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Biomedical subjects

K Savage

Publications and source records attributed to K Savage.

At least 19 recordsLinked to original sources
PubMed1997

Small hepatocellular carcinomas in cirrhotic explant livers: identification by macroscopic examination and lipiodol localization.

Small hepatocellular carcinomas (HCCs) in cirrhotic livers are difficult to detect. This study aimed to assess if small HCCs can be better identified using specific macroscopic sampling criteria and Lipiodol (iodized oil) localization on radiographs, and to evaluate thereby their incidence and morphology. Prospective cirrhotic recipients of orthotopic liver transplantation (OLT) were administered hepatic arterial Lipiodol at angiography. Posttransplantation, the explant livers were sliced and inspected as per routine for unusual nodules. If unusual nodules were found or HCC clinically suspected, the slices underwent soft-tissue radiography. Tissue samples were then taken as per protocol from all nodules with diameter > or =1 cm/unusual appearance/exophytic bulge, and from foci of radiographic Lipiodol uptake or high soft-tissue density. One hundred three lesions were assessed and classified histologically as HCC (n = 55) or regenerative nodule (n = 39) or borderline (n = 9). Sampling according to predetermined macroscopic criteria proved an effective method for identifying small HCCs: 44 cancers were detected, most <5 mm in diameter, additional to those picked up on routine assessment. Green nodules were more likely to be HCC (P < .0001). The cancers were all multifocal, and had characteristic histological features of HCC except for 12 unusual fibrotic cancers in livers with alcoholic cirrhosis. Lipiodolization alone identified one additional HCC. Lipiodol retention on x-ray is fairly specific for HCC (83%), and can even identify lesions 2 mm in diameter. But its sensitivity is poor (45%), and its routine use to identify HCCs in explant livers is not recommended.

Carcinoma, Hepatocellular↗
PubMed1997

Lymphocyte and macrophage phenotypes in chronic hepatitis C infection. Correlation with disease activity.

The pathogenesis of chronic hepatitis C and the mechanisms underlying progressive liver disease in patients with chronic hepatitis C infection are poorly understood. To demonstrate which inflammatory cells might be responsible for the necroinflammatory damage in chronic hepatitis C infection, we have correlated the phenotype of the intrahepatic lymphocytes and macrophages with histological activity in liver biopsy and explant specimens from 19 patients with chronic hepatitis C infection. In all stages of disease, more CD8+ than CD4+ lymphocytes were found. However, histologically active versus histologically mild hepatitis was associated with a trend toward greater parenchymal concentrations of CD4+ lymphocytes (0.71 +/- 0.27 per 10(4) microns 2 versus 0.35 +/- 0.15; not significant), significantly less parenchymal CD8+ lymphocytes (0.90 +/- 0.1 versus 1.70 +/- 0.3; t = 2.32, P = 0.03) and a greater parenchymal CD4/CD8 ratio (4.1 +/- 2.8 versus 0.91 +/- 0.3; t = 1.65, P = 0.07). No difference was found in the number of cells containing cytotoxic granules between the two groups. Greater numbers of CD4+ lymphocytes were found in liver biopsy specimens with little or no staining for hepatitis C virus antigen (1.47 +/- 0.88 versus 0.27 +/- 0.27; t = 2.28, P < 0.05). No significant differences were found in the macrophage subsets between the three stages of disease. Our data suggest that active histological disease in chronic hepatitis C infection may be associated with an increase in CD4+ lymphocytes and suggest that CD4+ T cells may play an important role in the hepatic injury in these patients.

CD4-CD8 Ratio↗
PubMed1996

Complications of midtrimester pregnancy termination: the effect of prior cesarean delivery.

OBJECTIVE: Our purpose was to determine whether a prior cesarean delivery affects the incidence of complications in women having an indicated midtrimester medical pregnancy termination. STUDY DESIGN: A retrospective review of women who underwent a midtrimester medical termination of pregnancy from January 1980 to July 1995 ascertained obstetric history, uterotonic agent(s), and the occurrence of uterine rupture, blood transfusion, or curettage. The frequencies of maternal complications were compared in women with and without a prior cesarean section. RESULTS: Our study population included 606 women with a mean gestational age of 21.1 +/- 3.1 weeks and a mean maternal age of 26.3 +/- 7 years. Seventy-nine (13%) had undergone a prior cesarean section. There was no significant difference in the need for curettage between women with and without a prior cesarean section. However, there was an increased need for blood transfusions in women with a prior cesarean delivery (11.4% vs 5.3%, odds ratio 2.3, 95% confidence interval 1.1 to 5.0, p = 0.04). The incidence of uterine rupture was significantly higher among women with a prior cesarean (3.8% vs 0.2%, odds ratio 20.8, 95% confidence interval 14.1 to 104, p = 0.008). CONCLUSION: Our data suggest that a prior cesarean section is a risk factor for uterine rupture and blood transfusion in women having a midtrimester pregnancy termination.

Abortion, Induced↗
PubMed1996

HCV-associated hepatocellular carcinoma without cirrhosis.

BACKGROUND/AIMS: Hepatocellular carcinoma is an aggressive malignancy and carries a poor prognosis. Hepatitis B and C virus infection, cirrhosis and aflatoxin B1 exposure are considered major risk factors. The role of hepatitis C virus in the causation of hepatocellular carcinoma has been debated. It is a positive, single-stranded RNA virus without a DNA intermediate in its replicative cycle, so that integration of hepatitis C virus nucleic acid sequences into the host genome seems unlikely. The most plausible explanation of hepatitis C virus-associated hepatocellular carcinoma so far is that the virus causes necroinflammatory hepatic disease with vigorous regeneration, fibrosis, and eventually cirrhosis. The aim of this study was to examine the relationship of hepatitis C, cirrhosis and hepatocellular carcinoma. METHODS: Sixty-six consecutive patients with hepatocellular carcinoma undergoing resection or transplantation at the Royal Free Hospital were reviewed. A combination of serological data and polymerase chain reaction assay was used to assign hepatitis C virus and hepatitis B virus infection. RESULTS: We found four HCV-RNA positive patients with hepatocellular carcinoma without cirrhosis. All four cases were positive for HCV-RNA and negative for all markers of hepatitis B virus infection. CONCLUSIONS: These four cases show that hepatocellular carcinoma may develop in patients with hepatitis C virus without pre-existing cirrhosis. However, the precise role of hepatitis C virus in hepatocarcinogenesis, the carcinogenic potential of the different genotypes and whether this role is influenced by other risk factors still have to be clarified.

Aged↗
PubMed1995

Orthotopic liver transplantation for chronic hepatitis in two patients with common variable immunodeficiency.

Two patients with common variable immunodeficiency underwent orthotopic liver transplantation for chronic hepatitis, unequivocally caused by hepatitis C virus in one case. Although one patient had pneumonia 8 days after surgery and the other developed hepatic venular stenosis in the transplanted liver, both had a reasonably good quality of life for at least 15 months. However, both subsequently died of recurrent hepatitis C virus hepatitis or hemorrhage after splenectomy for hypersplenism. This shows that severe infection is not a major problem in patients with common variable immunodeficiency after liver transplantation provided they undergo prophylactic antimicrobial and immunoglobulin therapy. The longer term prognosis must be regarded as poor until more data are available following transplantation in similar patients.

Adolescent↗
PubMed1995

Detection of HCV-RNA in paraffin-embedded liver biopsies from patients with autoimmune hepatitis.

BACKGROUND/AIMS: There may be a relationship between autoimmune hepatitis and viral infection. To examine this relationship, 19 patients with autoimmune hepatitis and/or chronic hepatitis C were studied. METHODS: Patients were selected initially on the basis of having autoantibodies (anti-nuclear, anti-smooth muscle, or anti-liver-kidney microsomal) in serum. Formalin-fixed, paraffin-embedded liver biopsies from these patients were tested for HCV-RNA by polymerase chain reaction. The biopsies were examined histologically to detect features suggestive of chronic hepatitis C or autoimmune hepatitis. The results were correlated with serum anti-HCV and HCV-RNA, and with response to steroid therapy. RESULTS: Five of the nineteen patients had detectable HCV-RNA in their liver biopsies. In two of three patients from whom serum was available, HCV-RNA was detectable. The remaining 14 patients were negative for HCV-RNA by tissue polymerase chain reaction. Serum was available from 11 of these patients, and serum HCV-RNA was negative in all. All of the three HCV-RNA-positive patients who were treated with steroids showed a partial response; tissue positivity for HCV-RNA was significantly higher in partial responders than in complete responders (60% vs 0%, p = 0.01). Severe portal and periportal inflammation with prominent plasma cells together with bridging parenchymal necrosis were seen more often in HCV-negative biopsies. Mild portal and periportal inflammation with portal lymphoid aggregates, apoptosis and spotty parenchymal necrosis were seen more in HCV-positive biopsies. CONCLUSIONS: These results show that hepatitis C virus can be detected in some patients with circulating autoantibodies. The ability to detect HCV-RNA in paraffin-embedded archival material provides a valuable addition to the battery of available HCV tests.

Adolescent↗
PubMed1995

Chronic hepatitis C virus infection in haemophilic patients: clinical significance of viral genotype.

We have undertaken a comprehensive study of hepatitis C virus (HCV) genotype and its clinical significance in haemophilic patients. 189 HCV RNA positive were typed, using the Simmonds classification scheme, by restriction fragment length polymorphism (RFLP) in an amplified segment of the 5' non-coding region of the HCV genome. Type 1 was found in 121 (64.0%), type 2 in 23 (12.2%), type 3 in 36 (19.0%), type 4 in 3 (1.6%), type 5 in 2 (1.1%) and mixed infection in 3 (1.6%). There were no type 6 infections and one patient (0.5%) could not be typed. Genotype was not associated with diagnosis, age, or with HIV infection. Type 1 was associated with higher serum HCV RNA levels, and with a poor response to interferon. Progression to hepatic decompensation has been seen less frequently in those with type 3 compared to type 1 infection (p = 0.07). Three out of eleven patients studied over a longer time course showed a change in genotype, the remainder were persistently infected with HCV type 1. In conclusion, HCV genotype has clinical relevance in the management of haemophilic patients. Those with type 1 are probably more likely to develop serious liver disease and since they respond poorly to interferon-alpha, should be considered for new treatment strategies aimed at sustained clearance of HCV RNA.

Chronic Disease↗
PubMed1994

Hepatitis C virus-polymerase chain reaction of routinely processed liver biopsies.

The aim of the study was to evaluate the specificity and sensitivity of detection of hepatitis C virus (HCV)-RNA in formalin-fixed paraffin-embedded (FFPE) liver biopsies by polymerase chain reaction (PCR). Routinely processed FFPE diagnostic needle liver biopsies as well as stored serum samples from 43 patients with liver disease were tested for HCV-RNA by reverse transcription-nested PCR using the same sets of primers and following strict anticontamination measures. Twenty-nine cases were positive and 14 were negative for serum HCV-RNA. Tissue HCV-RNA was detected in 17 out of the 29 serum HCV-RNA-positive cases but not in any of the 14 serum HCV-RNA-negative cases. Compared to serum-PCR, tissue-PCR was 100% specific, 58.6% sensitive, and 72% efficient. HCV-RNA was detected more frequently in biopsies stored for less than 1 year, than in those stored for more than 1 year (P = 0.046). In biopsies stored for up to 1 year detection of HCV-RNA by PCR was 81.8% sensitive and 90.9% efficient. Short (< 0.5 cm) liver biopsies were as sufficient for nucleic acid extraction and amplification as long (> 0.5 cm) ones. It is concluded that following strict anticontamination measures, HCV-RNA detection by PCR in routinely fixed, processed, and stored diagnostic liver biopsies provides a valuable adjunct to diagnosis of HCV infection. In this study, this option was free from contamination problems, even though routine batch histological processing schedules were used.

Base Sequence↗
PubMed1992

Thrombocytopoiesis in normal and sublethally irradiated dogs: response to human interleukin-6.

The response of megakaryocytes and platelets to the administration of recombinant human interleukin-6 (IL-6) was investigated in normal and sublethally irradiated dogs. IL-6 was administered for 2 weeks at doses of 10 to 160 micrograms/kg/d to normal animals to assess dose-response and toxicity. Subsequently, 40, 80, or 160 micrograms/kg/d for 2 weeks was administered to animals treated with 200 cG total body irradiation. Analysis of normal dogs showed a significant increment in the platelet count detectable approximately 11 days after initiation of IL-6 at all administered doses. Large platelets greater than 6.3 microns in diameter were observed 1 day after beginning IL-6, progressively increasing to as many as 19.1% of the total circulating platelets by day 10. The ploidy distribution of the marrow megakaryocytes did not differ from the normal at doses of less than or equal to 80 micrograms/kg/d, but at 160 micrograms/kg/d, a shift toward higher ploidy cells was noted. No change in total white count was noted; however, a decrease in hematocrit was seen at all doses. In the irradiated animals, the platelet count recovered earlier in the IL-6-treated dogs than in the controls, but no consistent change in the ploidy distribution was observed irrespective of dose. Large platelets were also noted in the treated animals, comprising up to 6.9% of the total platelet count. Fibrinogen levels were elevated to greater than 4 times normal. A significant decrease in hematocrit was seen in all animals, while no consistent change was noted in the white count. Elevations in serum cholesterol, triglycerides, and alkaline phosphatase, together with a decline in serum albumin were observed in all the treated animals (both normal and irradiated), but clinical symptoms were observed only in the dogs receiving greater than or equal to 80 micrograms/kg/d. The data show that IL-6 alone is capable of enhancing platelet recovery in dogs with bone marrow suppression.

Animals↗
PubMed1992

An immunohistochemical study of the blood vessels within primary hepatocellular tumours.

We studied the blood vessels in routinely formalin-fixed and paraffin-processed tissue from 18 hepatocellular carcinomas, three "small" hepatocellular carcinomas, and 15 benign nodular lesions representing a spectrum of conditions with which liver cell carcinomas may be confused. These were stained for a basement membrane component (collagen IV) and endothelial markers (Factor VIII-related antigen, Ulex europaeus lectin binding, and QBEnd10). The staining pattern of normal and cirrhotic liver was also examined in tissue removed with these tumours. There was an increased expression by small blood vessels for collagen IV in carcinomas and benign lesions compared with cirrhotic nodules. All endothelial markers (Factor VIII-related antigen, QBEnd10, and Ulex europaeus binding) were best expressed in liver cell carcinomas. These differences were of degree and pattern, and no single marker distinguished benign from malignant lesions. The differences in staining pattern taken together with other clinical and pathological information should be useful in diagnosis particularly of small liver cell carcinoma. The differences between benign and malignant lesions support the idea that malignant neoplastic blood vessels in the liver are of a different basic biological type from normal hepatic sinusoids, and this difference could be exploited further in future therapy.

Binding Sites↗
PubMed1992

Primary cerebral lymphoma: a study of 47 cases probed for Epstein-Barr virus genome.

AIMS: To determine the prevalence of Epstein-Barr virus genome in primary cerebral lymphomas occurring in the absence of immune suppression. METHODS: Forty eight consecutive patients with lymphomas restricted to the central nervous system were identified, all of whom had had neurosurgical biopsies performed at the National Hospitals for Neurology and Neurosurgery, London. Only five patients had some form of underlying immune deficiency; 43 were apparently normal. The tumours were studied with immunohistochemical markers and by in situ hybridisation, using a biotinylated probe to the internal repeat region of Epstein-Barr virus. RESULTS: All the lymphomas were B cell in origin. Tumours from the five immunosuppressed patients all showed hybridisation, as did two of the "spontaneous" tumours. CONCLUSIONS: This is the largest series of cerebral lymphomas so far probed for Epstein-Barr virus genome: as more are examined, it is suggested that a small proportion of the tumours from immunocompetent patients will also contain the virus.

B-Lymphocytes↗
PubMed1991

Insulin-sparing effects of pancreatic polypeptide in congenitally obese rodents.

Chronic treatment with bovine pancreatic polypeptide (bPP) is reported to decrease body weight and reduce fasting glucose and insulin concentrations in congenitally obese mice. The present study examines the effects of acute and chronic bPP treatment on insulin release and glucose clearance in lean and obese rodents. After single injections of 0, 5, 50, or 500 micrograms of bPP/kg of body weight, the insulin response to an intragastric glucose meal (5 g/kg of body weight) was substantially inhibited by the two higher doses of bPP. The change in glucose concentration over time was similar among all animals except those receiving the highest dose of bPP (500 micrograms/kg of body weight); in this group, glucose rose to higher levels and was slower to return to basal levels. Chronic treatment of rats with 200 micrograms of bPP/day/kg of body weight for 5 days did not modify glucose or insulin responses to the glucose meal, but did increase the activity of hepatic glycogen synthetase. In contrast, basal glucose levels were lower in obese mice (ob/ob) treated with bPP and glucose clearance was improved in the treated group after injection of exogenous insulin. Islet hormone concentrations in pancreatic extracts were compared in lean and obese mice treated with and without 200 micrograms of bPP/day/kg of body weight for 5 days. The pancreases of obese mice had higher concentrations of insulin and PP, and treatment with exogenous bPP increased endogenous PP in the pancreases of both phenotypes. Treatment with exogenous bPP also increased the insulin content of obese pancreases, but was without effect in pancreases of lean mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Detection of HSV-1 proteins prior to the appearance of infectious virus in mouse trigeminal ganglia during reactivation of latent infection.

Following corneal inoculation of mice HSV-1 produces an acute infection and establishes a latent infection in trigeminal ganglia. The latent virus can be reactivated in vitro by explantation of ganglionic tissue. Viral protein expression was studied in trigeminal ganglia during acute infection of mice and explant reactivation of latent infection. HSV-1 proteins were detectable by immunoprecipitation and immunostaining, in mouse ganglia only from 3-5 days post infection. Although during explant reactivation it has been demonstrated that at 24 h post-explant the trigeminal ganglia are all infectious virus negative (Spivack, O'Boyle II and Fraser (1987) J. Virol. 61, 3288-3291), we have found that three HSV-1 proteins, of 175 kDa, 110 kDa and 90 kDa, are present in latently infected trigeminal ganglia as early as 6-21 h post explantation. Initially, only neuronal cells were positive by immunostaining with anti HSV-1 polyclonal serum for HSV-1 antigens, but at later times HSV-1 antigens were seen in non neuronal cells as well. These proteins may play a role in the initial stages of the reactivation process.

Animals↗
PubMed1988

herpes simplex virus infection accelerates the age-related reactivity of mouse trigeminal ganglia neurons with anti-mouse IgG antibody in immunostaining.

The detection of viral proteins is a major goal of research on herpes simplex virus type 1 (HSV-1) latency. We used immunostaining to detect viral proteins in neuronal cells of trigeminal ganglia of Balb/c mice after corneal inoculation with HSV-1 virus. Viral proteins were detected in the neurons during the acute stage of infection, i.e. within one week after inoculation. However, the detection of viral antigens at the latent stage of HSV-1 infection has proven difficult. We have detected age-dependent non-specific reactivity with anti-mouse IgG antibody in the neurons of 10-week-old or older uninfected mice. This reactivity is accelerated in HSV-1 infected mice, being seen at 6 weeks of age (2 weeks post infection). The accelerated reaction and impact of this effect is discussed in relation to detection of viral proteins during latency.

Aging↗
PubMed1987

The effect of platelet-derived growth factor on cell division and glycosaminoglycan synthesis by human skin and scar fibroblasts.

The effect of platelet-derived growth factor (PDGF) on cell division and glycosaminoglycan (GAG) synthesis by fibroblasts isolated from skin and scar was measured. We found that PDGF stimulates cell division more efficiently in normal skin fibroblasts than in scar fibroblasts and decreases GAG synthesis in skin and scar fibroblasts. Using a 4-h pulse label with [3H]thymidine ([3H]Thd) following a 20-h incubation of confluent monolayer cultures with 0-5 units PDGF/ml Dulbecco's modified Eagle's medium, we found a concentration-dependent increase in [3H]Thd incorporation. After incubation of fibroblasts with [3H]glucosamine and 35SO4 in the presence or absence of PDGF, labeled constituents were isolated from the extracellular, pericellular, and cellular fractions by pronase digestion and column chromatography on Sepharose CL4B or DEAE-cellulose and analyzed by cellulose acetate electrophoresis. The presence of PDGF decreased the total amount of 35S incorporated into macromolecules by skin and scar fibroblasts and resulted in an altered distribution of labeled GAGs. Dermal fibroblasts exposed to PDGF for 24 h incorporated a greater percentage of radiolabeled 35S into dermatan sulfate prime (DS') and less into dermatan sulfate (DS) in the extracellular fractions and a greater percentage of 35S into heparan sulfate (HS) in the pericellular fractions than did parallel cultures grown in the absence of PDGF. It is thought than PDGF may have an effect on scar formation by increasing the fibroblast population in the wound tissue and by affecting the total amount and types of matrix components synthesized.

Cell Division↗
PubMed1985

A comparison of glycosaminoglycan synthesis by human fibroblasts from normal skin, normal scar, and hypertrophic scar.

Fibroblasts isolated from normal skin, normal scar, and hypertrophic scar tissues were compared with respect to their growth curves, protein contents, and abilities to synthesize glycosaminoglycans (GAGs). While no significant differences were found with respect to protein content or population doubling times, we did find significant differences in the proportions of radiolabel incorporated into the various GAGs among the 3 groups of cell lines. Using a dual-label technique to label both hyaluronic acid and the sulfated GAGs, we isolated labeled constituents from the extracellular, the pericellular, and the cellular fractions by pronase digestion and gel filtration and identified the various GAGs by electrophoresis and selective digestion with enzymes. Of the GAGs isolated from the extracellular fraction, hypertrophic scar fibroblasts incorporated proportionately more 35S into chondroitin sulfate and less into heparan sulfate and more [3H]glucosamine into hyaluronic acid than did normal skin fibroblasts. Of the GAGs isolated from the cellular fraction, hypertrophic scar fibroblasts incorporated proportionately more 35S into heparin and less into dermatan sulfate and more [3H]glucosamine into hyaluronic acid than did normal skin fibroblasts. These differences in biosynthesis may help to explain the differences in GAG content in skin and scars found in vivo and to give insight into the development of hypertrophic scars.

Cicatrix↗