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Biomedical subjects

M J Phillips

Publications and source records attributed to M J Phillips.

At least 73 records · Page 4Linked to original sources
PubMed1995

Tetrasomy of chromosome 8 in a patient with acute myeloid leukemia.

We report a case of acute myeloid leukaemia (AML), FAB classification M2, associated with tetrasomy 8. This chromosomal aberration was detected using conventional cytogenetics and flourescent in-situ hybridization (FISH). Using FISH, the pre-treatment cells with tetrasomy 8 were disomic for chromosome 7. A small number of tetrasomy 8 cells were found post-treatment, but these were tetrasomic for chromosome 7. The significance of this is considered, and the literature regarding tetrasomy 8 in acute myeloid leukaemia is reviewed.

Adult↗
PubMed1995

The structure and organization of the bile canalicular cytoskeleton with special reference to actin and actin-binding proteins.

The distribution of actin filaments and actin-binding proteins in the bile canaliculus (BC) of normal human hepatocytes was determined as a means of establishing the structure and organization of the BC cytoskeleton. Immunoblots demonstrated that actin, and the actin-binding proteins, myosin II, tropomyosin, vinculin, alpha-actinin, villin, were present, as were the non-actin-related proteins beta-tubulin, and cytokeratins. Three actin filament regions were identified: microvillus core filaments, a membrane-associated microfilamentous network, and a circumferential pericanalicular actin filament band. Actin-binding proteins were nonrandomly associated with actin in these regions. In the case of the pericanalicular band, there was also association with the zonula adherens junction. Intermediate filaments inserted into desmosomes. The ultrastructural localization of the actin-binding proteins was fundamentally linked to the arrangement and organization of the major canaliculus-associated microfilament structures. Structural organization of the cytoskeleton was also linked to distinct components of the intercellular junctions. It is notable that tropomyosin and a-actinin, which in muscle cells are regulatory proteins of contractile activity, and myosin II are associated with the pericanalicular actin microfilament band; it is the BC counterpart of the contractile actin filament band found in the apical region of other secretory cells. The outer sheath of noncontractile intermediate filaments likely stabilizes the canalicular compartment.

Actins↗
PubMed1994

Joubert syndrome with congenital hepatic fibrosis: an entity in the spectrum of oculo-encephalo-hepato-renal disorders.

Joubert syndrome is an autosomal recessive inherited condition characterized by agenesis or hypoplasia of the cerebellar vermis, retinal dystrophy, chorioretinal colobomata, oculomotor abnormalities, episodic hyperpnea, ataxia, and mental retardation. Congenital hepatic fibrosis has not previously been described in Joubert syndrome. We report two unrelated children with Joubert syndrome and hepatosplenomegaly. On histopathological examination, both had congenital hepatic fibrosis. Both were also found to have congenital medullary cystic disease of the kidneys. Joubert syndrome appears to be one of a spectrum of congenital malformation syndromes involving the central nervous system, eye, liver and kidneys.

Abnormalities, Multiple↗
PubMed1994

Prostaglandin E in the treatment of recurrent hepatitis B infection after orthotopic liver transplantation.

While orthotopic liver transplantation (OLT) has become the treatment of choice for most irreversible end-stage liver diseases, its role in patients with hepatitis B (HBV) infection is controversial. A high risk of reinfection of the transplanted graft, associated with significant morbidity and mortality, has been reported. Although passive and active immunization can delay reappearance of the virus in the allograft, there is not yet an effective therapy for recurrent HBV infection in liver transplant recipients. Between October 1985 and March 25, 1991, 28 OLT in 25 patients with acute and chronic HBV infections were performed. Twelve of the patients were HBV DNA-negative, six were HBV DNA-positive, and seven were not tested prior to transplantation. Only the 19 patients surviving more than 100 days after transplantation were considered to have sufficient duration of follow-up (mean 734 days; range 500-1545) to include in analysis of recurrence. Five (26%) were free of recurrent disease at the time of last follow-up (mean 1031 days, range 526 to 1770 days. Recurrent HBV in the allograft, as defined by positive immunoperoxidase stains of biopsy sections for viral antigens, was detected in 74% (13 male, 1 female; 7 Asian, 7 white) at a mean of 134 days posttransplantation. Histological changes of viral hepatitis, first appearing an average of 157 days (range 95-326) posttransplantation, were evident in 13 of 14 with positive immunostaining. Twelve of the 14 patients were treated, on an open trial basis, with intravenous and oral prostaglandin E (PGE) because of deteriorating clinical condition. Eleven of the twelve responded to PGE with an initial drop in serum transaminases, improvement in coagulopathy and resolution of encephalopathy. One patient failed to respond and died of a myocardial infarction within 9 days of institution of therapy. Three of the eleven patients with an initial response relapsed and died in liver failure as a direct result of recurrent HBV after 13, 16, and 37 days of treatment in association with generalized sepsis. Eight of the 12 patients (67%) had a sustained favorable response to PGE therapy (mean follow-up 737 days, range 403-1545). All patients with a sustained response had accompanying improvement in histology and reduction in viral antigen staining in hepatocytes. Treatment with PGE appeared to be of benefit in recurrent HBV infection of the transplanted liver with an initial response rate of 92% and a sustained response rate of 67%.

Administration, Oral↗
PubMed1994

Isolation of the bile canalicular actin-myosin II motor.

Cytoskeleton-rich canalicular membranes (CCMs) with preserved cytoskeleton and demembranated CCMs, consisting only of cytoskeletal elements, were used to examine the relationship of pericanalicular microfilaments, myosin II phosphorylation, and canalicular contraction. The components of CCMs were visualized by fluorescence microscopy using the filamentous actin probe rhodamine-phalloidin and by electron microscopy, before and after incubation in 1 microM Ca2+/1 mM ATP (contraction solution). Canalicular contraction (luminal closure) was evaluated by morphometric analysis. Myosin II was extracted from CCMs, purified by immunoprecipitation, and analyzed on Western blots. In sequential experiments, autoradiographs of gels from [gamma-32P]-ATP-treated CCMs in the presence or absence of Ca2+ were examined after 0.25, 0.50, 1, 2, 3, 5, and 10 min, and the effects of W7 (a calmodulin antagonist) and ML9 (a myosin light chain kinase inhibitor) were evaluated. The results showed that phosphorylation of the 20-kDa protein was low in controls but enhanced beginning 0.25-0.50 min after addition of contraction solution. Both W7 and ML9 significantly inhibited this reaction and inhibited canalicular contraction. The results indicate that phosphorylation of the regulatory 20-kDa myosin light chain of canaliculus-associated myosin II coincides with or precedes contraction of the canaliculus. We conclude that the canalicular contractile apparatus is composed of actin filaments and a myosin II motor.

Actins↗
PubMed1994

Multiple dose pharmacokinetics of an oral solution of itraconazole in autologous bone marrow transplant recipients.

The pharmacokinetics of itraconazole oral solution were measured in seven patients receiving chemotherapy followed by autologous bone marrow transplantation for leukaemia or lymphoma. Patients received 5 mg/kg/day itraconazole either as a once or twice daily dose. Drug concentrations reached steady state by day 15, in both groups. The mean pre-dose itraconazole serum concentration at hour 0, day 8 was 385 ng/mL in the od group and 394 ng/mL in the bd group, rising to 762 and 845 ng/mL by day 15, respectively. The mean AUCs for 0-24 h on day 8, 15 and 22 were 17,310 and 13,302 ng/mL/h, 24,476 and 25,154 and 22,621 and 21,423, for the od and bd groups, respectively. Thus serum concentrations of itraconazole suitable for antifungal prophylaxis can be attained in neutropenic patients, with the administration of an oral solution in a dosage of 5 mg/kg as either an od or bd schedule, following pre-autograft high-dose cytotoxic chemotherapy.

Adult↗
PubMed1994

Effects of different density gradient separation techniques on neutrophil function.

Investigation of the pathogenesis of inflammatory diseases has involved assessment of polymorphonuclear leukocyte (PMN) activity and a variety of techniques for separating PMNs from whole blood have been described. In this study the effects of Percoll gradient, Ficoll-Hypaque/Dextran sedimentation (FH/DS) and Mono-Poly Resolving Medium (M-PRM) on activation and function of PMNs were compared. All three separation techniques gave similar cell yield and purity. The mean (+/- SEM) percentage of cells demonstrating pseudopodia formation for Percoll, FH/DS and M-PRM were 39 +/- 9, 57 +/- 6 and 63 +/- 5, respectively, while superoxide release from resting cells was 1.9 +/- 0.9, 7.2 +/- 3.5 and 11 +/- 4.8 pmols per 10(6) cells min-1, respectively, indicating that activation of cells during separation may be less with Percoll compared to the other methods. The functional capacity of the cells to respond to a stimulus was similar for all methods as indicated by similar EC50 values for chemotaxis to zymosan-activated serum and similar superoxide production induced by tetradecanoyl phorbol acetate. All three separation techniques produce functionally active PMNs of high purity but the use of Percoll gradients may be preferable when a quick method of separation which causes minimum pre-activation of PMNs is required.

Cell Separation↗
PubMed1994

Absence of minimal residual disease detectable by FACS, Southern blot or PCR in patients with chronic lymphocytic leukaemia treated with fludarabine.

We report the results of assessment of minimal residual disease in four patients with chronic lymphocytic leukaemia, who achieved clinical and haematological complete response following treatment with fludarabine. Patients were assessed both before and after treatment by immunophenotyping, DNA electrophoresis, Southern blotting and PCR amplification to detect immunoglobulin gene rearrangements. Immediately after treatment, no patient had disease detectable by any method and there was evidence of recovery of normal B-cells. No patient has yet shown evidence of clinical or haematological relapse (follow-up 59-142 weeks). Two patients remain in immunophenotypic and molecular remission at 141 and 59 weeks. These methods have allowed more sensitive definition of elimination of residual disease, with PCR demonstrating the capacity to detect disease recurrence before any other evidence is available.

Aged↗
PubMed1994

Mitoxantrone, chlorambucil and prednisolone in the treatment of non-Hodgkin's lymphoma.

The management of low grade lymphoma, both de novo and relapsed disease, is a contentious area in which there has been little real progress in recent years. Regimens which increase the intensity of treatment may accelerate the response but are inevitably associated with greater toxicity. This cannot be justified in a disease whose median survival is between 4 and 10 years and where the median age at presentation is 57. We have assessed the response of 144 patients treated with a combination of mitoxantrone, chlorambucil and prednisolone in a heterogeneous group with lymphoma, both de novo and relapsed disease. In the subgroup with low grade relapsed/refractory disease our results suggest that this combination is clinically effective, low in toxicity and suitable for the outpatient management of this usually elderly patient population.

Adult↗
PubMed1994

A dose ranging study to evaluate dermatan sulphate in preventing deep vein thrombosis following total hip arthroplasty.

Dermatan sulphate catalyses thrombin inhibition by heparin cofactor II; it has a lower haemorrhagic to antithrombotic ratio than that of heparin in animal models. Consecutive patients aged forty years or more, electively undergoing total hip replacement under general anaesthesia, were randomly allocated to one of three dosage regimens of dermatan sulphate (MF701, Mediolanum Farmaceutici) given intramuscularly. These were 200 mg once daily (n = 50), 200 mg twice daily (n = 52) and 300 mg twice daily (n = 51), administered from twenty-four hours pre-operatively until the tenth postoperative day. The overall incidence of DVT assessed by bilateral venography was 53%, 51% and 34% respectively (Chi-square test for trend p = 0.06). The incidence of major proximal DVT was 10.6%, 8.5% and 2.1% respectively. Pulmonary embolism (PE) and bleeding were assessed in all 153 patients. There was one case of PE in each dose group. The incidence of bleeding episodes, volume of blood lost and blood transfusion requirements were low and showed no increase with increasing dose. The patients were followed up 4-8 weeks after discharge. We conclude that the two lower doses were subtherapeutic in this population, however dermatan sulphate given 300 mg twice daily, proved to be efficacious with an incidence of proximal major DVT of 2.1% and a low incidence of bleeding complications. A trial of dermatan sulphate 300 mg twice daily compared to standard prophylactic agents is needed.

Aged↗
PubMed1993

Small encapsulated hepatocellular carcinoma of the liver. Provisional analysis of pathogenetic mechanisms.

BACKGROUND: Small hepatocellular carcinomas frequently were found incidentally during routine pathologic examinations of adult livers removed at liver transplant. METHODS: Sixty-nine carcinomas of all sizes were found in 25 patients; 39 of the tumors were smaller than 1 cm in diameter, and 18 of the carcinomas in five patients were not clinically suspected. These small incidental carcinomas lend themselves to analysis of the morphologic basis of human hepatocellular carcinogenesis. RESULTS: All of these tumors arose in cirrhotic livers. Most of the small carcinomas were multilobulated and subdivided by pre-existing fibrous septa. The surrounding capsule usually was not a true capsule. They were all well differentiated, most formed bile, Mallory bodies, or showed alpha-1-antitrypsin (A1AT) positivity. Transition from cirrhotic nodular parenchyma to areas of hyperplasia or atypical hyperplasia to well-differentiated carcinoma were common. Large cell dysplasia also was common. CONCLUSIONS: These morphologic transitions closely parallel changes seen in experimental chemical carcinogenesis. They also strongly suggest a multicentric origin of the tumors. In addition, in every instance, the lesions were multiple in the liver and involved both lobes. This latter finding has possible implications for recurrence after local surgical excision of small hepatocellular carcinomas.

Adult↗
PubMed1993

Low molecular weight versus standard heparin for prevention of venous thromboembolism after major abdominal surgery. The Thromboprophylaxis Collaborative Group.

Low-molecular-weight heparin (LMWH) is effective in the prevention of postoperative venous thromboembolism but does it have the safety advantages over standard heparin (SH) that have been claimed? In a multicentre randomised trial in 3809 patients undergoing major abdominal surgery (1894 LMWH, 1915 SH) heparin was given preoperatively and continued for at least 5 postoperative days. Patients were assessed in the postoperative period and were followed up for at least 4 weeks, the emphasis being on safety. Major bleeding events occurred in 69 (3.6%) patients in the LMWH group and 91 (4.8%) patients in the SH group (relative risk 0.77, 95% confidence interval 0.56-1.04; p = 0.10). 93 indices of major bleeding were observed in the 69 LMWH patients and 141 in the SH patients. (p = 0.058). Severe bleeding was less frequent in the LMWH group (1.0% vs 1.9%; p = 0.02), as was wound haematoma (1.4% vs 2.7%; p = 0.007). Bleeding episodes with LMWH were less likely to lead to further surgery to evacuate a haematoma or to control bleeding, and injection site bruising was also less common in the LMWH group. No significant differences were found in the efficacy of the two agents. Perioperative death rates were 3.3% in the LMWH group and 2.5% in the SH group; pulmonary emboli were detected in 0.7% and 0.7%; and deep-vein thrombosis was diagnosed in 0.6% of patients in each group. Follow-up was done on 91% of 3699 evaluable patients. There were 19 further deaths (10 LMWH, 9 SH group) and 25 patients with thromboembolic complications (15 and 10). Of the 3 patients with fatal pulmonary emboli during follow-up 2 had received LMWH and 1 SH. The two drugs were of similar efficacy. The primary end point, the frequency of major bleeding, showed a 23% reduction in the LMWH group, but this difference was not significant. The secondary safety end points revealed that LMWH was significantly better than SH. Fatal pulmonary embolism occurs rarely (0.09%) following discharge from hospital so the cost benefit ratio would not justify prolonged prophylaxis in this setting.

Abdomen↗
PubMed1993

Simultaneous analysis of cell surface antigens and DNA content by flow cytometry.

Cells obtained from the blood or bone marrow of patients with haematological malignancies can both be stained with fluorescent labelled monoclonal antibodies to determine an immunophenotype and permeabilized with 30% ethanol then stained with propidium iodide for simultaneous DNA analysis. In the technique described here, no evidence of selective depletion of the malignant cell population was demonstrated and decreases in the mean fluorescence intensity of the surface markers were insufficient to affect the sensitivity of flow cytometric analysis. The combined method is simple and robust enough to allow incorporation of DNA analysis into routine immunophenotyping of leukaemia and lymphoma cells.

Antigens, Neoplasm↗
PubMed1993

Bile canalicular contraction is coincident with reorganization of pericanalicular filaments and co-localization of actin and myosin-II.

We examined the relationships between actin-myosin interaction and bile canalicular contraction using a new experimental model: cytoskeleton-enriched canalicular membranes (CCM). In CCM, the bile canaliculus compartment is isolated complete with membrane-attached pericanalicular actin filaments and the surrounding intermediate filament sheath. Immunofluorescence and immunoelectron microscopy showed that actin and myosin-II were distributed over pericanalicular microfilaments that insert into adherens (belt) junctions; intermediate filaments predominantly inserted into desmosomes. The addition of "contraction solution" (1 microM Ca2+, 1 mM ATP) resulted in closure of CCM lumens, which was interpreted as canalicular contraction. Contraction was also associated with shortening and/or twisting of canaliculi. Rearrangement of actin filaments and myosin-II with co-localization of actin and myosin was observed. Evidence is also provided for attachment of actin-myosin-II aggregates to intermediate filaments coincident with contraction, suggesting a key scaffold function for intermediate filaments of the canaliculus. Attention is drawn to the overall similarity of structure-function dynamics in hepatic apical membranes to those described in intestinal brush border membrane preparations. The results are consistent with dynamic actin-myosin interaction with co-localization of actin and myosin-II in filament clumps coincident with canalicular contraction.

Actin Cytoskeleton↗