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Biomedical subjects

C E Sarraf

Publications and source records attributed to C E Sarraf.

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

The role of growth factors in gastrointestinal cell proliferation.

The epithelial lining of the gastrointestinal (GI) tract is in a state of continuous cell renewal, and the proliferating and differentiating/differentiated cell populations are spatially clearly demarcated. Members of the epidermal growth factor (EGF) family of peptides, the trefoil peptides and enteroglucagon appear to be the most important enterotrophic molecules for both normal cell renewal and healing after cell damage. Transforming growth factor-a (TGF-a) appears to be the primary physiological ligand for the EGF receptor (EGFR), promoting normal cell renewal, and TGF-a/EGFR are part of an autocrine loop in many intestinal cancers. In response to damage, a differentiating cell lineage arises from adjacent epithelium secreting EGF, TGF-a and trefoil peptides; this may be viewed as part of a 'repair kit' in damaged endodermally-derived tissue.

Animals↗
PubMed1994

Perioperative histologic and ultrastructural changes in the pericardium and adhesions.

The presence of pericardial adhesions prolongs the operation time and increases the risk of serious damage to the heart and other major vascular structures during resternotomy. The reported incidence of such damage is 2% to 6%. Pericardial mesothelial cells exhibit fibrinolytic activity, and therefore have an actual or potential role in the breakdown of the fibrinous adhesions that serve as the initial scaffolding for the firm collagenous adhesions seen at reoperation. Ten patients undergoing primary cardiac procedures were studied to assess the morphologic changes that take place within the pericardium and to relate these to accompanying changes in the pericardial plasminogen activating activity. Samples were taken at 0, 75, and 135 minutes after pericardiotomy. Compared with samples obtained at the time of pericardiotomy, those taken at 75 and 135 minutes demonstrated a significant progression in the mesothelial cell damage (p < 0.01), together with increasing evidence of pericardial inflammation (p < 0.01). The findings from electron microscope studies confirmed and supplemented these findings. Furthermore, compared with its initial levels (median, 2.06 IU/cm2; range, 1.28 to 6.48 IU/cm2), the plasminogen activating activity of pericardial biopsy specimens was significantly reduced at 75 minutes (median, 0.64 IU/cm2; range, 0.12 to 2.44 IU/cm2; P < 0.05), with some recovery at 135 minutes (median, 1.45 IU/cm2; range, 0.12 to 4.39 IU/cm2; p = 0.059). This study has revealed that, during cardiac procedures, the pericardium undergoes inflammatory changes with concomitant damage to its mesothelium, together with a reduction in the pericardial mesothelial fibrinolytic potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Squamous cell carcinoma of the feline thymus with widespread apoptosis.

The present report documents a case of squamous cell carcinoma originating from the thymus of a 12-year-old short-haired male cat. The tumour had metastasised to the sternal lymphoid tissue and to the left lung. To the authors' knowledge, thymic carcinoma has not been reported in domestic animals. Furthermore, extensive apoptosis was observed in the tumour mass.

Animals↗
PubMed1993

Expression of hepatocyte growth factor mRNA during oval cell activation in the rat liver.

The customary wave of hepatocyte regeneration which occurs in the rat liver after two-thirds partial hepatectomy can be abolished by oral administration of the carcinogen 2-acetylaminofluorene. Instead, regeneration is achieved through the proliferation and differentiation of potential stem cells (oval cells) which appear to emanate from the portal space. Ultrastructural studies have illustrated the undifferentiated nature of these cells in the first 3 days after resection, but very rapidly they acquire features of small hepatocytes or biliary epithelia. Oval cell progeny can form either cohesive columns of cells within sinusoids which may later differentiate into new hepatic plates, or single cells that can insinuate within existing plates. Using a 35S antisense riboprobe to hepatocyte growth factor (HGF) mRNA, the synthesis of HGF mRNA was observed in sinusoid-lining cells. There were few HGF mRNA-expressing cells in the liver removed at resection, but numbers steadily increased in the remnant over the next 7 days. In particular, an almost nine-fold increase in the density of HGF mRNA-producing cells occurred in the periportal areas, resulting in approximately double the density present within the centrilobular parenchyma. The superabundance of HGF-producing cells in the immediate vicinity of oval cell proliferation and differentiation strongly suggests that this growth factor is involved in all aspects of stem cell behaviour--proliferation, migration, and differentiation, through a paracrine mechanism.

Animals↗
PubMed1993

Bromodeoxyuridine-labelled apoptosis after treatment with antimetabolites in two murine tumours and in small intestinal crypts.

Antimetabolites are S-phase specific anticancer drugs. Administration of bromodeoxyuridine (BrdUrd) to tumour bearing mice was followed by treatment with cytosine arabinoside or hydroxyurea. Anti-BrdUrd immunocytochemistry visualised susceptible tumour and intestinal crypt cells at electron microscope level, showing unequivocally that cells that were in S-phase at the time of administration of the drugs subsequently died by apoptosis.

Animals↗
PubMed1993

Severe subcellular damage in the rat exocrine pancreas after pancreatobiliary diversion.

Cholecystokinin (CCK) may contribute to the genesis of both pancreatic carcinoma and acute pancreatitis. By transposing a long segment of jejunum to lie between the pylorus and the duodenal papilla, pancreatobiliary diversion (PBD) causes a persistent increase in circulating CCK levels, as the normal feedback inhibition of jejunal CCK release by pancreatic juice is evaded. A number of morphological, physiological, and acinar cytokinetic changes ensue. This investigation has examined the ultrastructural changes in pancreatic acinar cells after PBD in the presence and absence of CR1409 (lorglumide), a CCK receptor antagonist. After 14 days there was degranulation and vacuolation of acinar cells with involvement of the enzyme acid phosphatase. The presence of morphologically distinct extracisternal acid phosphatase indisputably predisposed acinar cells to severe damage. Treatment with CR1409 largely prevented degranulation after PBD, but vacuolation of acinar cells still occurred, indicating a possible toxic effect of the receptor antagonist. This is the first report of CCK itself, rather than one of its analogues, causing in vivo pancreatic damage that is generally considered as a forerunner to acute pancreatitis. This is of fundamental importance to the understanding of the earliest stages of the disease.

Acid Phosphatase↗
PubMed1993

Transforming growth factor-alpha immunoreactivity in a variety of epithelial tissues.

The immunohistochemical expression of transforming growth factor-alpha (TGF alpha) has been examined in a range of normal adult epithelial tissues from both man and rat using an anti-hTGF alpha monoclonal antibody (GF10). No differences in distribution were apparent between man and rat. In the continually renewing epithelium of the gastrointestinal tract, no staining was seen within the proliferative compartments, but strong immunoexpression was noted in various differentiated populations. In the testis, the spermatogonia were unstained, but the more luminally orientated germ cells were strongly positive. In the gastrointestinal tract, at least, any mitogenic action of TGF alpha must be mediated through a relatively long paracrine loop. In contrast, the differentiated parenchyma of kidney, salivary gland and liver remained unstained apart from collecting ducts in the kidney, striated ducts in salivary glands and bile ducts in the liver. The association of TGF alpha with tubule formation was reinforced by the very strong staining of newly forming bile ducts in a model of liver oval cell proliferation. Thus, in all the epithelia studied there was a distinct spatial pattern of TGF alpha immunoreactivity.

Adult↗
PubMed1993

Evaluation of a proposed technique to assess unscheduled DNA synthesis and genotoxicity.

Results from a recent, new assay suggest that omeprazole, a potent inhibitor of gastric acid secretion, is genotoxic. The principle of this assay is that the non-proliferating zone of surface gastric epithelial cells can be selectively removed by controlled digestion so that any incorporation of tritiated thymidine into these cells represents unscheduled DNA synthesis. Parietal cells (which are located below the uppermost proliferating cells) and proliferating cells in semiconservative, regular DNA synthesis could always be shown in the digested fraction, and as regular DNA synthesis takes up a thousand fold more thymidine than unscheduled DNA synthesis, any signal from unscheduled synthesis would therefore be swamped. The digestion process was also uneven, as histological analysis showed denuded patches of mucosa, and gland like structures were seen in the digest. Quantification of the number of silver grains over the nuclei showed no increase in low level labelling after omeprazole administration, indicating that there was no unscheduled DNA synthesis. The labelling index of undigested gastric tissue from omeprazole treated rats was not significantly different from that of the control group, despite an increase in the plasma gastrin value.

Animals↗
PubMed1992

The nature of cytotoxic drug-induced cell death in murine intestinal crypts.

The nature of cell death in murine small intestinal crypts caused by potentially lethal doses of four classes of cancer chemotherapeutic agents was studied. The drugs used were cytosine arabinoside, vincristine, adriamycin and nitrogen mustard. The compounds readily induced massive cell death in the proliferating compartment of the crypt. In each case, cell death was apparent within an hour, and the incidence of dead cells peaked during the following 4-8 h. By 24 h, little damage was discernible in the crypt systems. Remarkably, dead cells or dead cell fragments were phagocytosed rapidly (within about 1 h) by neighbouring healthy enterocytes. When examined by light microscopy, transmission electron microscopy and scanning electron microscopy, the dead cells showed the characteristic features of having succumbed to an apoptotic mode of cell death without any trace of cell and organelle oedema characteristic of necrosis. The study suggests that cell death by apoptosis operates even when the cells are exposed to severe pathological perturbation and that the phenomenon is not solely a process which operates in response to either physiological stimuli or to mild physical or chemical trauma.

Animals↗
PubMed1992

Role of cholecystokinin in pancreatic adaptation to massive enterectomy.

Since pancreatic adaptation to massive proximal small bowel resection (PSBR) may be modulated through cholecystokinin (CCK) secretion, we tested the effect of the CCK antagonist CR-1409 on this response. Male Wistar rats (n = 72) weighing 220-225 g were randomised to receive either PSBR or transection/resuture followed by saline or CR-1409 (12 mg/kg daily subcutaneously). Rats were killed one, two, and three weeks post-operatively, at which time blood was obtained for CCK assay and the pancreas was assessed for proliferative activity by three parameters: nucleic acid and protein content, bromode-oxyuridine (BrdUrd) labelling index, and proliferating cell nuclear antigen (PCNA) expression. PSBR increased plasma CCK concentration by 83-102% at 1-3 weeks, irrespective of CR-1409 administration. Total pancreatic DNA content per 100 g body weight increased by 34% at two weeks (p less than 0.05) and by 82% at three weeks (p less than 0.05), while RNA content increased by 60% and 178% (p less than 0.001) and protein content by 20% and 57% (p less than 0.05). PSBR increased the BrdUrd labelling index and the percentage of PCNA immunoreactive cells. CR-1409 completely abolished this proliferative response and also prevented the rise in nucleic acid and protein contents. Apart from growth stimulation, PSBR also enhanced pancreatic exocrine function, as shown by ultrastructural evidence of an appreciable decrease in zymogen granules; CR-1409 also inhibited this functional effect of hypercholecystokininaemia. The results confirm the tropic role of CCK after PSBR, and CR-1409 prevents this pancreatic adaptation.

Animals↗
PubMed1992

Apoptosis: a gene-directed programme of cell death.

Apoptosis is a particular type of programmed cell death which commonly occurs in the developing embryo, in normal healthy adult tissues and in many pathological settings. In contrast to necrosis, apoptosis is not a passive phenomenon but is gene-directed, usually requiring ongoing protein synthesis. The dying cell is characterised by having a raised level of cytosolic Ca2+; this activates a non-lysosomal Ca(2+)- and Mg(2+)-dependent endonuclease which digests the chromatin into oligonucleosome length fragments. The dying cell may or may not fragment into a number of apoptotic bodies, but in all cases the cell contents are bounded by a membrane which prevents the spillage of harmful substances such as DNA. Apoptotic cells are eliminated through phagocytosis by neighbouring cells and macrophages, and cell surface changes on apoptotic cells aid their recognition and engulfment by the phagocytosing cells. Extrinsic signals can both stimulate and inhibit apoptosis, and even direct damage to the cell can activate the process. Apoptosis is widely involved in organ formation in the embryo, and its occurrence in response to noxious stimuli such as cytotoxic drugs, irradiation and hyperthermia may be viewed as an altruistic suicide. Apoptosis provides a safe disposal mechanism for neutrophils at inflamed sites, and within the immune system it is considered responsible for eliminating self-reactive T-cell clones and for the affinity maturation of antibody producing cells. A failure to undergo apoptosis has been invoked in the pathogenesis of low-grade follicular lymphoma, and the triggering of apoptosis with monoclonal antibodies specifically in tumour cells has been achieved in one or two cases.

Animals↗
PubMed1992

The biology and pathology of programmed cell death (apoptosis).

Apoptosis is a process by which cells die in a controlled and programmed manner in response to specific stimuli, often following extrinsic and intrinsic signals which ultimately cause the "switching on" of cell death regulatory genes. Condensation of chromatin and cytoplasm, fragmentation of the cell and formation of membrane-bound bodies containing intact organelles (apoptotic bodies), and phagocytosis of these bodies by resident cells are the major structural changes associated with apoptosis. Biochemically, activation of a nonlysosomal endonuclease is a cardinal feature of this mode of cell death. Several genes have been implicated in the execution of apoptosis. A signal transduction mechanism is suspected to regulate the phenomenon. Although apoptosis is widely considered as an adaptive response to physiological or near physiological stimuli, several noxious agents can initiate the reaction and thus it is often a toxicological response.

Animals↗
PubMed1991

Variations in the occurrence of silver-staining nucleolar organizer regions (AgNORs) in non-proliferating and proliferating tissues.

Previous studies on the subject of silver-staining nucleolar organizer regions (AgNORs) as indicators of precise proliferative status of tissues have sometimes resulted in ambiguity. The studies, however, have most frequently addressed themselves to the prognosis of neoplasias, with the aim of using AgNORs principally to distinguish between benign and malignant tumours. This investigation was to determine a base-line relationship of AgNOR clusters to proliferation and thus concentrated on normally proliferative tissues and conditionally renewing tissues after appropriate stimulation. Two murine transplantable tumours were also examined as examples of frank malignancy. As an example of the former, variations in AgNOR clusters were noted in the small intestine of man, mouse, and rat. The conditionally renewing systems of liver, prostate, and salivary glands were stimulated into proliferation by two-thirds partial hepatectomy, castration followed by treatment with testosterone, and isoproterenol treatment, respectively, in rat models; the murine sarcoma SaF and carcinoma CaNT provided relatively simple malignant tumours for AgNOR investigation. Proliferation was monitored by noting labelling indices after injection with bromodeoxyuridine (BrdUrd) in vivo followed by immunocytochemical visualization of S-phase cells. In all tissues, an increase in the size of AgNOR clusters rather than their number correlated positively with elevated labelling, particularly with the emergence of silver-staining regions of 2-3 microns visible diameter. Thus, increased AgNOR cluster size (diameter) as representative of AgNOR cluster/nucleolus volume was found to be dependent on proliferative activity in a range of normal and neoplastic tissues.

Animals↗
PubMed1991

Effect of alpha-difluoromethylornithine on the polyamine levels and proliferation in two transplantable tumours.

The effect of inhibition of polyamine biosynthesis by alpha-difluoromethylornithine (DFMO) on the growth of two murine transplantable tumours was studied. Female CBA mice were implanted with either the sarcoma F (SaF) or an anaplastic mammary carcinoma (CaNT), and 3% DFMO in the drinking water was provided once the tumours were established. Over a 10-day period control SaF tumours increased exponentially from 20 mm3 to over 800 mm3, whereas DFMO-treated SaF reached only 300 mm3. CaNT grew more slowly, requiring 22 days to achieve a similar volume increase, and DFMO was as effective in retarding growth as it had been in SaF. DFMO depleted tumour tissues of putrescine and spermidine, but did not reduce spermine levels. Metaphase arrest experiments with vincristine demonstrated that DFMO could substantially reduce the rates of tumour cell production, but there was no indication the DFMO accelerated the rate of cell loss from the tumours. Despite reduced rates of cell production, labelling studies with bromodeoxyuridine failed to detect differences between control and treated tumours: an increase in transit time through the S-phase was suspected. The number of nuclear organizer regions, detected by the argyrophilia of their associated proteins, was less in DFMO-treated tumours, and within a tumour the degree of silver deposition unequivocally reflected the proliferative heterogeneity. Ultrastructural studies revealed no differences between DFMO-treated and untreated tumours.

Animals↗
PubMed1991

Interleukin-1 beta stimulates human mesangial cells to synthesize and release interleukins-6 and -8.

Interleukin-1 beta (IL-1 beta) and tumor necrosis factor (TNF) have been reported to stimulate human mesangial cells (HMC) to proliferate and synthesize eicosanoids. We have examined whether they also induce HMC to release cytokines. In this study we show that both IL-1 and TNF stimulate HMC to release IL-6 and IL-8. Cycling and quiescent HMC were stimulated with various concentrations of either recombinant IL-1 beta or TNF for 1 to 24 hours. IL-1 beta at doses as low as 6 pg/ml stimulated mesangial cells to synthesize mRNA for both IL-6 and IL-8 as assessed by Northern analysis; mRNA for tubulin remained constant, which demonstrated a specific increase in mRNA. Secretion of IL-6 and IL-8 into the culture medium increased (4.5 to 18 ng/ml and 4 to 40 ng/ml, respectively) measured by ELISAs. TNF had similar effects but only in high concentrations (greater than 100 ng/ml). IL-1 beta did not stimulate cells to proliferate, as measured by 3H thymidine incorporation. TNF caused proliferation but only in concentrations over 100 ng/ml. We conclude that IL-1 beta is a potent stimulator of human mesangial cell production of IL-6 and IL-8, both of which may influence injury in nephritis. TNF also stimulates mesangial cells but only in pharmacological doses.

Cells, Cultured↗
PubMed1991

Inhibitory effect of a cholecystokinin antagonist on the proliferative response of the pancreas to pancreatobiliary diversion.

Since pancreatobiliary diversion probably stimulates pancreatic growth by increasing cholecystokinin secretion, the effect of the cholecystokinin antagonist CR-1409 on this adaptive response was tested. Male Wistar rats (n = 108) weighing 220-250g were randomised to receive either pancreatobiliary diversion (n = 60) or sham diversion (n = 48) and thereafter to receive either saline injections or CR-1409 (10 mg/kg/day, subcutaneously). Rats were killed at four, seven, and 14 days postoperatively, when blood was obtained for cholecystokinin assay and the pancreas was assessed for proliferative activity by three techniques: nucleic acid and protein assay, bromodeoxyuridine labelling, and metaphase arrest after vincristine administration (1 mg/kg, intraperitoneally). Pancreatobiliary diversion increased plasma cholecystokinin concentrations by 91% at seven days and 137% at 14 days, irrespective of CR-1409 treatment. Total pancreatic RNA content was doubled by pancreatobiliary diversion at four days (2.15 v 1.07 mg/100 g body weight: p less than 0.001) and at seven days (3.43 v 1.76 mg/100 g: p less than 0.001), and trebled at 14 days (4.27 v 1.32 mg/100 g: p less than 0.001). Pancreatobiliary diversion increased bromodeoxyuridine labelling index from 1.1 to 3.7% at seven days and the cell birth rate from 0.09 to 0.06%. CR-1409 completely abolished this proliferative response and partly prevented the rise in RNA. The results confirm pancreatic hypertrophy and increased acinar cell proliferation after pancreatobiliary diversion. CR-1409 prevents this adaptive growth, probably by blocking cholecystokinin receptors. Bromodeoxyuridine labelling and the metaphase arrest technique may be used to assess pancreatic cell kinetics.

Adaptation, Physiological↗
PubMed1991

Proliferating cell nuclear antigen immunolocalization in gastro-intestinal epithelia.

Proliferating cell nuclear antigen (PCNA), also called DNA polymerase delta-associated protein, is found in the cells of the proliferative compartment of normal tissues and is essential for DNA replication. It can be recognized by many monoclonal antibodies to various epitopes on the molecule. In this investigation one of these, PC10, has been used on formalin-fixed, paraffin-embedded, human and rodent gastro-intestinal epithelial tissues to assess numerically the labelling index of PC10 and to compare it, in the rat liver and gastrointestinal tract, with the S-phase fraction as determined by bromodeoxyuridine (BrdUrd) labelling. The distribution of PC10-labelled cells was recorded with respect to cell position in the intestinal crypts of man. In tissues where both modes of assessment were used, PC10 staining in the well-established proliferative compartments was found to be more extensive than that of BrdUrd. The higher labelling index with PC10 can be explained by its identification of PCNA outside the S phase of the cell cycle and also by the long half-life of PCNA protein in post-proliferative intestinal epithelial cells as they migrate towards the villus. Nevertheless the data suggest PC10 immunostaining in gastro-intestinal epithelia is an operational marker of cell proliferation which is reproducible, quantifiable and can be performed on routinely processed tissues.

Animals↗