Altered hippocampal-prefrontal activation in HIV patients during episodic memory encoding.

OBJECTIVE: To investigate the integrity of hippocampal-prefrontal circuitry during episodic encoding in patients with HIV. METHODS: Functional MRI was used to observe changes in blood oxygenation level-dependent (BOLD) signal in 14 HIV-positive participants and 14 age- and education-matched control subjects while performing an episodic encoding task. Subjects also completed neuropsychological measures of attention and memory. RESULTS: Behavioral results revealed no significant differences in neuropsychological performance. The fMRI results revealed that while both groups recruited brain regions known to be important for successful encoding, including bilateral medial temporal lobes and inferior prefrontal gyri, the HIV group demonstrated significantly reduced signal intensity changes in the right posterior hippocampus, right inferior frontal gyrus, and left lingual gyrus. Additionally, the HIV group exhibited more activity within lateral frontal and posterior parietal regions. CONCLUSIONS: This study demonstrates altered integrity of hippocampal-prefrontal regions during episodic encoding in HIV-positive patients. These results extend previous studies that have documented the effects of HIV on fronto-striatal circuits, and suggest the virus functionally impacts the hippocampal system as well.

Changes in liver histopathology in women infected with hepatitis C through contaminated anti-D immunoglobulin injections in Ireland.

OBJECTIVE: To evaluate histological findings in untreated chronic hepatitis C patients at diagnosis 17 years after infection and to assess histological progression on repeat liver biopsy 2 years later. PATIENTS: Thirty patients infected with hepatitis C virus (HCV), genotype 1b, by contaminated anti-D immunoglobulin in Ireland in 1977 were studied. These patients were diagnosed in 1994 for the first time. All patients were positive for HCV-RNA by polymerase chain reaction (PCR). METHODS: Each patient underwent two liver biopsies approximately 2 years apart 17 and 19 years after initial infection. The liver biopsies were scored by two pathologists by the modified histological activity index using a numerical score. At first liver biopsy at time of presentation, eight patients had normal alanine aminotransferase (ALT), four had an ALT of more than 100 IU/I and 18 had an ALT level between 40 and 100 IU/I. RESULTS: In the initial (1994) biopsies, the median grade (inflammation) was 5/18, range 1-9 and the median stage (fibrosis) was 2/6, range 0-6. One patient showed cirrhosis (stage 6/6) and six patients (20%) had developed moderate fibrosis (stage 3-4/6). On the repeat biopsy, 2 years later, median grade (inflammation) was 5/18, range 2-9 and stage (fibrosis) was 1/6, range 0-6. CONCLUSION: This group of patients, infected with HCV genotype 1b and untreated for 19 years, allows evaluation of the natural history of this virus. The majority of patients showed mild chronic hepatitis. Only one patient had developed cirrhosis. There was no significant histological disease progression between the two biopsy specimens over a 2 year period. The results suggest that the prognosis in such cases could at least be guardedly optimistic and that sequential liver biopsy may be performed less frequently.

The reliability of saliva as a sample for the detection of hepatitis A immunoglobulins under various sampling conditions.

BACKGROUND: Saliva is increasingly being investigated as an alternative to serum for diagnostic and epidemiological testing even though antibody levels are substantially lower in buccal cavity fluids. However, there has been little study on whether buccal cavity activity and/or the timing of saliva sampling affects the diagnostic outcome, particularly in seropositive subjects. The absence of influence by these factors may be critical to the use of saliva for pre-vaccination screening for example. OBJECTIVES: The effects of eating, brushing of teeth and circadian rhythm on the measureable salivary immune status of 42 healthy individuals known to be serum and saliva anti-HAV positive were examined. STUDY DESIGN: A total of 141 saliva samples obtained from the 42 healthy subjects, before and after meals, before and after brushing of teeth and at various timepoints throughout the day, were assayed for total anti-HAV using an in-house saliva based enzyme-immunoassay, previously shown to have a 100% correlation in terms of sensitivity and specificity with a serum based assay. RESULTS: The results indicated that total anti-HAV titres varied according to the time of day and that eating had no significant effect on the total anti-HAV titre, but brushing of teeth did. Titres never varied to the extent that a result was falsely negative at any timepoint. CONCLUSION: These results confirm the usefulness of saliva as a diagnostic sample for the detection of hepatitis A antibody, regardless of sampling times, eating or tooth-brushing.

Two year old hepatitis A vaccine is as good as new.

This was a randomized, controlled, double-blind study assessing the reactogenicity and immunogenicity of newly produced vs 2 year old hepatitis A vaccine. Overall 215 non-immune volunteers, 18-39 years old were divided into four groups and administered vaccine at months 0, 1 and 6. Three groups each received a different vaccine lot which had been stored at 4 degrees C for 2 years, and one group received recently produced vaccine as control. The mean local and general adverse reaction rates were 59.1% and 17.4%, respectively, and all vaccinees had seroconverted by month 2. There were no significant differences in geometric mean anti-hepatitis A virus (HAV) antibody titres between the four groups. In conclusion 2 year old HAV vaccine is safe and equally immunogenic as newly produced vaccine.

Porphyrin metabolism in hepatitis C infection.

Hepatitis C virus has been implicated as a major precipitating factor in porphyria cutanea tarda (PCT). To determine whether hepatitis C infection alone is sufficient to induce PCT, we screened two groups of patients with hepatitis C infection. The first group comprised women who had become HCV positive secondary to immunization with anti-D immunoglobulin (group 1). Group 2 included males and females who were HCV positive but HIV negative secondary to intravenous drug abuse. Though both groups had very abnormal liver function tests, we found no significant abnormalities in porphyrin metabolism in these groups of patients. Therefore, in this study population, we conclude that HCV infection alone is insufficient to cause porphyrin metabolic derangement.

Pancreatic vipomas: spectrum of presentation and evolution of diagnostic and therapeutic modalities.

Two patients are reported who presented with symptoms characteristic of a pancreatic vipoma. The necessity to measure more than one plasma VIP level for diagnosis, and the delay between the onset of illness and diagnosis is illustrated by both cases. Evidence suggests that vipomas are still under reported. The evolution of sophisticated diagnostic and therapeutic modalities over the twenty-five years separating both presentations is discussed.

Percutaneous endoscopic gastrostomy--results of an Irish single unit series.

The technique of percutaneous endoscopic gastrostomy (PEG) was first described in 1980, as an alternative to traditional surgical methods. The main indication for PEG is the need for longterm nutritional support. It is reported to have many advantages over surgical gastrostomy, being safer and cheaper. We reviewed our experience with the first 44 patients referred to our unit for PEG. The most common indications for referral were stroke, head injury and post brain surgery. There was a success rate of 97.6% and a complication rate of 13.8%. One patient (2.3%) suffered major complications as a result of early tube displacement. There were no procedure related deaths in our series and no deaths as a result of an underlying disease process within 30 days, reflecting appropriate patient selection. All patients benefited nutritionally from PEG placement. Two patients recovered sufficiently to no longer require a gastrostomy and the tube was easily removed in both cases.

Endoscopic retrograde cholangiopancreatography in the elderly: a single unit audit.

Endoscopic retrograde cholangiopancreatography (ERCP) has an established role in the management of pancreato-biliary disease, but its role in elderly patients has not been evaluated. A prospective study was carried out in 50 elderly patients, aged between 65 and 94 years, to compare the sensitivity and specificity of ERCP in this age group with ultrasound and liver blood tests, and to examine its safety and therapeutic effectiveness. ERCP was successful in 46 of 50 (92%) procedures. Thirty-four patients had abnormal findings, and 18 sphincterotomies were performed. No complications were recorded. There was a poor correlation between ultrasound and ERCP with agreement in only 45% of cases; sensitivity 35% and specificity 75%. Liver blood tests, alkaline phosphatase and gamma-glutamyl transferase were elevated in all 30 cases with obstructed ducts on ERCP. Ultrasound revealed obstruction in only 10 (33%) of these. Thus, liver biochemistry proved a more reliable indicator of biliary obstruction than ultrasound. In 22 cases endoscopic stone clearance or demonstration of inoperable lesions obviated surgery while in 9 cases surgery was indicated, because of multiple large stones not cleared at ERCP, or for bypass of a malignant stricture. ERCP is therefore safe and effective with a high diagnostic and therapeutic yield even in the poor risk elderly.

Randomised comparison of olsalazine and mesalazine in prevention of relapses in ulcerative colitis.

Sulphasalazine extends remissions and lessens disease activity during relapses of ulcerative colitis, but it also causes many adverse side-effects. The adverse reactions are mostly attributable to the sulphapyridine carrier moiety rather than the active principle 5-aminosalicylic acid (5-ASA), so agents to deliver 5-ASA to the colon by other means have been designed. We have compared the efficacy and tolerability of two such agents, olsalazine and mesalazine, in maintenance therapy of ulcerative colitis. 100 patients with ulcerative colitis in remission were recruited at one centre and assigned randomly to treatment with olsalazine (Dipentum; 1.0 g daily) or mesalazine (Asacol, with Eudragit-S coating; 1.2 g daily). Compliance, biochemical and haematological variables, and clinical evidence of disease activity were assessed every 3 months for 12 months by observers unaware of treatment allocation. In intention-to-treat analysis, which included as treatment failures patients withdrawn for protocol violations, adverse reactions, intercurrent illness, or non-compliance as well as those with relapses of ulcerative colitis, the olsalazine group had a significantly lower rate of treatment failure than the mesalazine group (12/49 [24%] vs 23/50 [46%]; p = 0.025). Analysis restricted to 64 patients still in remission at 1 year and 18 with relapses also showed a significant difference in relapse rate (olsalazine 5/42 [12%] vs mesalazine 13/40 [33%]; p = 0.024). Both drugs were well tolerated; only 9 patients reported substantial side-effects. Olsalazine was clearly superior to mesalazine in prevention of relapses in ulcerative colitis, especially in patients with left-sided disease.

Angiodysplasia and ileal carcinoid.

A case of angiodysplasia, symptomatic for 18 years, is presented. This case highlights the difficulty of establishing a diagnosis. Associated findings included aortic stenosis and a carcinoid tumour of the ileum. Despite transfusion of a total of 1200 units of blood the liver was normal at necropsy.

The emerging AIDS epidemic in Ireland--clinicopathological findings in 23 early cases.

A longitudinal study with follow up to the end of 1989 was carried out on 23 patients with AIDS who had attended St. James's Hospital, Dublin, by the end of 1987. Until then only 33 cases of AIDS had been reported in Ireland. The patients, all of whom had antibodies to human immunodeficiency virus (HIV), were predominantly male, young (mean age 31.3 years) and belonged about equally to three major risk groups: homosexuals, intravenous drug abusers (IVDA) and haemophiliacs. AIDS was diagnosed because of oesophageal candidiasis (8 cases), Kaposi's sarcoma (4), mycobacterial infection (4), pneumocystis carinii pneumonia (3), toxoplasmosis (2) or encephalopathy (2). Malignant lymphoma and a variety of infections occurred in the course of illness, and neurological involvement developed in 11 patients (48%). Mortality following diagnosis of AIDS was 39% at one year and 64% after two years. Autopsy in 10 of the 16 deaths contributed much to defining the extent and nature of the disease. The demographic pattern, risk group status, survival and range of complications were broadly similar to the pattern of AIDS as seen elsewhere in developed countries. However, compared to the profile of disease reported from the United States, oesophageal candidiasis (52%) and Mycobacterium tuberculosis (22%) were more prominent, pneumocystis carinii pneumonia (39%), Kaposi's sarcoma (22%) and Mycobacterium avium intracellulare (13%) were less frequent and cryptococcal infection was not identified. These regional variations in the frequency of the various complications and particularly the prominence of tuberculosis, probably reflect the interaction of the immunocompromised patient with the local environment and may have important diagnostic and therapeutic implications.

Prolonged IgM antibodies and histopathological evidence of chronicity in hepatitis A.

The case of a young man with hepatitis A and a chronic course is presented. The patient received a short course of steroid therapy for recurrence of symptoms following acute hepatitis A. Thereafter, liver enzymes have remained marginally elevated for 4 years and annual liver biopsies have shown evidence of chronicity. HAV IgM Ab persisted for 1034 days with subsequent development of HAV IgG Ab. The possibility of other viruses in the aetiology and the role of steroids in the development of chronicity are discussed.

Operation-associated neutrophils in a percutaneous liver biopsy: effect of prior transjugular procedure.

A young man with chronic active hepatitis was heavily sedated during an attempted transjugular liver biopsy. The procedure was abandoned after 3 h and an immediate percutaneous liver biopsy was performed. This showed features of chronic active hepatitis but, in addition, groups of polymorphonuclear leukocytes in the parenchyma. These were similar to the operation associated neutrophils encountered in liver biopsies taken during the course of abdominal surgery. In a review of 78 liver biopsies from patients with chronic active hepatitis, this type of infiltrate was seen in four of eight surgically resected specimens but not in 70 percutaneous biopsies. The neutrophilic infiltrate in the present case appears to be an unique occurrence in a percutaneous liver biopsy. It was probably related to hypoperfusion during the preceding prolonged sedation and illustrates the ease with which an already diseased liver can be further damaged.

Discrete regions of sequence homology between cloned rodent VL30 genetic elements and AKV-related MuLV provirus genomes.

Southern blot analyses using reduced stringency hybridization conditions have been employed to search for sequence homologies between rodent VL30 genes and murine leukemia virus (MuLV) proviruses. These constitute two classes of transposon-like elements previously believed to be genetically unrelated. Our results demonstrate that cloned representatives of both ecotropic and xenotropic-like proviruses share discrete regions of sequence homology with VL30 genes of both rat and mouse origin. These regions of homology exist in both 3' and 5' halves of the MuLV genome but do not include extensive portions of the long terminal repeat (LTR) or a 0.4 Kbp segment of the env gene specific for recently acquired ecotropic-type MuLV proviruses. DNA sequencing, however, revealed that the short inverted terminal repeat sequence of MuLV proviral LTRs is almost perfectly conserved at the terminus of an integrated mouse VL30 gene. These results suggest that recombination events with rodent VL30-type sequences occurred during early MuLV evolution. The strong conservation of the inverted terminal repeat sequence may reflect a common integration mechanism for VL30 elements and MuLV proviruses.

Evidence for an early evolutionary origin and locus polymorphism of mouse VL30 DNA sequences.

The VL30 sequences of mouse DNA are a family of sequences with retrovirus-like structure which code for a 30S RNA transcript that can be packaged into the virions of murine leukemia viruses and thereby transmitted from cell to cell. A Southern blot analysis of these sequences revealed that multiple copies are present in the DNA of all mice examined, regardless of species or geographic origin. Considerable locus polymorphism was also apparent, and at least one of these polymorphisms appeared to reflect the differing chromosomal location of a complete VL30 sequence. These data indicated that VL30 elements are not recent additions to the mouse genome and suggested that the evolution of the VL30 multigene family has been accompanied by duplication and dispersion of VL30 sequences to diverse genomic sites. In addition, we reexamined the issue of genetic relatedness between mouse VL30 sequences and a physically similar family of virus-like elements in the rat genome. We found that many, if not all, rat and mouse VL30 loci contain regions of sequence homology. These data suggested that rodent VL30 sequences have evolved from a common ancestral sequence.

Organization and expression of endogenous virus-like (VL30) DNA sequences in nontransformed and chemically transformed mouse embryo cells in culture.

A cloned mouse DNA fragment containing an endogenous "virus-like" DNA (VL30 DNA) sequence was identified by virtue of its ability to hybridize to the virus-like RNA component of mixed-pseudotype AKR-murine leukemia virus virions, its lack of detectable sequence homology with cloned AKR-murine leukemia virus DNA, and its hybridization to a 5.6 kilobase pair (30S) cellular polyadenylic acid [poly(A)]-containing RNA species. Restriction enzyme mapping of the cloned mouse fragment revealed the presence of a 5- to 6-kilobase pair VL30 DNA segment flanked by non-VL30 segments of approximately 7 and 0.3 kilobase pairs. Southern blot analysis of VL30 DNA sequence organization in the DNA of two nontransformed mouse cell lines (AKR-2B, C3H/10T 1/2) and two chemically transformed derivatives (AKR-MCA, C3H/MCA-58) revealed 15 to 20 bands organized in an apparent strain-specific pattern. Within a given strain, however, no differences were detectable between the nontransformed cells and their chemically transformed counterparts. The expression of VL30 genes in the above cell lines was assayed by hybridization of 32P-labeled poly(A)-containing polysomal RNA to several internal restriction fragments derived from the cloned VL30 DNA sequence. The level of VL30 RNA was enhanced approximately 10-fold in both chemically transformed cell lines as compared to the nontransformed cell lines (under normal growth conditions). In addition, nontransformed AKR-2B cells maintained in the presence of purified epidermal growth factor exhibited similarly enhanced levels of VL30 RNA sequences in polysomal RNA. Since these cells displayed several growth characteristics of transformed cells but, in an epidermal growth factor-dependent and completely reversible fashion, these data suggest that the expression of VL30 genes is not simply incidental to chemically transformed cells but may be related to alterations in growth control.