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PubMed1988

HLA haplotype A1 B8 DR3 as a risk factor for HIV-related disease.

Of 32 patients exposed to a single batch of factor VIII contaminated with human immunodeficiency virus (HIV), 18 became antibody positive. Serial T cell subset analyses over the succeeding four years have shown a progressive decline in circulating T4 cells in those 18 but no change in the 14 who remain seronegative. 2 of the seroconverters have died and a further 7 have symptoms attributable to HIV infection. In the group as a whole, the HLA haplotype A1 B8 DR3 was weakly associated with an increased risk of seroconversion on exposure to the virus while, in those who seroconverted, it was strongly associated with a rapid decline in T4 cells and development of HIV-related symptoms within four years of infection.

Adult↗
PubMed1992

Use of several second generation serological assays to determine the true prevalence of hepatitis C virus infection in haemophiliacs treated with non-virus inactivated factor VIII and IX concentrates.

To investigate the prevalence of hepatitis C virus infection in two risk groups, stored serum samples from treated haemophiliacs and intravenous drug users were tested for anti-HCV by both anti-C-100 based and second generation ELISAs (Abbott and Ortho) followed by testing in two confirmatory immunoblot assays that incorporate core as well as other non-structural antigens (Innogenetics LIA and Chiron RIBA-HCV test). Clear evidence of HCV infection was found in all but one of 78 haemophiliacs treated with non-virus inactivated clotting factor concentrates, but in none exposed only to super dry heat-treated concentrates. Only four samples gave rise to conflicting serological results between the four tests, two of these occurred in patients with advanced HIV related disease and almost certainly reflected loss of humoral immunity associated with disease progression, and the others occurred in the only two patients tested who were chronic carriers of hepatitis B infection and may reflect an interaction between the two viruses. Comparison of anti-C-100 versus second generation tests in immunocompetent drug users revealed a false negative rate of 20% using C-100 alone, indicating the advantage of using second generation assays for detection of past or current HCV infection. Of all of the antigens used in the confirmatory assay, positive sera showed strongest and most frequent reactivity with the C22 and C33c proteins (Ortho RIBA).

Drug Contamination↗
PubMed1980

Familial gout and renal failure in young women.

Six members of kindred with only one surviving male in three generations, a history of an unusual combination of precocious gout in a girl of nine and rapidly progressive renal disease in young women, have been investigated. Sensitive indicators of the familial defect were the early development of hyperuricemia, an inability to concentrate the urine, and a patchy non-specific interstitial nephritis at biopsy. All these features were disproportionately severe for the young age and sex of affected subjects, and the relatively moderate reduction of GFR in some. Identification of these characteristics enabled the recognition of an early stage of the disease in one young family member whose renal function had previously been normal. The histopathology of the renal lesion in this normotensive teenage girl was similar to that frequently attributed to ageing or hypertension in the archetypal middle-aged gouty male, indicating that neither age nor vascular lesions are necessarily implicated in the latter. Allopurinol has halted further progression of the renal lesion in this young girl over two years. It is thus possible that early diagnosis may benefit the subsequent clinical course and may be important since the number of such families in our experience suggests that precocious familial gout with renal failure is more prevalent than currently recognized.

Acute Kidney Injury↗
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

Identification of a 7-basepair deletion in the adenine phosphoribosyltransferase gene as a cause of 2,8-dihydroxyadenine urolithiasis.

We describe a family of Turkish origin with adenine phosphoribosyltransferase (APRT) deficiency and renal stone disease. The proband had 2,8-dihydroxyadenine urolithiasis but an older sister, who was also deficient in enzyme activity, is so far asymptomatic. The proband was homozygous for a 7-bp deletion in exon 3 of the APRT gene. One allele from each of the parents also contained this deletion. The patient and her father were homozygous for an intragenic TaqI RFLP (1.25-kb fragment) whereas the mother was heterozygous (1.25- and 1.91-kb fragments), indicating that the mutation was present on the allele carrying the 1.25 kb TaqI fragment. The deletion alters the reading frame downstream of codon 93 and would be expected to abolish enzyme activity.

Adenine↗
PubMedDate not supplied

HPRT deficiency as the cause of ESRD in a 24-year-old patient: a very rare presentation of the disorder.

A 24-year-old male with end-stage renal disease (ESRD) and disproportionately high uric acid plasma concentration was admitted to our unit. After studying the patient's medical history, as well as that of the entire family, hyperuricemia was discovered in his brother, while microscopic examination of his brother's and mother's urine revealed abundant uric acid crystals. After performing purine metabolic studies, it was determined that the two siblings suffered from partial hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (Kelley-Seegmiller syndrome). This report highlights the importance of clinical awareness and a thorough examination of the patient's medical history for establishing an early diagnosis and commencing treatment for such rare inherited metabolic disorders to prevent renal failure.

Adult↗
PubMed2002

Partial hypoxanthine-Guanine phosphoribosyltransferase deficiency as the unsuspected cause of renal disease spanning three generations: a cautionary tale.

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is an X-linked defect of purine metabolism. Clinical manifestations are usually related to the degree of enzyme deficiency: complete HPRT deficiency (Lesch-Nyhan syndrome) presenting with severe neurologic or renal symptoms, or partial HPRT deficiency (Kelley-Seegmiller syndrome) manifesting as a gout-urolithiasis syndrome. A 3-generation kindred is described in which the recognition of partial HPRT deficiency in 2 adolescent male siblings presenting with uric acid lithiasis led to the diagnosis in 2 maternal uncles already in renal failure of unknown cause. This report highlights the importance of clinical awareness leading to early diagnosis, appropriate diagnostic methodology, and therapy of a treatable inherited disorder of purine metabolism for the prevention of renal failure.

Adolescent↗
PubMed1990

Human immunodeficiency virus-infected individuals contain provirus in small numbers of peripheral mononuclear cells and at low copy numbers.

In human immunodeficiency virus (HIV)-infected individuals, the proportion of circulating mononuclear cells (PBMCs) which carry HIV provirus and the number of HIV proviral sequences per infected PBMC have been matters for conjecture. Using a double polymerase chain reaction which allows the detection of single molecules of provirus and a method of quantifying the provirus molecules, we have measured provirus frequencies in infected individuals down to a level of one molecule per 10(6) PBMCs. As a general rule, only a small proportion of PBMCs contain provirus (median value of samples from 12 patients, one per 8,000 cells), and most if not all of the infected cells carry a single provirus molecule. The frequency of provirus-carrying cells correlated positively both with the progression of the disease and with the success with which virus could be isolated from the same patients by cocultivation methods. Of seven asymptomatic (Centers for Disease Control stage II) patients, all but one contained one provirus molecule per 6,000 to 80,000 cells; of five Centers for Disease Control stage IV patients, all but one contained one provirus molecule per 700 to 3,300 cells. When considered in conjunction with estimates of the frequency of PBMCs that express viral RNA, our results suggest that either (i) the majority of provirus-containing cells are monocytes or (ii) most provirus-containing lymphocytes are transcriptionally inactive. We also present nucleotide sequence data derived directly from provirus present in vivo which we show is not marred by the in vitro selection of potential virus variants or by errors introduced by Taq polymerase. We argue from these data that, of the provirus present in infected individuals, the proportion which is defective is not high in the regions sequenced.

Base Sequence↗
PubMed1994

Redistribution of HIV outside the lymphoid system with onset of AIDS.

The basis for many of the symptoms and pathological changes found in patients with the acquired immunodeficiency syndrome (AIDS) remains poorly understood. We have used a quantitative polymerase chain reaction technique to investigate the extent to which direct infection with human immunodeficiency virus (HIV) produces the disease manifestations of AIDS. In five patients who died with AIDS-defining illnesses (Centers for Disease Control and Prevention class IV), we found variable, but in many cases extensive, infection by HIV at various sites, including brain, lung, colon, and liver. By contrast, in three HIV-positive subjects who died without HIV-related disease (CDC class II), we found no evidence of significant infection of any non-lymphoid organ. In both groups of patients there were high levels of infection in cells of the spleen, lymph nodes, and peripheral blood. Pathological examination of tissues from the AIDS patients revealed many abnormalities, of which some, such as giant-cell encephalitis in the brain, were specifically associated with the presence of high levels of HIV infection. These findings suggest that spread of HIV outside cells of the immune system is a late event in HIV infection and is extremely sensitive to the degree of immunosuppression in the patient.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Stereoselective metabolism of two keto-pyrrol analogues of 8-hydroxy-2-dipropyl-aminotetralin by freshly isolated rat hepatocytes.

In vitro metabolism models have been used to determine the relative metabolic stability of novel 2-aminotetralin analogues for the treatment of CNS diseases. Few of these new compounds had been produced as stereochemically pure materials and the achiral analytical techniques, used initially, measured the average metabolic clearance of the two enantiomers of the racemic mixtures. A chiral HPLC assay, using a Chiral AGP column, was developed for two of these racemic analogues and was used to measure the clearance of the enantiomers from suspensions of freshly isolated rat hepatocytes. Robust separations were obtained for both compounds and a number of metabolic products. The enantiomers of only one analogue were subject to different rates of metabolism. The extent of the difference was dependent upon the initial starting concentration of the incubation. The identity of certain metabolites was investigated using LC/MS. The enantio-selectivity appears to have arisen from the restricted hydroxylation of one analogue compared to that of the other.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Interferon treatment for chronic hepatitis C infection in hemophiliacs--influence of virus load, genotype, and liver pathology on response.

In this study, we assessed the effectiveness of interferon treatment in 31 hemophiliacs with chronic hepatitis C virus (HCV) infection. Interferon alfa-2a (3 MU three times weekly) was administered for 6 months. Response was assessed by both serial alanine transaminase (ALT) and HCV RNA levels measured by a sensitive semiquantitative polymerase chain reaction (PCR) method. HCV genotype was determined by restriction fragment length polymorphism (RFLP), and evidence of changing genotypes during interferon therapy was sought. Severity of liver disease was assessed by both noninvasive and invasive methods, including laparoscopic liver inspection and biopsy. Sustained normalization of ALT levels occurred in eight patients (28%), and seven (24%) became nonviremic as assessed by PCR (<80 HCV/mL). Responders universally cleared HCV RNA within 2 months of starting interferon. Genotype 3a was associated with a favorable response to interferon. No evidence was found for a change in circulating genotype in patients who failed to respond to interferon or who relapsed. This study confirms that response rates to interferon are low in hemophiliacs as compared with other groups with chronic HCV infection. We have also demonstrated that virus load measurement over the first 8 to 12 weeks of treatment is an extremely useful method to identify responders at an early stage.

Adolescent↗
PubMed2006

Impact of HIV on regional & cellular organisation of the brain.

There are many excellent reviews of HIV infection of the nervous system. However these all assume that the reader has a working knowledge of the structure and cellular architecture of the brain. It may be that specialised brain vocabulary represents an unwelcome hurdle for those scientists with expert knowledge of the effects of HIV in other cell systems and who wish to extend that interest to the brain. This review provides an introduction to the component structures and cells of the brain and an overview of their involvement in HIV/AIDS. HIV infection leads to death through its capacity to progressively devastate the immune system. Current anti-HIV therapy has achieved considerable success in halting and partially reversing this process. In the absence of treatment, the breakdown of immunity is marked by declining CD4 counts and increasing vulnerability to opportunistic infections. In parallel with these effects on the lymphoid system, the nervous system is frequently the site of an initially stealthy infection which leads ultimately to symptomatic disease in a significant proportion of HIV infected individuals. The most feared manifestation of central nervous system (CNS) involvement is dementia. Unfortunately, serial CD4 counts and measurement of blood viral load do not serve to identify or monitor early infection of brain tissue. Since effective anti-HIV therapy has not achieved eradication of virus from lymphoid tissues, and anti-HIV drugs do not enter the nervous system easily, it is hardly surprising that HIV infection of the nervous system continues to cause clinical problems. Even in treatment-compliant patients, a measurable degree of cognitive impairment may develop, signalling previous or present HIV-related brain injury. The cause of HIV associated dementia and cognitive disability remains poorly understood. Perhaps most significantly, the long-term consequences of clinically occult brain infection are unknown and will require further investigation.

AIDS Dementia Complex↗
PubMed1984

Nonmedical costs to patients and their families associated with outpatient chemotherapy.

One hundred thirty-nine patients receiving outpatient chemotherapy kept diaries of nonmedical expenses resulting from their disease and its treatment. Diaries were kept for both treatment and nontreatment weeks. Results showed that the mean cost to patients and their families for treatment weeks was $72.81, and for nontreatment weeks it was $45.88. Approximately 45% of these costs were out-of-pocket expenses, and 55% were wages lost. Transportation and food were the largest out-of-pocket expenses. Patients living at greater distance from treatment had higher out-of-pocket costs, and younger patients reported more wages lost. Fourteen percent of the patients were estimated to be spending more than 50% of their weekly incomes on nonmedical expenses, and these patients were found largely in the lower-income categories. A method is proposed for using these data to estimate total nonmedical expenses for different treatment regimens, and also for estimating cancer patients' total nonmedical costs nationally.

Adolescent↗
PubMed2000

Complete DNA sequence of a serogroup A strain of Neisseria meningitidis Z2491.

Neisseria meningitidis causes bacterial meningitis and is therefore responsible for considerable morbidity and mortality in both the developed and the developing world. Meningococci are opportunistic pathogens that colonize the nasopharynges and oropharynges of asymptomatic carriers. For reasons that are still mostly unknown, they occasionally gain access to the blood, and subsequently to the cerebrospinal fluid, to cause septicaemia and meningitis. N. meningitidis strains are divided into a number of serogroups on the basis of the immunochemistry of their capsular polysaccharides; serogroup A strains are responsible for major epidemics and pandemics of meningococcal disease, and therefore most of the morbidity and mortality associated with this disease. Here we have determined the complete genome sequence of a serogroup A strain of Neisseria meningitidis, Z2491. The sequence is 2,184,406 base pairs in length, with an overall G+C content of 51.8%, and contains 2,121 predicted coding sequences. The most notable feature of the genome is the presence of many hundreds of repetitive elements, ranging from short repeats, positioned either singly or in large multiple arrays, to insertion sequences and gene duplications of one kilobase or more. Many of these repeats appear to be involved in genome fluidity and antigenic variation in this important human pathogen.

Antigenic Variation↗
PubMed2005

Using a bundle approach to improve ventilator care processes and reduce ventilator-associated pneumonia.

BACKGROUND: A "bundle" of ventilator care processes (peptic ulcer disease prophylaxis, deep vein thrombosis prophylaxis, elevation of the head of the bed, and a sedation vacation), which may also reduce ventilator-associated pneumonia (VAP) rates, can serve as a focus for improvement strategies in intensive care units (ICUs). Between July 2002 and January 2004, teams of critical care clinicians from 61 health care organizations participated in a collaborative on improving care in the ICU. METHODS: ICU team members posted data monthly on a Web-based extranet and submitted narrative descriptions describing the changes tested and the strategies implemented. RESULTS: For the 35 units that consistently collected data on ventilator bundle element adherence and VAP rates, an average 44.5% reduction of VAP was observed. DISCUSSION: The goal-oriented nature of the bundle appears to demand development of the teamwork necessary to improve reliability. The observations seem sufficiently robust to support implementing the ventilator bundles to provide a focus for additional change in ICUs.

Canada↗
PubMed1996

Response to interferon-alpha of Egyptian patients infected with hepatitis C virus genotype 4.

Hepatitis C virus (HCV) genotype 4 is the principal HCV genotype found in Egypt and the Middle East. Little is known concerning its propensity to cause disease and the frequency with which infected individuals respond to interferon-alpha (IFN-alpha). We have investigated the response to treatment in a cohort of 100 chronic hepatitis C patients infected with genotype 4. All patients had biopsy-proven chronic active liver disease. Each was treated with 3 million units (MU) IFN-alpha, thrice weekly. Response was monitored, in 92 patients who completed treatment, by alanine aminotransferase (ALT) measurements and by polymerase chain reaction (PCR) for HCV. ALT levels remained abnormal in 64 patients during treatment (69.6%). Of the 28 patients who showed a biochemical response during treatment (30.4%), 18 maintained this over the 6-month posttreatment period. Amongst the sustained biochemical responders, HCV RNA was cleared from serum in only four of the 18 (22.2%) in this period. Histological improvement was observed in 26/51 (50.9%) of the patients who had a second biopsy. Hence, patients infected with HCV genotype 4 show a poor response to IFN-alpha therapy compared with genotypes 2 and 3, but a similar response to IFN-alpha compared with those infected with type 1b HCV. These findings have major implications for treatment strategies in the Middle East, including Egypt, where HCV genotype 4 is widely distributed.

Adult↗
PubMed1994

In vivo distribution and cytopathology of variants of human immunodeficiency virus type 1 showing restricted sequence variability in the V3 loop.

The distribution, cell tropism, and cytopathology in vivo of human immunodeficiency virus (HIV) was investigated in postmortem tissue samples from a series of HIV-infected individuals who died either of complications associated with AIDS or for unrelated reasons while they were asymptomatic. Proviral sequences were detected at a high copy number in lymphoid tissue of both presymptomatic patients and patients with AIDS, whereas significant infection of nonlymphoid tissue such as that from brains, spinal cords, and lungs were confined to those with AIDS. V3 loop sequences from both groups showed highly restricted sequence variability and a low overall positive charge of the encoded amino acid sequence compared with those of standard laboratory isolates of HIV type 1 (HIV-1). The low charge and the restriction in sequence variability were comparable to those observed with isolates showing a non-syncytium-inducing (NSI) and macrophage-tropic phenotype in vitro. All patients were either exclusively infected (six of seven cases) or predominantly infected (one case) with variants with a predicted NSI/macrophage-tropic phenotype, irrespective of the degree of disease progression. p24 antigen was detected by immunocytochemical staining of paraffin-fixed sections in the germinal centers within lymphoid tissue, although little or no antigen was found in areas of lymph node or spleen containing T lymphocytes from either presymptomatic patients or patients with AIDS. The predominant p24 antigen-expressing cells in the lungs and brains of the patients with AIDS were macrophages and microglia (in brains), frequently forming multinucleated giant cells (syncytia) even though the V3 loop sequences of these variants resembled those of NSI isolates in vitro. These studies indicate that lack of syncytium-forming ability in established T-cell lines does not necessarily predict syncytium-forming ability in primary target cells in vivo. Furthermore, variants of HIV with V3 sequences characteristic of NSI/macrophage-tropic isolates form the predominant population in a range of lymphoid and nonlymphoid tissues in vivo, even in patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Analysis of the hepatitis C virus genome in patients with anti-LKM-1 autoantibodies.

Hepatitis C virus genotypes have been characterized in 22 patients with anti-LKM-1 positive chronic hepatitis C. Following the Simmonds classification, 77% of patients were infected by hepatitis C virus genotype 1, 18% by genotype 2 and 5% by genotype 3, thus excluding the association of the autoimmune reaction with a particular viral type. Prevalences of genotype 1 and 2 were significantly different from those obtained in 79 patients with chronic hepatitis C who were negative for anti-LKM-1, as these were more rarely infected by genotype 1 and more frequently by genotype 2. Clinical findings of anti-LKM-1 positive patients were similar in all three groups. Sequence analysis of the amplified 5'UTR provided identification of peculiar and identical nucleotide substitutions in two out of four patients with genotype 2. The analysis of the secondary structure of this region showed that the observed nucleotide mutations increased the stability of the stem formed in this position.

Adolescent↗