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M K Bennett

Publications and source records attributed to M K Bennett.

At least 109 records · Page 6Linked to original sources
PubMed1990

Alpha 1-antitrypsin granules in the liver--always important?

We have studied the clinical histories and liver biopsy findings in 1951 consecutive adult patients with suspected chronic liver disease, and in four known PiZ-homozygous alpha 1-antitrypsin-deficient patients with emphysema (candidates for lung transplant) and no known liver disease, in order to assess the importance of periportal alpha 1-antitrypsin granules in the liver and their possible causal role in liver disease, and to assess the value of possible screening tests. Periportal granules were found in 30 (1.5 per cent) of the 1951 liver biopsies and in all four known PiZ-homozygous subjects. They were the sole putative aetiological agent in eight of 85 patients (9.4 per cent) with otherwise cryptogenic cirrhosis and present in 2.5 per cent of patients with cirrhosis of known aetiology (alcohol, autoimmune etc.). All but one were Z phenotype (seven homozygotes, 22 heterozygotes). alpha 1-Antitrypsin granules were seen in 12 patients (including three of four lung transplant candidates) with no histological chronic liver disease. Determination of serum alpha 1-antitrypsin levels was quite unhelpful in identifying these patients. This study does not support the concept that periportal alpha 1-antitrypsin granules are necessarily pathogenic, but in some cases they may be causally related to otherwise cryptogenic liver disease. The presence of granules gave no important diagnostic, therapeutic or prognostic information.

Adult↗
PubMed1989

Epidermal growth factor receptor in human bladder cancer: a comparison of immunohistochemistry and ligand binding.

Epidermal growth factor receptors were measured in biopsies from patients with newly diagnosed bladder cancer. Two methods to detect these receptors were compared: immunohistochemical staining of frozen sections, and a ligand binding study using radiolabeled epidermal growth factor and tumor cell membranes. We studied 101 patients by immunohistochemistry and 47 patients by both methods. An association was found between immunohistochemical positivity for epidermal growth factor receptors and high tumor stage (p less than 0.001). Thus, most of the muscle invasive tumors were positive (35 of 49, 71 per cent) and more stage pT1 tumors were positive (8 of 18, 44 per cent) than were stage pTa tumors (5 of 34, 15 per cent, p less than 0.05). The ligand binding study was slightly more sensitive in detecting receptors than immunohistochemistry (30 of 47, 64 per cent and 25 of 47, 53 per cent, respectively). Greater amounts of receptors were found in muscle invasive tumors compared to tumors not invading muscle (p less than 0.05). A significant association was found between the 2 methods in the detection of receptors (p less than 0.001) and no discrepancies were found between the 2 methods in tumors containing high levels of receptors. Immunohistochemistry provides a satisfactory method to detect receptors in tumors with high levels of receptors, although ligand binding is more sensitive in tumors with low levels of receptors.

Adult↗
PubMed1989

Progression of autoimmune damage in primary biliary cirrhosis: an immunohistochemical study.

Aberrant MHC Class II antigen expression and the nature of the infiltrating lymphoid cells were studied by immunohistochemical techniques in liver biopsies from 37 patients with Primary biliary cirrhosis (PBC) (11 histological stage I, 13 stage II-III, 13 stage IV) and 15 patients with chronic non autoimmune liver disease. Bile duct epithelial cells expressed HLA-DR, DP and DQ antigens in biopsies from patients with early (Stage I) PBC and less frequently in the late cirrhotic phases of the disease (Stage IV); these observations support the hypothesis that induction of Class II antigens on epithelial cells may be involved in initiating autoimmune responses towards bile duct components. The presence of cytotoxic/suppressor T cells around the bile ducts in Stage I suggests a role for cell mediated destruction of the ducts at this early stage. The nature of the chronic inflammatory cell infiltrate in the portal tracts, periportal areas and lobular parenchyma does not establish the mechanism(s) involved in disease progression. However, the lack of Class II antigen expression on hepatocytes is compatible with the hypothesis that hepatocellular damage is non-specific and may be secondary to the initial bile duct injury.

Adult↗
PubMed1988

Release of putative exocytic transport vesicles from perforated MDCK cells.

Mechanically perforated MDCK cells were used to study membrane transport between the trans-Golgi network and the apical and basolateral plasma membrane domains in vitro. Three membrane transport markers--an apical protein (fowl plague virus haemagglutinin), a basolateral protein (vesicular stomatitis virus G protein), and a lipid marker destined for both domains (C6-NBD-sphingomyelin)--were each accumulated in the trans-Golgi by a 20 degrees C block of transport and their behaviour monitored following cell perforation and incubation at 37 degrees C. In the presence of ATP and in the absence of calcium ions a considerable fraction of the transport markers were released from the perforated cells in sealed membrane vesicles. Control experiments showed that the vesicles were not generated by non-specific vesiculation of the Golgi complex or the plasma membrane. The vesicles had well defined sedimentation properties and the orientation expected of transport vesicles derived from the trans-Golgi network.

Animals↗
PubMed1988

Conserved and variable regions in the subunits of brain type II Ca2+/calmodulin-dependent protein kinase.

Brain type II Ca2+/calmodulin-dependent protein kinase is a holoenzyme composed of several copies each of three subunits, alpha (50 kd), beta (60 kd), and beta' (58 kd), in varying proportions. The deduced amino acid sequences of alpha (reported here) and beta are highly similar but not identical. The major difference between them is the deletion from alpha of two short segments (residues 316-339 and 354-392 in beta). cDNAs that appear to encode beta' are identical to beta except for the deletion of a segment encoding residues 378-392. Thus, the structural differences among alpha, beta, and beta' arise primarily from deletions (or insertions) in a variable region lying immediately carboxyl to the protein kinase and calmodulin-binding domains. The alpha and beta subunits are encoded by distinct genes expressed primarily, if not exclusively, in brain. Rather than being encoded by a third gene, beta' may arise by alternative splicing of the beta gene transcript.

Amino Acid Sequence↗
PubMed1988

Differing interpretations by pathologists of the pT category and grade of transitional cell cancer of the bladder.

The UICC pT category for transitional cell cancer (TCC) of the bladder was recorded as assigned from the routine service of a pathology laboratory. All reports had been passed for release after review by pathologists of the status of senior registrar or above. After 99 cases had been collected, the slides available to the original pathologist were reviewed by one dedicated pathologist in continuous session who was ignorant of the original report. No new sections were cut. There was disagreement with the original report of pT category in 14 cases: 13 were downstaged (including 6 from invasive to superficial) and 1 upstaged. There was disagreement with the original differentiation grade in 13 cases: 10 TCC were considered to be more differentiated and 3 less differentiated than the original report. A second pathologist reviewed the pT category only of 13 of the 14 cases, disagreeing with the original pT category on 8 occasions and with the pT category assigned by the dedicated pathologist on 7 occasions. These findings have important implications for advising patients on prognosis and clinical management and in the design and reporting of therapeutic trials.

Carcinoma, Transitional Cell↗
PubMed1988

Hepatic epithelioid haemangioendothelioma: difficult name, difficult diagnosis?

Two patients with epithelioid haemangioendotheliomata of the liver are described. Both presented with abdominal pain and malaise, with hepatomegaly and a variable degree of hepatocellular dysfunction. Diagnosis was delayed in both cases, each patient undergoing a protracted series of investigations including repeated liver biopsies. The major obstacles to early diagnosis were a lack of clinical awareness of the condition and difficulties in interpretation of the liver histology: the widespread sclerosis in the tumour tissue is easily mistaken for a post-necrotic or cirrhotic process. The key to the diagnosis is the demonstration of cells containing Factor-VIII-related antigen confirming the endothelial origin of the tumour. One patient died within three months of presentation and the other after 18 months. The tumour may, therefore, be more aggressive than earlier reports seem to suggest. It seems likely that the tumour is being under-diagnosed and although no specific therapy has been shown to be of value, a greater awareness of the condition, resulting in a more prompt diagnosis, should save patients from undergoing unnecessary investigation.

Female↗
PubMed1987

8-Amino-9-substituted guanines: potent purine nucleoside phosphorylase (PNP) inhibitors.

A series of 8-amino-9-substituted guanines was synthesized and their activity evaluated against human purine nucleoside phosphorylase (PNP). All compounds were found to be potent inhibitors of human PNP (IC50s: 0.17-126 microM). They were also selectively cytotoxic to MOLT-4 lymphoblasts in the presence of a nontoxic amount (10 microM) of the PNP substrate, 2'-deoxyguanosine (GdR). The most potent of these analogs, 2,8-diamino-1,9-dihydro-9-(2-thienylmethyl)-6H-purin-6-one (8-amino-9-(2-thienylmethyl)guanine; PD 119,229) has an IC50 of 0.17 microM (Ki = 0.067 microM), significantly more potent than the known standard, 8-aminoguanosine (IC50 = 1.40 microM). Thus it represents the most potent PNP inhibitor known to date when tested without limiting the concentration of inorganic phosphate.

Cell Line↗
PubMed1987

Preliminary report on 8-amino-9-(2-thienylmethyl)guanine (PD 119,229), a novel and potent purine nucleoside phosphorylase inhibitor.

PD 119,229 [8-amino-9-(2-thienylmethyl)guanine] is a novel and potent inhibitor of human erythrocyte purine nucleoside phosphorylase (PNP) with a Ki of 0.067 microM. In a cell line assay using human MOLT-4 (T cell) and MGL-8 (B cell) lymphoblasts, PD 119,229 alone had no effect on the growth of either cell line at the highest concentration tested (100 microM). However, in the presence of a nontoxic concentration of 2'-deoxyguanosine (10 microM), the IC50 values of PD 119,229 for MOLT-4 and MGI-8 40-fold either cell line at the highest concentration tested (100 microM). However, in the presence of a nontoxic concentration of 2'-deoxyguanosine (10 microM), the IC50 values of PD 119,229 for MOLT-4 and MGI-8 were 0.9 and greater than 100 microM, respectively. The inhibition of growth of MOLT-4 was accompanied by a 40-fold increase in dGTP and a two-fold reduction in GTP, while no alteration in nucleotide profile was noted in MGL-8. Both the inhibition of growth of MOLT-4 and the accumulation of dGTP were substantially prevented by coaddition of 2'-deoxycytidine.

Cell Division↗
PubMed1987

Deduced primary structure of the beta subunit of brain type II Ca2+/calmodulin-dependent protein kinase determined by molecular cloning.

cDNA clones coding for the beta subunit of rat brain type II Ca2+/calmodulin-dependent protein kinase were isolated and sequenced. The clones, including one containing the entire coding region, hybridize at high stringency to a single band of poly(A)+ RNA of length 4.8 kilobases. The subunit coded for by the clones was identified by in vitro transcription of the cDNA followed by translation of the resulting RNA. The DNA sequence of the clones contains a single long open reading frame (1626 nucleotides) coding for a protein of 542 amino acids with a molecular weight of 60,333, the amino-terminal half of which is homologous to several other protein kinases. Potential ATP- and calmodulin-binding domains were identified. Two independent clones contain an identical 45-nucleotide deletion, relative to the clones described above, resulting in a shorter open reading frame coding for a protein of molecular weight 58,000. This suggests that the minor, 58-kDa beta' subunit of the type II Ca2+/calmodulin-dependent kinase may be synthesized on a separate message.

Amino Acid Sequence↗
PubMed1987

Histochemical study of lectin binding in neoplastic and non-neoplastic urothelium.

A histochemical study of lectin binding was performed to assess staining with lectins and, therefore, the expression of complex carbohydrates in human neoplastic urothelium. Forty-seven patients with transitional cell carcinoma of the bladder and six controls were studied. Cryostat sections were stained with a panel of 10 biotinylated lectins by means of the avidin-biotin-peroxidase technique. Sixteen tumours were also studied after conventional formalin fixation and paraffin embedding. In general, staining by lectins of tumours was more intense than staining of control urothelium and staining of tumours invading bladder muscle was greater than that of superficial tumours (both P less than 0.001). A small but statistically significant diminution of staining was observed after formalin fixation and paraffin embedding (P less than 0.05). Four lectins--Bandeiraea simplicifolia (P less than 0.01), Vicia villosa (P less than 0.01), peanut agglutinin (P less than 0.001) and soyabean agglutinin (P less than 0.001) stained invasive tumours more frequently than superficial tumours in frozen sections. Thus, increased binding of certain lectins was found in human transitional cell tumours and correlated with muscle invasion and poor differentiation.

Aged↗
PubMed1987

Formation of a fibrin based gelatinous coat over repairing rat gastric epithelium after acute ethanol damage: interaction with adherent mucus.

A gelatinous coat, heterogeneous in appearance, was formed over damaged rat gastric mucosa recovering from acute ethanol injury. This coat, in places 1.6 mm thick (median thickness 680 microns), was 10 times thicker than the translucent layer of adherent mucus (median thickness 70 microns) covering the undamaged mucosa. Immunohistochemistry and periodic acid Schiff staining showed this gelatinous coat to be predominantly a fibrin gel with an exterior layer rich in mucus and necrotic cells. The plasma clotting time was significantly decreased in vitro by pig gastric mucus gel and soluble mucus glycoprotein (90% and 13% respectively) suggesting that in vivo the mucus layer remaining after epithelial damage could act as a template for fibrinogen-fibrin conversion. These results show that a fibrin based gelatinous coat, quite distinct from the adherent mucus layer and with considerable protective potential could be formed over the repairing rat gastric mucosa after acute ethanol damage.

Animals↗
PubMed1987

The gastric mucosal epithelial barrier: role of mucus and fibrin.

A continuous layer of insoluble mucus gel is adherent to the luminal surface of the gastric epithelium. The true thickness of the gel and its continuity can only be observed on unfixed sections of mucosa since histological fixatives cause dehydration and denaturation of mucus. The mucus:bicarbonate barrier can protect the undamaged epithelium from the endogenous luminal aggressors acid and pepsin but does not appear to offer much protection against exogenous damaging agents such as topical alcohol. Following acute ethanol injury, damaged epithelium is replaced by cells migrating from the gastric pits. In rat gastric mucosa this process of re-epithelialisation is protected by a gelatinous coat ten times thicker than the normal adherent mucus layer. Our studies now show this coat to be a fibrin gel with mucus and necrotic cells. Evidence suggests that the existing mucus layer can act as a template for the fibrinogen--fibrin conversion. These results demonstrate that a fibrin based gelatinous coat, quite distinct from the adherent mucus layer and with considerable protective potential, can be formed over the repairing damaged gastric mucosa.

Animals↗
PubMed1985

Epidermal-growth-factor receptors in human bladder cancer: comparison of invasive and superficial tumours.

The presence of epidermal-growth-factor (EGF) receptors in normal and neoplastic human urothelium was studied in 12 control patients and in 48 patients with transitional cell carcinoma of the bladder, 24 with invasive (pT3) and 24 with superficial tumours (9 pT1, 15 pTa). EGF receptors were identified on frozen sections by means of an indirect immunoperoxidase technique with a monoclonal antibody against the EGF receptor. Significantly more invasive tumours (21 of 24) than superficial (7 of 24) were stained positively for the EGF receptor (X2 = 14.49; p less than 0.001). Significantly more poorly differentiated tumours (18 of 21) than moderately differentiated tumours (10 of 27) were EGF-receptor positive (X2 = 9.6; p less than 0.01). No control sample stained positively for the EGF receptor. These findings suggest that the presence of a high intensity of staining for the EGF receptor in human bladder tumours is associated with poor differentiation and with invasion.

Adult↗
PubMed1985

Role of the faecal stream in the maintenance of Crohn's colitis.

The role of the faecal stream in the maintenance of the inflammation in Crohn's disease has been studied. Small bowel effluent and a sterile ultrafiltrate of it were reintroduced into the defunctioned colon of patients with Crohn's colitis treated by split ileostomy. The systemic effect of these challenges on the patients was assessed clinically and by laboratory tests, and the effect on the local disease was assessed by endoscopy, histology, and quantitative analysis of lamina propria plasma cell populations. There was little response to the ultrafiltrate challenge. In contrast the clinical responses to challenge with ileostomy effluent were marked in some patients. One patient relapsed and eight others had clinically detectable responses. On the other hand changes in laboratory, endoscopic, histological, and morphometric tests in response to the faecal challenge were less pronounced. The only significant changes in the laboratory results were a relative lymphopenia (p less than 0.05) and a raised ESR (p less than 0.02) after seven days challenge with the effluent. The plasma cell density also increased but not significantly. In conclusion, these results suggest that factors greater than 0.22 microns in the faecal stream are responsible for the maintenance and exacerbation of inflammation in Crohn's disease.

Colon↗