 mg/m2 on day 1 with G-CSF 5 micrograms/kg/d on days 4 to 14. Surgery was scheduled at week 6 to be followed by three further cycles of chemotherapy at 2-week intervals. RESULTS: Two-week chemotherapy was feasible, but delays and dose reductions only allowed 74% and 78% of the intended dose-intensity of DOX and CDDP to be administered. Thrombocytopenia accounted for 50% of delays. Significant toxicity included neutropenic sepsis, severe mucositis, prolonged nausea and vomiting, and electrolyte disturbances. Twenty-one limb-salvage procedures and one amputation were performed. There were eight episodes of excessive perioperative bleeding. CONCLUSION: Intensive 2-week chemotherapy with intercurrent surgery is feasible and allows a greater dose-intensity of chemotherapy to be administered compared with the same regimen administered at 3-week intervals without G-CSF. The toxicity is considerable, but manageable.

Adolescent↗
PubMed1993

Induction of myelin genes during peripheral nerve remyelination requires a continuous signal from the ingrowing axon.

The effect of a permanent transection on myelin gene expression in a regenerating sciatic nerve and in an adult sciatic nerve was compared to establish the degree of axonal control exerted upon Schwann cells in each population. First, the adult sciatic nerve was crushed, and the distal segment allowed to regenerate. At 12 days post-crush, the sciatic nerve was transected distal to the site of crush to disrupt the Schwann cell-axonal contacts that had reformed. Messenger RNA (mRNA) levels coding for five myelin proteins were assayed in the distal segment of the crush-transected nerve after 9 days and were compared to corresponding levels in the distal segments of sciatic nerves at 21 days post-crush and 21 days post-transection using Northern blot and slot-blot analysis. Levels of mRNAs found in the distal segment of the transected and crush-transected nerve suggested that Schwann cells in the regenerating nerve and in the mature adult nerve are equally responsive to axonal influences. The crush-transected model allowed the genes that were studied to be classified according to their response to Schwann cell-axonal contact. The levels of mRNAs were 1) down-regulated to basal levels (P0 and MBP mRNAs), 2) down-regulated to undetectable levels (myelin-associated glycoprotein mRNAs), 3) upregulated (mRNAs encoding 2'3'-cyclic nucleotide phosphodiesterase and beta-actin), or 4) not stringently controlled by the removal of Schwann cell-axonal contact (proteolipid protein mRNAs). This novel experimental model has thus provided evidence that the expression of some of the important myelin genes during peripheral nerve regeneration is dependent on continuous signals from the ingrowing axons.

Animals↗
PubMed1993

Chemotherapy of malignant fibrous histiocytoma of bone.

BACKGROUND: Malignant fibrous histiocytoma of bone (MFHB) is a rare tumour with a 3 year survival of 30%-40% when treated with surgery alone. A small number of patients have previously been treated with pre-operative chemotherapy and responses observed. The aim of the present study was to further determine the response of MFHB to pre-operative chemotherapy. PATIENTS AND METHODS: A non-randomised study of 18 patients with MFHB. Twelve had localised disease and 6 had pulmonary metastases. In 14 patients pre-operative treatment consisted of methotrexate 8 g/m2 on day 1, ifosfamide 3 g/m2 and doxorubicin 60 mg/m2 on day 10. This regimen was given twice and twice post-operatively. A further 4 patients received cisplatin 100 mg/m2 on day 1 and doxorubicin 25 mg/m2 on days 1, 2, 3. Three cycles were given pre- and post-operatively. RESULTS: 15 patients had surgery after chemotherapy. Tumour necrosis was present in all resection specimens and ranged from 50%-100%. 7/15 had > 90% necrosis. Disease free survival is 82% for those patients with a greater than 2 year follow-up. CONCLUSION: This study confirms previous reports that MFHB is a chemosensitive tumour. In view of its rarity collaborative trials are needed to establish the optimum drug treatment including drug selection dose and duration.

Adolescent↗
PubMed1992

A yeast gene (BEM1) necessary for cell polarization whose product contains two SH3 domains.

Cell polarization requires that a cellular axis or cell-surface site be chosen and that the cytoskeleton be organized with respect to it. Details of the link between the cytoskeleton and the chosen axis or site are not clear. Cells of the yeast Saccharomyces cerevisiae exhibit cell polarization in two phases of their life cycle, during vegetative growth and during mating, which reflects responses to intracellular and extracellular signals, respectively. Here we describe the isolation of two mutants defective specifically in cell polarization in response to peptide mating pheromones. The mutants carry special alleles (denoted bem1-s) of the BEM1 gene required for cell polarization during vegetative growth. Unlike other bem1 mutants, the bem1-s mutants are normal for vegetative growth. Complete deletion of BEM1 leads to the defect in polarization of vegetative cells seen in bem1 mutants. The predicted sequence of the BEM1 protein (Bem1p) reveals two copies of a domain (denoted SH3) that is found in many proteins associated with the cortical cytoskeleton and which may mediate binding to actin or some other component of the cell cortex. The sequence of Bem1p and the properties of mutants defective in this protein indicate that it may link the cytoskeleton to morphogenetic determinants on the cell surface.

Adaptor Proteins, Signal Transducing↗
PubMed1992

Regulation of 2',3'-cyclic nucleotide phosphodiesterase gene expression in experimental peripheral neuropathies.

2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNPase) is an enzyme associated with central nervous system myelination. Although present in the mammalian peripheral nerve, it is not clear what its role is during myelination nor how the expression of this gene is regulated in the PNS. In this study, CNPase gene expression was studied in the crushed and permanently transected rat sciatic nerve, two models of peripheral nerve neuropathy. The Schwann cells of the crushed nerve initially demyelinate, remain in a non-myelinating condition until active regeneration induces remyelination (10-21 days after injury), whereas those of the permanently transected nerve remain in a quiescent, non-myelinating state after the initial demyelination. An increase of CNPase mRNA levels is observed during degeneration and remains high whether the peripheral nerve is regenerating or not, suggesting transcriptional activation of CNPase mRNA and/or increased CNPase mRNA stability as a response to nerve injury. In contrast, the steady state level of CNPase protein did not increase during degeneration or regeneration suggesting either negative translational regulation of CNPase gene expression or a higher turnover of this protein in the injured peripheral nerve. Furthermore, CNPase activity dropped sharply during early degeneration and remained low in the quiescent cells of the permanently transected nerve while it increased in the regenerating nerve. The results suggest that although transcriptional or post-transcriptional regulation of CNPase gene expression is not dependent on Schwann cell-axonal contact, the activity of CNPase appears to be dependent on myelination and indirectly dependent on the presence of axons in the peripheral nerve.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1992

Ewing sarcoma: MR imaging of chemotherapy-induced changes with histologic correlation.

In a study group of 18 consecutive patients with Ewing sarcoma proved by means of biopsy, the signal intensity characteristics of tumor on magnetic resonance (MR) images were assessed before and after chemotherapy. Sixteen patients underwent MR imaging at 1.5 T before chemotherapy; all 18 patients underwent MR imaging at 1.5 T within 10 days after chemotherapy. Standard spin-echo sequences were used with T1 and T2 weighting in all patients. The primary tumor was visualized in all 16 patients who underwent MR imaging before chemotherapy. Histologic correlation, obtained in 14 patients, showed that areas of high T2-weighted signal intensity on MR images obtained after chemotherapy may represent tumor necrosis, cystic hemorrhagic areas, and fibroblastic repair tissue. In 10 patients (71%), microscopic clusters of viable tumor cells were depicted in areas of both low and high signal intensity after treatment. It is concluded that MR imaging is unreliable for exclusion of active disease, although a pattern of change in signal intensity is qualitative evidence of chemotherapeutic effect.

Adolescent↗
PubMed1991

A suppressor of a yeast splicing mutation (prp8-1) encodes a putative ATP-dependent RNA helicase.

Five small nuclear RNAs (snRNAs) are required for nuclear pre-messenger RNA splicing: U1, U2, U4, U5 and U6. The yeast U1 and U2 snRNAs base-pair to the 5' splice site and branch-point sequences of introns respectively. The role of the U5 and U4/U6 small nuclear ribonucleoprotein particles (snRNPs) in splicing is not clear, though a catalytic role for the U6 snRNA has been proposed. Less is known about yeast splicing factors, but the availability of genetic techniques in Saccharomyces cerevisiae has led to the identification of mutants deficient in nuclear pre-mRNA splicing (prp2-prp27). Several PRP genes have now been cloned and their protein products characterized. The PRP8 protein is a component of the U5 snRNP and associates with the U4/U6 snRNAs/snRNP to form a multi-snRNP particle believed to be important for spliceosome assembly. We have isolated extragenic suppressors of the prp8-1 mutation of S. cerevisiae and present here the preliminary characterization of one of these suppressors, spp81. The predicted amino-acid sequence of the SPP81 protein shows extensive similarity to a recently identified family of proteins thought to possess ATP-dependent RNA helicase activity. The possible role of this putative helicase in nuclear pre-mRNA splicing is discussed.

Adenosine Triphosphate↗
PubMed1991

Immunocytochemical localization of follicle regulatory-protein (FRP) in testis.

Follicle regulatory protein (FRP) can exert paracrine control over follicular development. It is synthesized by the granulosa cells of the developing follicles and was localized in the cytoplasm of the mural cells by immunocytochemistry. When administered to male dogs and rats, FRP causes impairment of spermatogenesis. In the intact male rat, it has been postulated that FRP manifests its effects at a stage prior to the conversion of testosterone to dihydrotestosterone. Sertoli cells of the seminiferous tubules are implicated in testosterone metabolism. Furthermore, Sertoli cells in male gonads are regarded as the counterpart of granulosa cells in ovaries. The exact source of FRP in the male is not known. Therefore, it was of interest to study the localization of FRP in the male gonads. Testicular sections of the pig, dog, cat, rat, mouse, monkey, and man were immunocytochemically stained with monoclonal antibody to porcine FRP of ovarian origin. Sections of pig ovaries were used as controls throughout the study. Specificity of immunocytochemical localization was established by preabsorption. FRP antibody predominantly localized to the interstitial compartment of the pig testis. In the seminiferous tubules, FRP localization was limited to basal spermatogonia and Sertoli cells of tubules at few specific stages of spermatogenesis. The study also showed that the monoclonal antibody against porcine FRP is species-specific. Antibody binding was found only in pig testis, whereas tissues from the cat, dog, mouse, rat, monkey, and man did not display any immunocytochemical reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Myelin basic protein-mRNA used to monitor trimethyltin neurotoxicity in rats.

Trimethyltin (TMT) is an alkyltin that targets neurons of the limbic system. A gene probe (i.e., mRNA) for myelin basic protein (MBP), a major component of central nervous system myelin, was used to monitor this toxic neuropathy in Sprague-Dawley rats. Animals were administered a single intraperitoneal injection of TMT-hydroxide at a neuropathic (8.0 mg/kg/body wt) or nonneuropathic (0.8 mg/kg/body wt) dose and sampled at 1, 3, or 7 days postexposure to correlate the progression of hippocampal neuropathology with probe (i.e., MBP-mRNA) levels. Microscopic examination of the brain showed only moderate but progressive damage over the 7-day postexposure period in animals treated with the neuropathic dose. Neuronal loss was first observed in the dendate gyrus and CA4 at 1 day postexposure, and progressed to the CA3c sector at 3 and 7 days postexposure. Elsewhere in the brain, minimal involvement of the entorhinal cortex neurons occurred 3 days postexposure and intensified by 7 days. No histological damage was seen at the nonneuropathic (0.8 mg/kg) dose. For gene probe analysis, the brain was divided into anterior and posterior halves. In rats treated with the neuropathic dose of TMT, the anterior brain showed progressive depressions of MBP-mRNA levels over the 1-, 3-, and 7-day postexposure period that correlated with increasing hippocampal neuropathology. The posterior brain showed no significant changes in MBP-mRNA levels with respect to that of controls over the same time period. At the nonneuropathic dose (0.8 mg/kg) a significant depression of MBP-mRNA levels occurred in the anterior brain at 7 days postexposure in the absence of overt histological damage.

Animals↗
PubMed1991

Levels of proteolipid protein mRNAs in peripheral nerve are not under stringent axonal control.

The proteolipid protein (PLP) is the major protein in the myelin sheath of the CNS. It was recently reported that PLP coding transcripts are also found in the PNS, although the protein was not detectable in peripheral nerve myelin. In the present investigation, levels of mRNA for PLP in sciatic nerve were studied during development and following transection and crush injury. Results were compared to those for P0, the major PNS myelin protein, and the myelin-associated glycoprotein (MAG). PLP transcript levels were very low at 21 days in sciatic nerve and remained unchanged in the adult sciatic nerve. This contrasts markedly with P0 and MAG mRNAs, which are expressed at high levels during development and decrease in content significantly by adulthood. The level of PLP messages was reduced approximately 40% in the quiescent Schwann cells in the distal segment of the sciatic nerve at 21 days after permanent transection, yet P0 mRNA levels were very low, and MAG mRNAs were undetectable in this tissue. The distal segment of the crush-injured sciatic nerve is characterized by transient demyelination followed by rapid myelination. PLP mRNA levels remained comparatively unaffected in the 3-week period following crush injury. RNase protection experiments using two antisense riboprobes confirmed that levels of PLP-derived protected fragments, corresponding to PLP and DM-20 messages, remained unchanged in the developing and adult sciatic nerve. These results indicate that myelin-specific P0 and MAG genes are tightly controlled at the level of transcription through Schwann cell-axonal interactions, whereas PLP transcription in the peripheral nerve remains nearly dissociated from axonal influences.

Animals↗
PubMed1991

The prognostic significance of pretreatment serum lactate dehydrogenase in patients with small-cell lung cancer.

Pretreatment serum lactate dehydrogenase (LDH) levels were assayed in 288 patients presenting with small-cell lung cancer (SCLC) between 1976 and 1985. Patients were routinely staged by physical examination, chest x-ray, bone, brain, and liver scans, and bone marrow evaluation. Clinical response and survival were assessed following treatment with combination chemotherapy as part of four clinical trials. Patients with extensive disease (ED) presented with a higher incidence (108 of 147, 73%) of abnormally elevated LDH (greater than 193 IU/L) than those (65 of 141, 46%) with limited disease (LD) (P = 2 x 10(-6)). Forty percent of patients had an initial normal LDH level and a higher response rate (89 of 108, 82%; complete response [CR], 47%) than those with elevated values of LDH (119 of 156, 76%; CR, 29%). The CR rate varied inversely with the level of LDH in patients with LD (P = .026) but not in those with ED (P = .300). The median survival time and 1-year and 2-year survival rates for patients with elevated LDH were 39 weeks and 33% and 6%, respectively, whereas for those with a normal LDH level these were 53 weeks and 54% and 16%, respectively. Patients with LD and elevated levels of LDH manifested a higher relative death rate (1.63:1) when compared with patients with LD and LDH in the normal range (P = .0083). The survival of patients with ED did not differ between those with normal and elevated levels of LDH (P = .273). A significant survival advantage persisted for patients with LDH in the normal range following adjustments for extent of disease, performance status (PS), and treatment protocol (P = .044, log-rank analysis). In conclusion, serum LDH appears to be a significant independent pretreatment prognostic factor in patients with SCLC that correlates with stage of disease, response to treatment, and survival.

Adult↗
PubMed1991

Myelin basic protein-messenger RNA (MBP-mRNA) expression during triethyltin-induced myelin edema.

Triethyltin (TET) is a neurotoxicant that produces severe but transient cerebral edema, characterized ultrastructurally by vacuolation of the intraperiod line of central nervous system (CNS) myelin. TET has been reported to depress levels of myelin basic protein (MBP), a protein thought to play a critical role in myelin compaction. In the present study, the genomic expression (i.e., mRNA) of MBP was monitored throughout the pathogenesis of TET-induced myelin edema and recovery in Sprague-Dawley rats given a single injection of a neuropathic (8.0 mg/kg) or non-neuropathic (0.8 mg/kg) dose of TET-bromide. Levels of MBP-mRNA from the anterior and posterior brain were collected 1 hr, 3 hr, 2d, and 7d, postexposure. The optic nerve and caudal brainstem, representing anterior and posterior brain sites, respectively, were examined at the same time-points for ultrastructural evidence of edema and recovery. Our data indicate that neuropathic doses (8.0 mg/kg) of TET significantly stimulated MBP transcript throughout the brain at all exposure time-points. The magnitude and time-course of this stimulation differed in the anterior and posterior brain, with the latter region showing higher levels of MBP-mRNA. In the posterior brain, the highest levels of mRNA correlated with the appearance of edema in the caudal brainstem. In the anterior brain, MBP-mRNA levels were only marginally increased over controls. Ultrastructural evidence of myelin edema was confined to the brainstem in rats treated with neuropathic dose of TET. Intralamellar vacuolation appeared at 3 hr and 2d postexposure and could be correlated with peak levels of MBP transcript, whereas, recompacted myelin, which appeared by 7d postexposure, was associated with declining levels of the mRNA. Ultrastructural changes in the oligodendroglia were suggestive of metabolic stimulation and correlated with high MBP-mRNA levels. In summary, these data indicate that an initial genomic event in TET-induced myelin edema is stimulation of MBP transcript.

Animals↗
PubMed1991

Gene probe for P0 messenger RNA used to index acrylamide toxic neuropathy in rats.

Cumulative exposure to the neurotoxicant acrylamide produces axonal damage in the distal ends of both central (CNS) and peripheral (PNS) nerve fibers and subsequent hind-limb paralysis. The messenger RNA which codes for the PNS myelin glycoprotein P0 (P0-mRNA) was used to monitor this toxic neuropathy in Sprague Dawley rats prior to, concurrent with, and subsequent to, ultrastructurally and immunocytochemically defined nerve damage. Rats were dosed every other day with acrylamide (50 mg/kg, IP) and sampled intermittently throughout a 4 week exposure period. Slot blot and Northern gel analyses of the proximal and distal sciatic nerve were used to determine a quantitated measure of P0-mRNA. Twenty-four hours after the first treatment, in the absence of ultrastructural damage, P0-mRNA increased 55% over control levels in the distal sciatic nerve. After 12 treatments, and concomitant with the appearance of spinal cord and PNS neuropathic damage and hindlimb dysfunction, P0-mRNA decreased 45% below control levels. Levels of P0-mRNA from rats exposed to 12 treatments of acrylamide but allowed to recover for 40 days, returned to 79% of control values to reflect the regeneration and remyelination occurring in the distal sciatic nerve. In spite of these fluctuations in levels of P0-mRNA, immunocytochemical staining of P0 protein in plastic sections of the distal sciatic nerve was present throughout all sample times. These results suggest that changes in neural specific mRNAs are sensitive to neurotoxic damage and can be used to monitor the pathogenesis of nerve degeneration.

Acrylamide↗
PubMed1990

Concurrent chemoradiation in advanced cervical cancer.

The pelvis is the predominant site of failure following radical radiotherapy (RT) for locally advanced cervical cancer. We report the results of phase I-II studies on 200 patients with bulky (greater than or equal to 5 cm) carcinoma of the cervix. Patients were treated between 1981 and 1988 on sequential protocols of concurrent chemoradiation to establish an acceptable treatment regimen. RT with daily or partially hyperfractionated pelvic (n = 154) or pelvic plus paraaortic (n = 46) fields was given by continuous (n = 154) or split course (n = 46) regimens. Infusional fluorouracil (5-FU) in a dose of 1 g/m2/day was given on the first and last 4 days of a 5-week course of continuous RT, or with both halves of split course RT. Seventy-eight patients received bolus mitomycin C (Mit-C), 6 mg/m2, once or twice with the start of the 5-FU infusion. The median external RT dose was 46 Gy (range 40 to 65 Gy) followed in 90% (n = 181) by a single intracavitary application of 40 Gy using a linear source of cesium-137. Median follow up is 2.5 years (range 0.6 to 6.9 years) and is sufficient to reliably estimate late toxicities. Acute toxicities were transient oral mucositis (13), RT interruption for enteritis (7), febrile neutropenia (3), and thrombocytopenic tumor bleed (1). Serious late toxicities resulted in death in 3 patients and occurred in bladder in 6 and in bowel in 25, including 8 patients with tumor recurrence. The incidence of late bowel toxicity correlated with the specific therapy given and decreased with each successive protocol. On logistic regression the only treatment variable showing a statistically significant effect on complications was the use of Mit-C (P = 0.0053). Pelvic RT and 5-FU alone produced fewer complications, only 4/105, than historically seen with standard pelvic RT alone. Three-year pelvic control and survival rates were 85 and 71% respectively in stage Ib/II (n = 100) and 50 and 42% in stage III/IV (n = 100). Encouraged by these results and decreased toxicity, we have begun a phase III study to determine whether the addition of concurrent 5-FU to continuous partially hyperfractionated pelvic RT improves local control and survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Parosteal osteosarcoma. Treatment by wide resection and prosthetic replacement.

We have reviewed 20 cases of parosteal osteosarcoma treated by wide local resection and prosthetic replacement and followed up for six to 17 years. Limb function was excellent in 85%. One patient with grade III histological disease developed pulmonary metastases. Four patients had local recurrences, which were related to repeated preliminary biopsies, inappropriate siting of biopsy and vascular encroachment by the tumour. After this mode of treatment, the outcome was not related to medullary invasion by the tumour.

Adolescent↗
PubMed1989

Magnetic resonance imaging: comparison of four pulse sequences in assessing primary bone tumours.

A prospective magnetic resonance imaging (MRI) study was carried out in 13 patients (19 examinations) with primary bone tumours to assess the relative value of each of four pulse sequences in showing the extent and nature of the lesion. The four pulse sequences used were a T1-weighted spin-echo (SE544/44), a T2-weighted spin echo (SE1500/80), a short TI inversion recovery (STIR) (IR500/100/44), and a partial saturation (PS) (PS500/22) with field echo data collection. For soft tissue disease the combination of PS and STIR gave better definition of the boundary of the tumour than the more conventional T1 and T2-weighted spin echo sequences. For the demonstration of bone cortex, periosteal change and calcification, T1 and T2-weighted spin echo sequences were better. However, for calcified tissues, plain radiographs were better than either MRI combination. On the assumption that plain films will be available in all cases, PS and STIR sequences could therefore be substituted for T1 and T2-weighted spin echo sequences allowing an increase in soft tissue detectability for lesions in both red and yellow marrow.

Adolescent↗