Search PubMed⌕ Search

Biomedical subjects

J M Ward

Publications and source records attributed to J M Ward.

At least 19 recordsLinked to original sources
PubMed1992

Production of mature bovine pancreatic ribonuclease in Escherichia coli.

The coding sequence for the bovine pancreatic ribonuclease (RNase) precursor has been cloned and produced in Escherichia coli using the polymerase chain reaction (PCR) technique. A PCR amplification has been carried out utilizing as template the recombinant plasmid, pQR138, which contains the coding sequence for the RNase precursor, and primers that allow for the addition of new sequences at the 5' and 3' ends of the coding sequence. The resultant fragment contains two coding sequences, one for a hexapeptide and the other for pre-RNase. This fragment has been cloned into the expression vector, pKK223.3, under the control of the tac promoter, to form a two-cistron vector. Upon induction with IPTG, E. coli cells harboring this construct generate a bicistronic mRNA which upon translation produces a hexapeptide and pre-RNase. The RNase precursor is efficiently translocated into the periplasmic space of E. coli. Upon translocation, the signal sequence is removed generating mature RNase. Formation of the disulfide bridges in RNase is facilitated by the oxidative environment of the periplasm and a fully active protein is obtained. RNase produced in E. coli has been purified to homogeneity by cation-exchange chromatography, and the removal of the signal sequence has been verified by N-terminal sequencing. The total process from inoculation of media to obtaining pure and fully active recombinant RNase is achieved in 48 h.

Amino Acid Sequence↗
PubMed1992

K-ras activation and ras p21 expression in latent prostatic carcinoma in Japanese men.

Twenty-three clinically silent prostatic carcinomas discovered in Japanese men at autopsy were surveyed for ras proto-oncogene mutations by mutation-specific oligonucleotide probe hybridization after polymerase chain reaction (PCR) amplification from a section of formalin-fixed, paraffin-embedded tissue. Six of the 22 that were satisfactory amplified contained activating point mutations in codon 12 of K-ras, a significantly higher frequency than has been reported in patients with clinically advanced disease in the United States. Of the six cases with activating point mutations in codon 12 of K-ras, one had a GGT----GAT transition, four had GGT----GTT transversions, and one had both GGT----GAT and GGT----GTT mutations. Sections from the same tissues were immunohistochemically stained with an anti-ras p21 antibody. Carcinoma cells stained for ras p21 to some degree in 13 cases. Immunohistochemically detectable expression of p21 was always focal and was not necessarily associated with K-ras mutation. K-ras oncogene activation in prostatic carcinoma appears to merit additional study as a significant event in the pathogenesis of this neoplasm.

Aged↗
PubMed1992

A pleiotropic response to phenobarbital-type enzyme inducers in the F344/NCr rat. Effects of chemicals of varied structure.

The effects of a number of phenobarbital-type inducers on selected drug-metabolizing enzymes in male F344/NCr rats were determined by measuring specific catalytic activities and/or by measuring the levels of RNA which hybridize with specific probes for the corresponding genes. The effects on hepatic CYP2B1 were assessed by measuring the levels of CYP2B1-specific RNA and benzyloxyresorufin O-dealkylase and testosterone 16 beta-hydroxylase activities. Levels of CYP3A were monitored by measuring the rate of hydroxylation of testosterone at the 6 beta-position. Microsomal epoxide hydrolase activity was determined by measurement of cellular RNA specific for this form and by assaying the hydrolysis of benzo[a]pyrene-4,5-oxide. UDP-glucuronyltransferase activity was assayed by measuring the glucuronidation of 3-hydroxybenz[a]anthracene. Levels of glutathione S-transferase Ya/Yc were measured by quantifying total cellular RNA coding for the proteins. When male F344/NCr rats were administered various doses of phenobarbital or dichlorodiphenyltrichloroethane (DDT), strong correlations between the induction of CYP2B1 and the induction of epoxide hydrolase or UDP-glucuronyltransferase activities were observed. Treatment of rats with barbiturates, hydantoins, halogenated pesticides such as DDT or alpha-hexachlorocyclohexane, 2,4,5,2',4',5'-hexachlorobiphenyl, CYP2B1 inhibitors such as clotrimazole or clonazepam, or such structurally-diverse compounds as 2-hexanone or diallyl sulfide resulted in induction of CYP2B1-mediated enzyme activity and induction of certain other forms of cytochrome P450, microsomal epoxide hydrolase, at least one form of UDP-glucuronyltransferase, and multiple forms of glutathione S-transferase. This suggests that, as a class, compounds which induce CYP2B1 also induce a coordinate hepatic pleiotropic response which includes induction of these other phase I and phase II drug-metabolizing enzymes.

Animals↗
PubMed1992

A markedly diminished pleiotropic response to phenobarbital and structurally-related xenobiotics in Zucker rats in comparison with F344/NCr or DA rats.

Phenobarbital (PB) and certain structurally-related compounds induce a variety of hepatic drug-metabolizing enzymes in many strains of rats. Thus, following administration of PB (300, 500 ppm), barbital (BB, 1500 ppm) or 5-ethyl-5-phenylhydantoin (EPH, 500 ppm), CYP2B1-mediated benzyloxyresorufin O-dealkylase activity and epoxide hydrolase activity were profoundly induced in female DA and F344/NCr rats. In contrast, outbred female lean and obese Zucker rats showed markedly reduced CYP2B1 responses (less than 15% and less than 5% of those observed in the female DA or F344/NCr rat) to PB (doses less than or equal to 300 ppm), BB (1500 ppm) or EPH (500 ppm). In parallel studies, profound increases in RNA levels coding for CYP2B1, glutathione S-transferases Ya/Yc (alpha subclass), or epoxide hydrolase were detected in the female F344/NCr rat following treatment with PB (300 ppm), BB (1500 ppm) or EPH (500 ppm). In contrast, lean Zucker rats showed a strong response only to the highest dose of PB (500 ppm), implying that the diminished response in the Zucker rats may occur at some pretranslational level. Similar studies with lower doses of PB, EPH or BB in male lean Zucker rats showed a decreased response, relative to that in male F344/NCr rats. However, this insensitivity was not as profound as that observed in the female Zucker rats. In fact, the response to PB-type inducers in male or female Zucker rats is probably most clearly explained as a shift of the dose-response curve sharply to the right (decreased responsiveness, compared to F344/NCr or DA rats of the same sex). This decreased responsiveness of female lean Zucker rats to induction of CYP2B1, relative to that of F344/NCr rats, was also observed with the structurally-diverse PB-type inducers clonazepam, clotrimazole and 2-hexanone. In contrast, the female Zucker rat (obese or lean) displayed a pronounced response to induction of CYP1A-mediated ethoxyresorufin O-deethylase activity by beta-naphthoflavone, a prototype inducer of CYP1A1 and CYP1A2. The Zucker rat would thus appear to represent a potentially exploitable genetic model for examining the mechanism of enzyme induction by the myriad xenobiotics which induce a PB-type response.

Animals↗
PubMed1992

Tamoxifen prevents induction of hepatic neoplasia by zeranol, an estrogenic food contaminant.

Zeranol (alpha-zearalanol) is a beta-resorcylic acid lactone (RAL) that has estrogen activity. It is synthesized by molds and is difficult to avoid in human food products. We tested the ability of this mycoestrogen to damage the liver of the Armenian hamster, a rodent that is especially sensitive to hepatotoxic effects of exogenous estrogens. Zeranol induced acute hepatotoxicity and, subsequently, hepatic carcinogenesis; both effects were blocked by tamoxifen, suggesting estrogen receptor mediation. Because zeranol is acting alone as a primary initiator of hepatic neoplasms, this model provides an unusual opportunity to study the pathogenesis of estrogen-initiated tumorigenesis.

Animals↗
PubMed1992

Vacuolar H(+)-translocating ATPases from plants: structure, function, and isoforms.

The vacuolar H(+)-translocating ATPase (V-type ATPase) plays a central role in the growth and development of plant cells. In a mature cell, the vacuole is the largest intracellular compartment, occupying about 90% of the cell volume. The proton electrochemical gradient (acid inside) formed by the vacuolar ATPase provides the primary driving force for the transport of numerous ions and metabolites against their electrochemical gradients. The uptake and release of solutes across the vacuolar membrane is fundamental to many cellular processes, such as osmoregulation, signal transduction, and metabolic regulation. Vacuolar ATPases may also reside on endomembranes, such as Golgi and coated vesicles, and thus may participate in intracellular membrane traffic, sorting, and secretion. Plant vacuolar ATPases are large complexes (400-650 kDa) composed of 7-10 different subunits. The peripheral sector of 5-6 subunits includes the nucleotide-binding catalytic and regulatory subunits of approximately 70 and approximately 60 kDa, respectively. Six copies of the 16-kDa proteolipid together with 1-3 other subunits make up the integral sector that forms the H+ conducting pathway. Isoforms of plant vacuolar ATPases are suggested by the variations in subunit composition observed among and within plant species, and by the presence of a small multigene family encoding the 16-kDa and 70-kDa subunits. Multiple genes may encode isoforms with specific properties required to serve the diverse functions of vacuoles and endomembrane compartments.

Amino Acid Sequence↗
PubMed1992

Effects of the oxazolidinedione anticonvulsants trimethadione and dimethadione and the barbiturate homolog 5,5-dimethylbarbituric acid on N-nitrosodiethylamine-initiated renal and hepatic carcinogenesis in the F344/NCr rat.

The oxazolidinedione anticonvulsant trimethadione (3,5,5-trimethyl-2,4-oxazolidinedione, TMO) as well as its major metabolite, dimethadione (5,5-dimethyl-2,4-oxazolidinedione, DMO), and a structural analog from the barbiturate series, 5,5-dimethylbarbituric acid (DMB), were fed to F344/NCr male rats previously given a single initiating injection of N-nitrosodiethylamine (NDEA). The known promoter, phenobarbital (5-ethyl-5-phenylbarbituric acid, PB), was employed in this study as a positive control. At dosage levels equimolar to 500 ppm PB, none of the three compounds promoted development of hepatocellular adenomas or carcinomas, in contrast to PB. The two oxazolidinedione analogs and DMB caused minimal or no induction of cytochrome P450 isozyme 2B1 (CYP2B1)-mediated alkoxyresorufin O-dealkylase activities following short-term (2 weeks) feeding to separate groups of 6-week-old male F344/NCr rats, in contrast to the dramatic induction caused by PB. Promotion of neither thyroid nor renal neoplasia was observed following prolonged feeding of any of the tested compounds, although a significantly higher frequency of premalignant renal cortical tubular lesions (dysplasias) was seen in rats exposed to TMO following NDEA initiation than in those treated with NDEA alone. These studies provide important additional data on structure/liver tumor promoting activity relationships, and yield further evidence that within this group of structurally related anticonvulsants, it is possible to separate anticonvulsant activity from tumor promoting activity in the rat liver.

Animals↗
PubMed1992

Lack of renal tumour-initiating activity of a single dose of potassium bromate, a genotoxic renal carcinogen in male F344/NCr rats.

The renal tumour-initiating activity of potassium bromate (KBrO3), a known genotoxic rat renal carcinogen, was investigated in male F344/NCr rats. 6-wk-old rats were given KBrO3 intragastrically as a single dose of 300 mg/kg body weight, which was confirmed by our preliminary toxicity study as a maximum tolerated single dose for this strain of rat. Starting 2 wk after KBrO3 treatment, groups of 39 rats received either a basal diet or a diet containing 4000 ppm barbital sodium (BBNa) as a promoting regimen and were killed at 30, 52, or 104 wk. Control rats received either dietary BBNa (4000 ppm) or the basal diet alone from wk 2 to 52 or 104 wk. Nephropathy was observed in all rats treated with KBrO3 followed by BBNa at 30 wk and in rats receiving BBNa alone, but not in rats exposed to KBrO3 alone. Dysplastic renal tubular cell foci (DTF), putative preneoplastic renal tubular cell lesions were found associated with nephropathy in rats exposed to KBrO3 followed by BBNa from 47 wk. The incidences and multiplicities of DTF and renal tubular cell tumours observed from 31 to 104 wk revealed no initiating effect of KBrO3 treatment. These results indicate that the KBrO3 dose of 300 mg/kg did not initiate renal carcinogenesis.

Animals↗
PubMed1992

A 4-week feeding study of ground red chilli (Capsicum annuum) in male B6C3F1 mice.

The toxicity of red chilli was examined in male B6C3F1 mice fed a commercial meal diet mixed with ground Capsicum annuum (Linn.) at levels of 0.5, 1.0, 2.5, 5.0, 7.5 and 10% by weight. Mice were offered control or test diets ad lib. starting at 6 wk of age. Food consumption was measured daily and individual body weights recorded weekly for the 4-wk feeding period. General health, body weight and food intake were apparently not adversely affected at any level of pepper consumption. Histopathological evaluation revealed slight glycogen depletion and anisocytosis of hepatocytes in the 10% group. However, other organs did not reveal any lesions attributable to the chilli exposure. It appears that red chilli is relatively non-toxic at the doses tested in male B6C3F1 mice.

Animal Feed↗
PubMed1992

Tumor-promoting and hepatocarcinogenic effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in DBA/2NCr and C57BL/6NCr mice and an apparent promoting effect on nasal cavity tumors but not on hepatocellular tumors in F344/NCr rats initiated with N-nitrosodiethylamine.

The tumor-promoting and carcinogenic effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in the liver and in other organs were quantified and compared to those of phenobarbital (PB) in two inbred strains of mice (C57BL/6NCr, DBA/2NCr) and in F344/NCr rats initiated at 5 weeks of age with N-nitrosodiethylamine (NDEA; 90 mg/kg in mice, 75 mg/kg in rats). Two weeks later animals were placed on a regimen of TCPOBOP once every 2 weeks (administered i.p. or i.g.) or on a diet containing 500 p.p.m. PB as a positive control for the duration of the experiment. Mice were administered TCPOBOP (3.0 mg/kg/dose) for 30 weeks followed by control diet, while rats were given the TCPOBOP regimen (3.0 or 30 mg/kg/dose) for the full 78 weeks of the experiment. TCPOBOP was a complete carcinogen and an extremely potent promoter in both strains of mice, particularly the DBA strain in which NDEA followed by TCPOBOP (i.p.) resulted in death of all the animals within 30 weeks from multiple hepatocellular tumors. TCPOBOP alone induced 100% tumor incidence in DBA mice within 60 weeks. In addition, in both strains of mice, a high proportion of those animals with liver tumors had metastases to the lungs. In contrast, TCPOBOP was ineffective as a liver tumor promoter in F344 rats at even 10 times the dose administered to mice. Interestingly however, TCPOBOP, when given subsequent to NDEA, caused a significant increase in nasal cavity tumors in F344 rats. PB was an effective liver tumor promoter in male DBA mice and male F344 rats, but was relatively ineffective as a promoter in C57 mice. When tumor-promoting activity and induction of cytochrome P450 IIB1 were compared, good agreement between these two parameters was observed. PB was an effective inducer of P450 IIB1 in the rats and in both strains of mice and a potent liver tumor promoter in both DBA mice and F344 rats, whereas TCPOBOP was a potent inducer and tumor promoter in both strains of mice but was negligibly effective as either an inducer or a promoter in F344 rats at even 10-fold higher dosage.

Animals↗
PubMed1992

Progressive atypia in spontaneous and N-nitrosodiethylamine-induced hepatocellular adenomas of C3H/HeNCr mice.

The progression of hepatocellular adenomas to carcinomas has been less well documented in mice than in rats. We studied progression of spontaneous and chemically induced hepatocellular adenomas in male C3H/HeNCr mice by image analysis. Spontaneous lesions in 15, 18 and 21 month old untreated male C3H/HeNCr mice and experimentally induced lesions were examined. Experimental group 1 received a single i.p. injection of N-nitrosodiethylamine (DEN) (5 mg/kg body wt) at 15 days of age. Groups 2 and 3 were injected a second time with DEN at 15 or 20 weeks of age (75 mg/kg body wt), with interim sacrifices at 11, 16 and 34 weeks after the second DEN injection. Atypia in adenomas were classified into four grades according to cell size, tinctorial changes, cellular pleomorphism and trabecular pattern. At earlier stages of the neoplastic process (11 or 16 weeks after the second DEN dose), most adenomas were well-differentiated lesions with no atypia or focal grade 1 or 2 atypia. At later stages (34 weeks after the second DEN dose), a large proportion of hepatocellular tumors were classified as adenoma with grade 3 atypia or carcinoma. The proportion of carcinomas in mice treated with a second dose of DEN at 20 weeks of age was significantly higher than in mice treated with a single dose of DEN or in mice given a second dose of DEN at 15 weeks. A positive correlation was found between increase in the size of lesions and increased atypia in both spontaneous and DEN-induced lesions and with age for spontaneous tumors. These results support the hypothesis that mouse hepatocellular adenomas are truly neoplastic lesions in different stages of progression toward malignancy.

Aging↗
PubMed1992

Up-and-down regulation of skeletal muscle acetylcholine receptors. Effects on neuromuscular blockers.

Multiple factors alter the interaction of muscle relaxants with the NMJ. This review has focused on the aberrant responses caused principally by alterations in AChRs (table 1). Many pathologic states increase (up-regulate) AChR number. These include upper and lower motor neuron lesions, muscle trauma, burns, and immobilization. Pre- or postjunctional inhibition of neurotransmission by drugs or toxins also up-regulate AChRs. These include alpha- and beta-BT, NDMR, anticonvulsants, and clostridial toxins. We speculate that other bacterial toxins also up-regulate AChR. With proliferation of AChRs, agonist drug dose-response curves are shifted to the left. The exaggerated release of potassium when depolarization occurs with the use of agonists such as SCh and decamethonium can be attributed to the increased number of AChR. Thus, SCh should be avoided in patients who are in the susceptible phase (see section V). In the presence of increased AChR, the requirement for NDMR is markedly increased. Thus, the response to NDMR may be used as an indirect estimator of increased sensitivity to SCh (table 1). The most extensively studied pathologic state in which there is a decrease in AChRs is myasthenia gravis; there is immunologically mediated destruction and/or functional blockade of AChRs. The pathophysiologic and pharmacologic changes in LEMS are quite distinct from those of myasthenia gravis. Decreased AChRs in myasthenia gravis result in resistance to agonists and increased sensitivity to competitive antagonists. In conditioning exercise, the perturbed muscles show sensitivity to NDMR that may be due to decreased AChRs. Chronic elevations of ACh observed with organophosphorus poisoning or chronic use of reversible cholinesterase inhibitors results in down-regulation of AChRs. In this condition, SCh should be avoided because its metabolic breakdown would be impaired; the requirement for NDMR may be decreased. All of the varied responses to SCh and NDMR, which are associated with concomitant changes in AChRs, are analogous to drug-receptor interactions observed in other biologic systems.

Animals↗
PubMed1992

Persistent infection of rabbits with bovine immunodeficiency-like virus.

Chronic infection of rabbits was induced by a single intraperitoneal injection of bovine immunodeficiency-like virus (BIV)-infected cells. Ten BIV-infected animals were monitored serologically for up to 2 years. Results of serologic and virus rescue assays indicated that all animals became infected and demonstrated a rapid and sustained BIV-specific humoral response. BIV was rescued by cocultivation from spleen, lymph nodes, and peripheral blood leukocytes of infected animals. Viral DNA in immune tissues was confirmed by polymerase chain reaction amplification of BIV sequences. These data and specific immunohistochemical staining of mononuclear cells of the spleen for BIV antigen suggest that the infection is targeted to immune system cells.

Animals↗
PubMed1992

Tolerance and upregulation of acetylcholine receptors follow chronic infusion of d-tubocurarine.

The hypothesis that chronic competitive antagonism of nicotinic acetylcholine receptors (nAChR), even in the absence of immobilization or paralysis, induces proliferation of the receptor and tolerance to the competitive antagonist was tested. Chronic antagonism of the nAChR was achieved in rats by an infusion of d-tubocurarine (dTC) via subcutaneously placed osmotic pumps. After 2 wk of dTC or saline, the neuromuscular pharmacodynamics and nAChR number were examined. No differences in weight gain or mobility were observed between groups. Chronic dTC infusion at 2 wk resulted in a baseline concentration of 0.41 +/- 0.07 (SE) micrograms/ml, which, if achieved acutely, would cause a depression of the twitch tension to 60% of control twitch height. Moreover the experimental group was able to develop a baseline twitch tension of 50 g, similar to that of controls. Despite the baseline dTC concentration in the experimental group, the effective doses of dTC for twitch depression were similar to those of controls. The plasma dTC concentration required for steady-state twitch inhibition was significantly (P less than 0.05) higher in the experimental group (0.83 +/- 0.04 vs. 0.50 +/- 0.15 micrograms/ml) as were the extrajunctional nAChR (19.76 +/- 1.77 vs. 13.37 +/- 1.82 fmol/mg protein). The diaphragmatic nAChR were unaltered. This study confirms that chronic doses of dTC cause tolerance to its effects and proliferation of nAChR even in the absence of immobilization. The absence of nAChR changes in the diaphragm may be due to the higher margin of safety of the diaphragm for muscle relaxants than for peripheral muscles. Intensive Care Unit patients receiving chronic infusions of dTC to facilitate mechanical ventilation will require increased doses with time.

Animals↗
PubMed1992

Immunohistochemical evidence of high concentrations of metallothionein in pancreatic hepatocytes induced by cadmium in rats.

A recent study from our laboratory has shown that cadmium, a toxic heavy metal, is one of the most effective agents known for inducing hepatocytic transdifferentiation of the rat pancreas. With repeated injections of cadmium, the incidence of rats with pancreatic hepatocytic foci can be as high as 93%. Cadmium is also well known as a very potent inducer of metallothionein, a metal-binding protein that appears to be important in the biologic response to several toxic heavy metals in most tissues, including the pancreas. Therefore, the present study sought to determine if metallothionein was associated with cadmium-induced transdifferentiation of pancreatic cells. Expression of metallothionein was studied immunohistochemically by the peroxidase-antiperoxidase method in tissue sections of the pancreas of rats with pancreatic hepatocytes. High levels of metallothionein were localized primarily within the pancreatic hepatocytes. Surrounding normal pancreatic islet and acinar cells were not immunoreactive. Thus, metallothionein is expressed actively in cells transdifferentiated to hepatocytes by cadmium within the pancreas.

Animals↗
PubMed1992

Induction of tumours of the haematopoietic system by cadmium in rats.

Several of our recent studies in rats indicate an association between exposure to cadmium and haematopoietic tumours. In the first study, male WF rats received dietary cadmium (0-200 micrograms/g cadmium as cadmium chloride) for up to 77 weeks. A dose-related increase in large granular lymphocyte (LGL) leukaemia was observed with a maximal incidence in rats fed 100 micrograms/g cadmium. In a second study, male F344 rats received a single high dose of cadmium chloride (30 mumol/kg, s.c.) and were observed for 90 weeks. The high natural incidence of leukaemia in these rats (24%) was markedly reduced (6%) by this dose of cadmium. The paradoxical effects of cadmium on haematopoietic tumours may be the result of a dose-related spectrum of lymphotoxicity ranging from cell-specific cytotoxicity and carcinogenicity to destruction of key progenitor cell populations.

Animals↗
PubMed1992

Vimentin metaplasia in renal cortical tubules of preneoplastic, neoplastic, aging, and regenerative lesions of rats and humans.

Vimentin expression was studied immunohistochemically in renal cortical tubules of untreated male rats of various ages, rats exposed to toxins (barbital sodium, folic acid) and carcinogens (streptozotocin, N-bis(2-hydroxypropyl)nitrosamine, barbital sodium, and in humans of various ages with or without renal epithelial tumors. Fetal, neonatal, and young adult rats did not express vimentin in renal cortical tubules. Regenerative renal tubular lesions from rats with aging nephropathy and from rats with toxic nephropathy both expressed vimentin. Mitogenic lesions induced by folic acid at 24 hours, however, were not immunoreactive for vimentin. Carcinogen-induced preneoplastic renal cortical tubular lesions in rats were most often focally immunoreactive whereas strong vimentin expression was found in almost all induced renal tumors. In kidneys of three children (younger than 2 years of age), vimentin was not found in renal cortical tubular cells except in rare individual cells in one case. Vimentin was abundant in basophilic regenerative tubules in kidneys of aged individuals, however. Most (7/10) human renal carcinomas and latent preneoplastic or neoplastic renal tubular lesions found incidentally at autopsy (2/4) showed vimentin expression. The authors suggest that the switching to vimentin expression in phenotypically normal renal cortical tubular cells in rats and humans, which do not usually express the intermediate filament protein vimentin, should be considered vimentin metaplasia. Vimentin expression is dissociated from increased cell proliferation in hyperplastic and neoplastic lesions, however. Instead the degree of dedifferentiation of the tubule cells and changes in phenotype were associated with vimentin expression.

Age Factors↗