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Biomedical subjects

P D Griffiths

Publications and source records attributed to P D Griffiths.

At least 109 records · Page 6Linked to original sources

Loss of cytomegalovirus (CMV) viraemia following highly active antiretroviral therapy in the absence of specific anti-CMV therapy.

OBJECTIVE: To determine the effect of highly active antiretroviral therapy (HAART) on cytomegalovirus (CMV) viraemia and retinitis in patients at high risk of disease. DESIGN: Sixteen patients with CMV viraemia, but no evidence of end organ disease at the time of first receipt of HAART including a protease inhibitor, were studied. No patient had ever received specific anti-CMV therapy. METHODS: CMV load in blood was measured using quantitative competitive PCR at baseline and for a median follow-up of 21 months. Regular ophthalmological screening for retinitis was conducted throughout the study period. RESULTS: All 16 patients became CMV negative by PCR following the commencement of HAART. CMV loads prior to treatment ranged from 2.0 x 10(3) to 4.1 x 10(6) copies/ml (median, 7.6 x 10(4) copies/ml). The median time to becoming PCR negative was 13.5 weeks (range, 5-40 weeks). Fourteen patients remained CMV negative throughout follow-up. CMV viraemia recurred in two patients; these individuals were indistinguishable with respect to either baseline parameters or response to antiretroviral therapy. None of the 16 patients developed CMV retinitis. CONCLUSIONS: HAART including a protease inhibitor can result in the complete suppression of CMV viraemia, an effect not previously observed in HIV-infected patients in the absence of specific anti-CMV therapy. This response correlated with protection against CMV retinitis in a group of patients at high risk of development of disease. These results help to explain why the natural history of CMV disease has altered since the introduction of such therapeutic regimens.

AIDS-Related Opportunistic Infections↗

Schinzel-Giedion syndrome: evidence for a neurodegenerative process.

We report on a case of Schinzel-Giedion syndrome in which serial magnetic resonance (MR) brain-imaging studies demonstrated a progressive neurodegenerative process. These findings in addition to "coarse" facial appearance and skeletal abnormality suggest that a progressive metabolic defect underlies this syndrome. However, results of detailed investigations for metabolic disorder were all normal.

Abnormalities, Multiple↗

Interactions between beta-herpesviruses and human immunodeficiency virus in vivo: evidence for increased human immunodeficiency viral load in the presence of human herpesvirus 6.

In vitro, beta-herpesviruses can stimulate or inhibit HIV replication under particular circumstances. In order to investigate the effects of beta-herpesvirus infection on HIV replication and vice versa at an organ level, we determined the quantitative relationships between cytomegalovirus (CMV), human herpesviruses (HHV) 6 and 7, and HIV-1 proviral DNA using quantitative competitive PCR methods in 141 organs collected at autopsy from 11 AIDS patients. The presence of HHV-6 DNA in an organ was significantly associated with elevated HIV-1 proviral DNA (difference in HIV median loads, 1.3 log10 genomes; P = 0.004). Consistent with this, there was a trend for the presence of HIV-1 proviral DNA to be associated with an elevated HHV-6 load (0.44 log10 difference; P = 0.07). In contrast, there were no significant differences between viral loads in the combinations of either CMV or HHV-7 with HIV-1 proviral DNA load. Pairwise combinations of the beta-herpesviruses revealed that the quantity of HHV-7 was increased in the presence of HHV-6 (difference in median loads, 1.3 log10; P = 0.001) and the quantity of HHV-6 was increased in the presence of HHV-7 (difference in median loads, 0.7 log10; P=0.002). These results demonstrate that the presence of HHV-6 in an organ is significantly associated with an elevated HIV-1 proviral load and have implications for understanding HIV pathogenesis in the human host and the role that beta-herpesviruses, especially HHV-6, might play as cofactors in the HIV disease process.

AIDS-Related Opportunistic Infections↗

Shorter survival in HIV-positive patients with diarrhoea who excrete adenovirus from the GI tract.

Adenoviruses have been described as a cause of diarrhoea in patients infected with the human immunodeficiency virus (HIV). The prevalence of adenoviruses was studied in all HIV-positive patients presenting with diarrhoea at the Royal Free Hospital in London between 1991 and 1995. In addition, all postmortems carried out in HIV-positive individuals registered at the same centre between 1990 and 1997 were reviewed for evidence of adenovirus infection. Adenovirus was detected in 16.1% of patients presenting with diarrhoea. These individuals had a significantly lower CD4 count and were more likely to have had a diagnosis of acquired immunodeficiency syndrome (AIDS) than patients with diarrhoea in whom adenovirus was not detected. The median survival was 1 year compared with 2.4 years for those without adenoviruses; this difference remained significant (P = .008) after controlling for differences in CD4 counts between the groups. Gastrointestinal adenovirus excretion occurs at an advanced stage of HIV disease, and is associated with a poor prognosis. We suggest that adenoviruses may contribute to mortality in this population.

Adenoviridae↗

Human herpesviruses 6 and 7 as potential pathogens after liver transplant: prospective comparison with the effect of cytomegalovirus.

Because cytomegalovirus (CMV) is an important opportunistic infection after liver transplant, we conducted a prospective study to see if the same applied to human herpesviruses (HHV)-6 and -7. We used polymerase chain reaction (PCR) methods optimised to detect active, not latent, infection and studied patients not receiving antiviral prophylaxis for CMV. Post-transplant, 536 blood samples were tested by PCR (median 7; range 4-50). Active infection with CMV was detected in 28/60 (47%), HHV-6 in 19/60 (32%), and HHV-7 in 29/60 (48%) of patients. The PCR-positive samples were tested by quantitative-competitive PCR to measure the virus load of each betaherpesvirus. The median peak virus load for CMV was significantly greater than that for HHV-6 or HHV-7. Detailed clinicopathological analyses for the whole population showed that CMV and HHV-6 were each significantly associated with biopsy-proven graft rejection. Individual case histories suggested that HHV-6 and HHV-7 may be the cause of some episodes of hepatitis and pyrexia. It is concluded that HHV-6 is a previously unrecognized contributor to the morbidity of liver transplantation, that HHV-7 may also be important and that both viruses should be included in the differential diagnosis of graft dysfunction.

Adult↗

Diabetic neuropathic pain in a leg amputated 44 years previously.

The mechanism of neuropathic pain in the diabetic limb is far from clear. Phantom limb pain likewise is of obscure aetiology. The development of typical pain in an absent leg in a patient with diabetes many years after the amputation stimulates thought as to the mechanism, not only of neuropathic pain, but also of phantom limb pain. A 58-year-old man was diagnosed with type 2 diabetes 44 years after having undergone left below knee amputation for congenital AV malformation, at the age of 13. Eight months before the diagnosis of diabetes he began to complain of pain in the leg on the amputated side-pain very similar to that described in typical diabetic neuropathy. This was followed by similar pain in the right leg. MR scan of the spine revealed a small syringohydromyelia of the thoracic cord in addition to a prolapse of disc at L(5)/S(1) level on the left side, which was first noted 5 years previously. There were no other features of S(1) compression. The typical neuropathic character of the pain involving both the amputated and the intact limbs that developed with the diagnosis of type 2 diabetes suggest that the neuropathic pain may originate from centres higher than peripheral nerves.

Amputation, Surgical↗

Diagnostic approaches to cytomegalovirus infection in bone marrow and organ transplantation.

Cytomegalovirus (CMV) continues to be a clinical problem, impairing the overall success rate of transplantation, either through direct involvement of a variety of end-organs or by inducing indirect effects such as graft rejection. We review here how the virus manages to evade host immune responses and replicate extensively in allograft recipients. Recent studies show that the quantity of CMV (viral load) is related directly to the development of CMV disease. We review how clinically significant levels of CMV viral load can be defined and summarize the results of studies showing that a high CMV viral load is the major determinant of CMV disease, explaining the previously reported risk factors of pre-transplant serostatus and the post-transplant detection of CMV viremia.Note

Bone Marrow Transplantation↗

HHV-6-related secondary graft failure following allogeneic bone marrow transplantation.

We report the case of an 11-year-old boy who underwent allogeneic bone marrow transplantation (BMT) for relapsed acute lymphoblastic leukaemia. Despite adequate engraftment, on day 45 he developed marrow aplasia with haemophagocytosis. HHV-6 was detected in blood and bone marrow by nested PCR. Retrospective testing showed that viraemia had started on day 24. Following therapy with foscarnet and ganciclovir, viral load declined to undetectable levels and his donor marrow recovered contemporaneously. This case suggests that HHV-6 may be a treatable cause of graft failure following BMT and provides clinical and virological evidence for the anti-HHV-6 activity of ganciclovir and foscarnet.

Antiviral Agents↗

Neurofibromatosis type 1: the role of neuroradiology.

Neurofibromatosis type 1 is the commonest of the phakomatoses with a prevalence of 1 in 3-4000. In common with most of the other phakomatoses it is a genetic disorder with typical dermatological manifestations. Many organ systems can be affected but brain, spine, cranial nerve and peripheral nerve involvement is frequent. In this review we will describe the central nervous system manifestations of neurofibromatosis type 1 and discuss some of the controversies raised by investigating children with this disorder.

Brain↗

Quantitative effects of valacyclovir on the replication of cytomegalovirus (CMV) in persons with advanced human immunodeficiency virus disease: baseline CMV load dictates time to disease and survival. The AIDS Clinical Trials Group 204/Glaxo Wellcome 123-014 International CMV Prophylaxis Study Group.

Virus load is a major risk factor for disease in many human viral infections, especially human immunodeficiency virus (HIV) disease. The effect of cytomegalovirus (CMV) load on disease progression and the influence of antiviral chemotherapy on surrogate markers of replication was investigated in 310 patients with advanced HIV disease in a randomized controlled trial that compared the effects of valacyclovir with those of acyclovir. Sequential blood and urine samples were analyzed by polymerase chain reaction (PCR), for human CMV (HCMV) DNA. In multivariate analyses, elevated virus load in both blood and urine at baseline was associated with increased risk of HCMV disease (relative hazard, 1.49 and 1.44 per log increase, respectively). Elevated virus load in blood at baseline was also associated with a significantly shorter survival time (log rank, P=. 0001). In time-updated analyses, valacyclovir significantly suppressed the virus load in subjects who were PCR positive at baseline (in blood or urine), when compared with the combined acyclovir arms.

AIDS-Related Opportunistic Infections↗

Asymptomatic primary cytomegalovirus infection: virologic and immunologic features.

We followed 45 seronegative adolescents for acquisition of cytomegalovirus (CMV); 6 (5 female, 1 male) seroconverted after a median of 7.5 months. All were free of signs and symptoms. CMV was isolated from 32 (59.2%) of 54 urines, 2-80 weeks after infection; viruria was less frequent after 6 months. CMV was isolated from saliva of 3 subjects, vaginal swabs of 2 of 5, and 1 white blood cell (WBC) sample. CMV DNA was detected by polymerase chain reaction in WBCs and plasma from all subjects tested. The proportion of WBC samples with CMV DNAemia was 75%-80% within 16 weeks of infection, declining to 0%-25% after 48 weeks. The rate of plasma DNAemia was 25%-40% at 8-16 weeks, declining with time. IgG antibody to CMV, glycoprotein B (gB), and neutralizing antibody were present after 6-8 weeks. Lymphocyte proliferative responses to CMV and to gB were low, compared with those of controls. CMV shedding was of shorter duration than expected. Although antibody response was prompt and vigorous, CMV DNA could be detected in blood for months.

Adolescent↗

Iron in the basal ganglia in Parkinson's disease. An in vitro study using extended X-ray absorption fine structure and cryo-electron microscopy.

Iron is found in high concentration in some areas of the brain, and increased iron in the substantia nigra is a feature of Parkinson's disease. The purpose of this study was to investigate the physical environment of brain iron in post-mortem tissue to provide information on the possible role of iron in neurodegeneration in Parkinson's disease. Iron has also been implicated as the cause of signal loss in areas of high brain iron on T2-weighted MRI sequences. Knowledge of the physical environment of the brain iron is essential in interpreting the cause of signal change. Post-mortem tissue was obtained from six cases of Parkinson's disease and from six age-matched controls. Iron levels were measured using absorption spectrophotometry. Extended X-ray absorption fine structure was used to evaluate the atomic environment of iron within the substantia nigra and both segments of the globus pallidus. Cryo-electron transmission microscopy was used to probe the iron storage proteins in these areas. Iron levels were increased in the parkinsonian nigra and lateral portion of the globus pallidus. Spectra from the extended X-ray absorption fine structure experiments showed that ferritin was the only storage protein detectable in both control and parkinsonian tissue in all areas studied. Cryo-electron transmission microscopy studies showed that ferritin was more heavily loaded with iron in Parkinson's disease when compared with age-matched controls. In summary we have shown that iron levels are increased in two areas of the brain in Parkinson's disease including the substantia nigra, the site of maximal neurodegeneration. This produces increased loading of ferritin, which is the normal brain iron storage protein. It is possible that increased loading of ferritin may increase the risk of free radical-induced damage. Differences in ferritin loading may explain regional differences in iron's effect on the T2 signal.

Aged↗

Specific patterns of cognitive impairment in patients with idiopathic normal pressure hydrocephalus and Alzheimer's disease: a pilot study.

OBJECTIVES: Eleven patients with idiopathic normal pressure hydrocephalus (NPH) were selected from an initial cohort of 43 patients. The patients with NPH fell into two distinctive subgroups: preshunt, group 1 (n=5) scored less than 24 on the mini mental state examination (MMSE) and were classified as demented and group 2 (n=6) scored 24 or above on the MMSE and were classified as non-demented. METHODS: All patients were neuropsychologically assessed on two occasions: preshunt and then again 6 months postshunt. Group 1 completed the mini mental state examination (MMSE) and the Kendrick object learning test (KOLT). In addition to the MMSE and KOLT, group 2 completed further tasks including verbal fluency and memory and attentional tasks from the CANTAB battery. Nine of the 11 patients also underwent postshunt MRI. RESULTS: Group 1, who, preshunt, performed in the dementing range on both the MMSE and KOLT, showed a significant postoperative recovery, with all patients now scoring within the normal non-demented range. Group 2, although showing no signs of dementia according to the MMSE and KOLT either preshunt or postshunt, did show a specific pattern of impairment on tests sensitive to frontostriatal dysfunction compared with healthy volunteers, and this pattern remained postoperatively. Importantly, this pattern is distinct from that exhibited by patients with mild Alzheimer's disease. Eight of the nine patterns of structural damage corresponded well to cognitive performance. CONCLUSIONS: These findings are useful for three main reasons: (1) they detail the structural and functional profile of impairment seen in NPH, (2) they demonstrate the heterogeneity found in this population and show how severity of initial cognitive impairment can affect outcome postshunt, and (3) they may inform and provide a means of monitoring the cognitive outcome of new procedures in shunt surgery.

Aged↗

Neurofibromatosis bright objects in children with neurofibromatosis type 1: a proliferative potential?

OBJECTIVES: The purpose of this study was to investigate the natural history of the high signal intensities shown on long TR sequences-neurofibromatosis type 1 bright objects (NBO)-in children with neurofibromatosis type 1 (NF1). We have paid particular attention to the development of tumors in these areas of abnormality. METHODS: During a 12-month period in 1992 to 1993, 46 children with clinically proven NF1 had a magnetic resonance (MR) examination at our institution. These were reviewed along with any previous or subsequent MR examinations that had been performed. We recorded the number, volume, and distribution of the abnormal high signal intensities and their change with time when serial examinations were performed. RESULTS: NBO were found in 93% of 46 children with NF1 on the original cross-sectional study. The most common anatomic sites were the globus pallidus (30.4%), cerebellum (23.5%), and midbrain (16.2%). The number and volume of NBO varied significantly with age. NBO were uncommon in children younger than 4 years but were very common and extensive between 4 to 10 years. A significant reduction in the number and volume of NBO was demonstrated in children older than 10 years as shown on both the cross-sectional and longitudinal portions of the study. Eight brain tumors (nonoptic pathway) were demonstrated in the 46 children (17%) with 1 child having two tumors. Only 1 child had symptoms referable to the tumor at the time of diagnosis. Five tumors developed in NBO that were documented on serial MR examinations. All those cases developed in children aged 7 to 12 years, and all these children had higher than average numbers and volumes of NBO. CONCLUSIONS: NBO occur commonly in children with NF1 and are most prevalent between the ages of 4 and 10. We have shown a high frequency of brain tumors in our children with NF1, but the majority of these were asymptomatic. We have demonstrated proliferative change NBO in 11% of 46 children. Most NBO regress with age and seem to be benign, however, young children with a large number and volume of NBO should be followed closely with regular MR examinations because of an increased risk of proliferative change. neurofibromatosis type 1, magnetic resonance, tumor, astrocytoma, childhood.

Brain↗