The development of a more equitable approach to resource allocation and manpower planning for undergraduate teaching in a UK medical school.

CONTEXT: Resource allocation and manpower planning in the clinical faculty of a UK medical school. PURPOSE: To design a model, which is perceived to be fair, to determine indicative undergraduate teaching budgets to departments within the school from university resources and to specialty care groups of the main university hospital from service increment for teaching (SIFT) resources, and to aid manpower planning. METHOD: The student load for each department is measured in full-time-equivalent student numbers (FTEs) for each specialty and compared with the total load for the whole curriculum to derive each department's percentage share of available undergraduate teaching resources. Data on staff numbers available for teaching, both from the school and NHS, are also included. Student load and teaching capacity are then compared. RESULT: Undergraduate teaching resources relate to student load in the resource allocation process, and changes to the course are automatically reflected. Staff data, when compared with student load, facilitate rational planning of establishment levels to meet the teaching needs of the undergraduate curriculum. Of the respondents to a survey of heads of departments and the faculty's management board, 88% agreed that it was a better approach to resource allocation than the previous historical basis. PRESENT LIMITATIONS AND SCOPE FOR DEVELOPMENT: Data are currently entered manually but will be transmitted electronically in the future via the Web. Further consideration will be given to the possible inclusion in the model of weighting factors for different types of teaching and to how appropriate measures of quality may be incorporated into the resource allocation process. CONCLUSION: The model, despite some limitations, is a cost-effective and pragmatic management tool.

Service increment for teaching (SIFT): a review of its origins, development and current role in supporting undergraduate medical education in England and Wales.

OBJECTIVES: To describe the ways in which total resources available for the Service Increment for Teaching (SIFT) have been determined and related to numbers of undergraduate medical students; and the development and current arrangements for allocating SIFT to the providers of service support for teaching. DESIGN: The derivation of SIFT from excess costs of teaching hospitals over general hospitals is described. The official principles of organizing SIFT to reimburse the service costs of teaching undergraduate medical students are explained. The crucial development that is examined is the change from SIFT being a global subsidy to being related to educational contracts. This development has facilitated both the specification of standards and innovative uses of SIFT. These are illustrated with examples. SETTING: Hospital and Community Health Services and Primary Care in the National Health Service (NHS) in England and Wales. SUBJECTS: Medical students. RESULTS: There is often confusion caused by SIFT being intended to cover the service costs of teaching but not having been derived in this way. This causes problems in deciding what providers should be paid through contracts for teaching of different kinds. CONCLUSIONS: The new contractual basis has enabled medical schools to use contracts to improve the clinical teaching of undergraduate medical students in the NHS. These developments may offer useful models for other countries.

Hepatitis C infection and autoimmunity.

Since the first tests for antibodies to components of the hepatitis C virus became widely available there has been considerable interest in evidence linking HCV infection with autoimmune liver diseases and other autoimmune conditions. With respect to autoimmune hepatitis, it is now clear that the early tests were quite non-specific and that it was the abnormalities in serum globulins in autoimmune hepatitis which led to such high positivity rates in this disease. Careful surveys across Europe have now made it clear that there are true associations between HCV infection and autoimmune liver diseases, but that their frequency is much higher in the south than the north. This is particularly striking for that variety of autoimmune hepatitis positive for antibodies to the liver/kidney microsomal antigen (cytochrome P450 2D6). Here there are distinct subgroups; one a "true" autoimmune group of younger females with more active disease, and a second, containing older patients with a more even sex distribution, where the virus seems to be driving an autoimmune reaction. The mechanisms underlying these associations are not yet clear, although analysis of the amino-acid sequences of selected virus and host proteins has shown some significant homology. Interestingly, and surprisingly, the overall incidence of periportal hepatitis is lower in HCV infection than in acute or chronic HBV infection, or acute HAV hepatitis. There is a parallel distribution in the frequency and titre of antibodies to the asialoglycoprotein receptor, one of the important targets for autoimmune reactions on the liver cell membrane. There are many reports of associations between HCV infection and other immune-mediated conditions, and although the strength of such associations is always difficult to judge, HCV infection in some conditions, such as cryglobulinaemia, is clearly an important driving force. Here, treatment of the HCV infection with interferon may led to striking remission in associated vascular lesions. Clinically, it can be very difficult to distinguish between liver disease due to HCV infection and autoimmune hepatitis co-existing with HCV infection, but because the treatment for these two conditions is quite different, the distinction is important. Alpha-interferon, the current treatment of choice for HCV infection, often induces a relapse in autoimmune hepatitis, while steroids, the treatment of choice for autoimmune hepatitis, may be permissive for HCV replication, and thus, at least in theory, may militate against the success of a subsequent course of alpha-interferon. A pragmatic approach to the choice of a first therapeutic agent is recommended based on the relative local prevalence of the two conditions, the use of readily available clinical tests, and the results of appropriate specialised assays in the most difficult cases.

The major histocompatibility complex influences the development of chronic liver disease in male children and young adults with cystic fibrosis.

BACKGROUND/AIMS: Chronic liver disease is a well-recognised complication of cystic fibrosis. Recent reports suggest that its development is not determined by specific mutations within the cystic fibrosis gene; however, familial clustering of portal hypertension cases and inappropriate immune responses against liver membrane antigens demonstrated in children with cystic fibrosis and chronic liver disease suggest that other genetic loci may be relevant. As the major histocompatibility complex has an important immunoregulatory role, we have investigated for associations with this complex and chronic liver disease in cystic fibrosis. METHODS: We have determined human leucocyte antigen class I (A and B) and class II (DR) phenotypes by serological tissue typing and class II (DR and DQ) and class III (complement component C4 and 21-hydroxylase) gene polymorphisms in 274 children and young adults with cystic fibrosis, of whom 82 had evidence of chronic liver disease with portal hypertension in 49, and 146 healthy controls. RESULTS: A marked difference in human leucocyte antigen frequency was limited to DQ6, which was found in 66.7% of cystic fibrosis patients with liver disease compared to 32.9% of patients with no liver disease (Pc < 0.03) and 28.8% of controls (Pc < 0.006). An increased frequency of the two antigens in strong linkage disequilibrium with DQ6 was also observed within this patient group, namely DR15 and B7. When the patients were stratified for the presence of portal hypertension, these observations were confirmed, but the human leucocyte antigen associations were significant only for male patients and there was no association with the age of onset of liver disease. CONCLUSIONS: These data suggest that the haplotype B7-DR15-DQ6 may carry an increased risk of development of liver disease in male cystic fibrosis patients.

Induction of T-helper cell response to hepatitis B core antigen in chronic hepatitis B: a major factor in activation of the host immune response to the hepatitis B virus.

The T helper (Th) cell response to hepatitis B core antigen (HBcAg) was analyzed in 76 chronic hepatitis B virus (HBV) carriers with varying degrees of hepatic inflammation and HBV replication. Fifty-five patients had active viral replication, 28 with minimal histological changes and normal alanine transaminase (ALT) and 27 with active hepatic inflammation and elevated ALT. The remaining 21 chronic hepatitis B surface antigen (HBsAg) carriers had undetectable HBV replication, minimal histological activity, and normal ALT. In addition, 34 chronic HBV carriers were studied prospectively during treatment with alpha-interferon. The HBcAg-specific Th cell response was evaluated by a proliferative assay using 3H-thymidine uptake and gamma-interferon production by peripheral blood mononuclear cells. The proliferative response and gamma-interferon production of patients with active hepatic inflammation were significantly higher than in patients with minimal histological changes and in controls. In the longitudinal analysis during alpha-interferon treatment, 22 of 34 patients sustained an ALT flare accompanied by a parallel, significant Th cell response, which preceded or coincided with the ALT flare. The elevation in the Th cell response and the ALT flare were followed by a significant rise in the serum immunoglobulin (Ig) M anti-HBc index. Ten of twenty-two patients with an enhanced Th cell response and an ALT flare seroconverted after alpha-interferon treatment. The Th cell activity in the 10 responders rapidly subsided after hepatitis B e antigen (HBeAg) to anti-HBe seroconversion, whereas in the 12 nonresponders it remained elevated.(ABSTRACT TRUNCATED AT 250 WORDS)

Viral infection and cancer.

Infection with specific viruses has a role in the pathogenesis of some cancers in human beings. However, the incidence of such cancers is much lower than the frequency of virus infection, suggesting either that infection alone does not result in cancer and that cellular events in addition to the presence of the virus must occur, or that cancer occurs only if viral proteins are expressed in an appropriate cell type or in an immunocompromised host. Molecular analysis of viruses found in association with cancer has revealed that they function, at least in part, by encoding proteins which can associate with and subvert the function of host cell-encoded tumour suppressor proteins which regulate pathways of growth arrest and apoptosis. Better understanding of the mechanisms underlying this association will have diagnostic, prognostic, and therapeutic implications in the near future.

Antibody-directed complement-mediated cytotoxicity to hepatocytes from patients with chronic hepatitis B.

The susceptibility of hepatocytes from patients with chronic hepatitis B to complement-dependent cytotoxicity mediated by heterologous antibodies to hepatitis B virus core (anti-HBc) and surface (anti-HBs) antigens and to hepatic asialoglycoprotein receptor was examined using a microcytotoxicity assay. The anti-HBc-induced cytotoxicity was found to be markedly enhanced against hepatocytes isolated from patients with chronic active hepatitis (72.6 +/- 9.5% (mean +/- s.e.m.); n = 6) over that against hepatocytes from individuals with chronic persistent hepatitis or inactive liver cirrhosis (40.6 +/- 18.6%; n = 4) (P = 0.019). Overall, values of the anti-HBc-directed cytotoxicity were higher in patients positive for HBcAg in hepatocytes and seropositive for hepatitis B virus e antigen (HBeAg). Hepatocytotoxicity was also exerted by anti-HBs and anti-asialoglycoprotein receptor antibodies in the presence of complement, but it was not seemingly related to disease activity. These results indicate that hepatitis B virus core and surface antigens and asialoglycoprotein receptor at the hepatocyte surface can be recognized by antibodies, and raise the possibility that complement-dependent cytolysis may contribute to the injury of hepatitis B virus-infected hepatocytes. The data also suggest that liver cells of patients with severe chronic hepatitis might be more susceptible to anti-HBc antibody-directed complement-mediated cytotoxicity than those with inactive liver histology.

T-cell receptor constant beta germline gene polymorphisms and susceptibility to autoimmune hepatitis.

BACKGROUND/AIMS: Susceptibility to autoimmune hepatitis is associated with HLA A1-B8-DR3 and DR4. T-Cell antigen receptors (TCR) are candidates for genetic susceptibility to autoimmune diseases because they recognize peptide antigens in the context of HLA molecules. The aim of this study was to investigate the possible role of TCR germline polymorphisms in susceptibility to autoimmune hepatitis. METHODS: TCR constant beta (C beta) region polymorphisms were investigated using restriction fragment length polymorphism analysis in 60 unrelated northern European White patients with autoimmune hepatitis and 190 racially and geographically matched healthy controls. RESULTS: A significant increase in the frequency of homozygous status for the 10-kilobase/Bgl II of the TCR C beta was found in the patients compared with controls (42% vs. 21%; corrected P value [Pc] < 0.0075; relative risk [RR] = 2.8). This difference was more pronounced in patients without HLA-DR3 and DR4 (50% vs. 14%; Pc < 0.015; RR = 6.1). Furthermore, heterozygosity for TCR C beta was significantly decreased in early-onset patients presenting with HLA-DR3 before 30 years of age (12% vs. 48%; Pc < 0.03; RR = 0.16). CONCLUSIONS: The present findings provide evidence that genetic susceptibility to AIH may be determined by both the TCR C beta genes and HLA genes and that the genotype of the TCR C beta may be one of the factors in influencing the age at onset of disease.

Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis.

Susceptibility to autoimmune hepatitis in white patients is associated with the human leukocyte antigen class II antigens DR3 and DR4. To analyze the molecular basis of these associations, we used oligonucleotide probes to determine the DRB, DQA and DQB hypervariable nucleotide sequences in 119 patients with autoimmune hepatitis and 177 matched controls. DRB3*0101, which encodes DR52a, predisposed patients most strongly to the disease. It was present in 58% of patients and 25% of controls (corrected P < 0.000005), whereas DQA1*0101 and 0102 conferred protection in males only. The DR4 subtype, DRB1*0401, was raised in the DRB3*0101-negative patients; 81% possessed either DRB3*0101 or DRB1*0401, compared with 42% of controls (corrected P < 0.0000001). These alleles encode the amino acid sequence Leu-Leu-Glu-Gln-Lys-Arg at positions 67 to 72 of the DR beta polypeptide, which was present in 94% of patients and 64% of controls (corrected P < 0.000001) and in all patients who tested positive for autoantibodies to the hepatic asialoglycoprotein receptor. The patients with DRB1*0401 had less severe disease, relapsed less frequently and were first seen significantly later in life than those patients with DRB3*0101; and whereas a single copy of DRB1*0401 predisposed to autoimmune hepatitis, DRB3*0101-associated susceptibility had a dose-related effect. These data provide evidence that specific residues in the DR beta polypeptides predispose to autoimmune hepatitis in white patients and genes linked to DRB3*0101 and DRB1*0401 may determine two clinically distinct disease patterns.

Polymorphism in the human complement C4 genes and genetic susceptibility to autoimmune hepatitis.

Susceptibility to autoimmune hepatitis is associated with the HLA-DR3 and DR4 haplotypes, but which genes are directly involved in the pathogenesis, has not been established. Low levels of complement component C4 and elevated frequencies of C4 null allotypes have been described in patients, suggesting that the C4 genes, which are closely linked with the HLA loci, may play a role. We therefore examined restriction fragment length polymorphisms in the C4 and 21-hydroxylase genes, and determined HLA-A and B phenotypes, and HLA-DR, DQ and DP genotypes in a large series of Caucasoid patients with autoimmune hepatitis and matched controls. A DNA deletion of the C4A gene and the 21-hydroxylase A pseudogene was found to be present in 50% of patients compared to 23% of controls (Pc < 0.005, relative risk = 3.3). This increase, however, appears to be due to linkage disequilibrium with HLA-DR52a which was most strongly associated with the disease. Complete C4A deficiency, determined by homozygosity for the deletion increased the risk to 18.1 (16% versus 1%, Pc < 0.005), suggesting an additional role for C4 in disease susceptibility. C4 deletions were associated with an increased mortality and tendency to relapse whilst on treatment but did not correlate with age of onset of disease. Our data suggest that MHC-encoded susceptibility to autoimmune hepatitis is polygenic, involving the HLA-DR genes plus other loci, and C4 deficiency may be a marker of disease susceptibility and/or severity.

Human leukocyte antigen A1-B8-DR3-DQ2-DPB1*0401 extended haplotype in autoimmune hepatitis.

Genetic susceptibility to autoimmune hepatitis is associated with the human leukocyte antigen haplotype A1-B8-DR3 and DR4. To date, only one study in Japan has considered the human leukocyte antigen DP locus in this disease, and no studies have been reported in whites. In this study we used a series of sequence-specific oligonucleotide probes to determine human leukocyte antigen DPB1 genotypes in 101 unrelated white northern European patients and 105 racially and geographically matched controls. The aims of the study were twofold: first, to determine the degree of DPB-encoded susceptibility to autoimmune hepatitis, and, second, to establish whether susceptibility can be extended to include human leukocyte antigen DPB. None of 17 DPB1 alleles was significantly associated with the susceptibility to autoimmune hepatitis. Although one particular seven-locus haplotype A1-B8-DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201-++ +DPB1*0401 was significantly associated with the disease (27% vs. 7%, relative risk = 5.14, p < 0.0005), the association with this haplotype was weaker than that for the six-locus haplotype excluding DPB (40% vs. 11%, RR = 5.52, p < 0.0005). When the patients first seen at ages younger than 16 yr (pediatric patients) were considered separately, the greatest relative risk was for the seven-locus haplotype (41% vs. 7%; relative risk = 9.60, p < 0.0005). The results of this study further confirm that major histocompatibility complex-encoded susceptibility to autoimmune hepatitis is located at or close to the human leukocyte antigen DR locus; however, the A1-B8-DR3-DQ2-DPB1*0401 extended haplotype may be important in determining the age of onset and severity of disease.

Specific deletions in the hepatitis B virus core open reading frame in patients with chronic active hepatitis B.

The polymerase chain reaction (PCR) and DNA sequencing were used to examine genomic variation in the pre-core/core open reading frame of the hepatitis B virus (HBV) in chronically infected patients. Gel electrophoresis of amplification products showed the presence of shortened forms of the core gene in addition to the full length product. These shortened forms were seen only in patients with chronic active hepatitis (CAH) seropositive for HBeAg and not in patients with chronic persistent hepatitis (CPH) or HBeAg minus CAH. Cloning and DNA sequencing revealed the presence of a number of overlapping deletions within the core gene, the majority being in-frame, which were clustered within aa 81-114 of the core gene product. These deletions were found in patients with CAH from different racial and geographical backgrounds, whereas PCR analysis of the surface and X open reading frames showed no shortened forms suggesting deletions to be specific to the core gene in these patients. Because the product of the core gene--the HBV core antigen--is believed to be the major target for T-cell-mediated liver damage, it seems likely that the products of core genes carrying deletions will alter immune recognition and may be of importance in the progression of inflammatory liver damage.

Identification of hepatitis B virus-DNA in the liver by in situ hybridization using a biotinylated probe. Relation to HBcAg expression and histology.

The cellular localisation of hepatitis B virus (HBV)-DNA in liver tissue was studied by in situ hybridisation using biotinylated and radiolabelled probes on samples from HBsAg carriers with a spectrum of disease and related to the presence of HBV-DNA in serum and intrahepatic HBcAg expression. Sixteen of the 31 patients studied were seropositive for HBV-DNA; nine had chronic active hepatitis and seven had chronic persistent hepatitis. HBV-DNA was detected in the liver tissue in seven of these patients. In each, HBV-DNA was detected in both cytoplasm and nuclei. All seven also had nuclear and/or cytoplasmic HBcAg which in six was associated with chronic active hepatitis. HBcAg (without tissue HBV-DNA) was detected in the remaining nine patients with an exclusively nuclear pattern in two. Fifteen patients were seronegative for HBV-DNA. HBV-DNA was not detected in the tissue of any of these. Three of these were HBcAg positive but in each this was confined to occasional nuclei and each had inactive disease. The close association between the presence of detectable HBV-DNA in tissue, cytoplasmic HBV-DNA expression and chronic active hepatitis in one group and a failure to detect HBV-DNA in those with nuclear HBcAg and benign disease suggests that there may be two distinct patterns of HBV replication in chronic HBV carriers which may influence the development of liver damage.

Detection of genomic and intermediate replicative strands of hepatitis C virus in liver tissue by in situ hybridization.

Nonisotopic in situ hybridization using a digoxigenin-labeled cDNA probe to the 3' nonstructural region (NS5) of hepatitis C virus (HCV) was performed on liver tissue from 33 patients. The results were compared with PCR detection of HCV RNA performed on 24 of the biopsies. Nonisotopic in situ hybridization correlated well with PCR findings. Hybridization signals were detected, within the cytoplasm and nuclei/nucleoli of hepatocytes, mononuclear, and biliary epithelial cells. In patients with clinically and histologically defined chronic active hepatitis related to active HCV infection, HCV genome was frequently detected in biliary epithelium and correlated well with biliary damage, an otherwise uncommon finding in chronic active hepatitis due to other hepatotropic viruses. Further studies using sense and antisense probes synthesized from the 5' non-coding region of the HCV genome confirmed the localization of positive strand of HCV in the above cell populations. The replicative intermediate strand was also present in all cells, although less frequently observed, apart from biliary epithelium, where negative strand of HCV was undetectable. The findings of HCV genome in liver biopsies of two patients with no significant histological abnormalities may suggest that the damage seen in chronic HCV infection is immune mediated, although the cytopathic effect of the virus may also be important.

Virus- and immune-mediated liver damage in hepatitis.

It has been assumed for many years that liver damage associated with hepatitis B virus (HBV) infection is due to cytolytic immune reactions directed at viral antigens expressed on infected liver cells. Recent studies, however, suggest that in some clinical settings, changes in the HBV genome, possibly selected by immune pressure, can interfere with the export of viral proteins from hepatocytes and lead to direct virus-induced liver damage.

Comparison of pre-core/core hepatitis B virus region in liver tissue and serum from patients with chronic hepatitis B infection.

We examined the relationship between HBV-DNA isolated from the liver and from the serum in patients with various serological characteristics of chronic hepatitis B infection. Amplification and direct sequencing of the HBV pre-core/core region was carried out in 9 patients who were seropositive for HBsAg and HBV-DNA--4 HBeAg positive and 5 anti-HBe positive. Complete sequence identity was observed between HBV-DNA isolated from the serum and the liver in individual patients. In addition, shortened forms of the HBV core ORF were detected in patients with chronic active hepatitis, but not in patients with chronic persistent hepatitis.