Ganciclovir therapy for neonates with congenital cytomegalovirus infection.
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Antiviral Agents↗
Biomedical subjects
Paul Griffiths
Publications and source records attributed to Paul Griffiths.
Advances in the antiviral therapy of herpes virus infection in children.
Herpes viruses are ubiquitous and primary infections, with many of these viruses common during childhood. In general, children tolerate primary infection well, with only mild symptoms, but in the immunocompromised, including the newborn, infection can be associated with serious morbidity and mortality. Drug treatment for many of the herpes infections is available but is often associated with serious side effects. In the pediatric age group, treatment is further hindered by a lack of information on suitable dosing regimes, unavailability of oral solutions and a lack of clinical trials specifically investigating response to treatment in this group of patients. This article will review current evidence regarding the pharmacokinetics and dosing of the most commonly used antiherpetic agents and will look specifically at the treatment of the more common herpes virus infections in children.
Antiviral Agents↗
Editorial: herpes simplex virus and toll-like receptors.
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Herpes Simplex↗
Sustained, spontaneous disappearance of serum HCV-RNA under immunosuppression after liver transplantation for HCV cirrhosis.
Immunosuppression is a main determinant for the increased Hepatitis C Virus (HCV) replication after liver transplantation and the accelerated course of recurrent HCV liver disease. We present two patients both with diabetes, renal dysfunction with proteinuria converted to sirolimus therapy, who cleared serum HCV RNA without antiviral treatment. This is a potentially important observation that should stimulate study into factors that may help viral clearance from blood.
Diabetes Mellitus, Type 1↗
Immunosuppression and donor age with respect to severity of HCV recurrence after liver transplantation.
In HCV cirrhotic patients after liver transplantation, survival and recurrence of HCV appears to be worsening in recent years. Donor age has been suggested as a cause. However, it is not clear if early and/or late mortality is affected and whether donor age is a key factor, as opposed to changes in immunosuppression. The aim of this study was to assess impact of donor age and other factors with respect to the severity of HCV recurrence posttransplant. A consecutive series of 193 HCV cirrhotic patients were transplanted with cadaveric donors, median age 41.5 years (13-73) and median follow-up of 38 months (1-155). Donor age and other factors were examined in a univariate/multivariate model for early/late survival, as well as fibrosis (grade 4 or more, Ishak score) with regular biopsies, 370 in total, from 1 year onwards. Results of the study indicated that donor age influenced only short-term (3 months) survival, with no significant effect on survival after 3 months. Known HCC independently adversely affected survival, as did the absence of maintenance azathioprine. Severe fibrosis (stage > or = 4) in 51 patients was related to neither donor age nor year of transplantation, but it was independently associated with combined biochemical/histological hepatitis flare (OR 2.9, 95% CI 1.76-4.9) whereas maintenance steroids were protective (OR 0.4, 95% CI 0.23-0.83). In conclusion, in this cohort donor age did not influence late mortality in HCV transplanted cirrhotic patients or development of severe fibrosis, which was related to absence of maintenance steroids and a hepatitis flare. Maintenance azathioprine gave survival advantage.
Adult↗
Development and validation of models for the investigation of blood clotting in idealized stenoses and cerebral aneurysms.
An in vitro model of blood clotting is presented using hypercoaguable milk as an analog for blood. Milk clot formation was studied for periods of 2, 5, 10, 20, and 30 min within an idealized stenosis geometry. Clot formation was recorded using photography, clot casting, and clot mass calculation. The distribution of clot within the fluid was seen to be in good agreement with a previous study that used a residence time model to predict areas of clot formation in thrombin solution. A numerical model was formulated within computational fluid dynamics package CFX that allowed local activation of blood clotting to be simulated. This model was applied to the analysis of an idealized cerebral aneurysm geometry. An idealized coil geometry was included within the aneurysm and clotting fluid concentration and fluid residence time were modeled using transport equations within CFX. The viscosity of the fluid was defined as a function of both residence time and clotting fluid concentration. The model was seen to produce features consistent with observations of thrombosis within cerebral aneurysms, while avoiding the unrealistic build up of clot in near-wall regions that is associated with a pure residence time model.
Animals↗
Induction of labour: following guidelines.
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Adult↗
Detection of elements of the staphylococcal cassette chromosome (SCC) in a methicillin-susceptible (mecA gene negative) homologue of a fucidin-resistant MRSA.
OBJECTIVES: To determine the DNA relatedness of an outbreak of community-acquired fucidin-resistant methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) isolated from intravenous drug users (IVDUs). MATERIALS AND METHODS: Relatedness was determined by PFGE analysis of macro-restricted chromosome, together with a variety of PCR methods, to determine polymorphisms in the accessory gene regulator (agr) locus, the structure of the staphylococcal cassette chromosome (SCCmec) and the presence or absence of the gene encoding Panton-Valentine leucocidin (PVL). RESULTS: Clonality of the MRSA and MSSA was established by PFGE, a finding further supported by agr analysis. By PCR, the MRSA contained the typical genetic organization of SCCmec type-1. However, the MSSA, though mecA-negative, contained certain fragments of the SCC. Genes encoding PVL were not detected. CONCLUSIONS: This outbreak involved a community-acquired fucidin-resistant MRSA and its methicillin-susceptible homologue. The MSSA did not contain the mecA gene but did contain elements of the mobile type-I SCC. The MSSA were associated with a change in PFGE pattern with a deletion in fragment size of approximately 215-195 kb.
Bacteremia↗
Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection.
Progress in the fight against the HIV/AIDS epidemic is hindered by our failure to elucidate the precise reasons for the onset of immunodeficiency in HIV-1 infection. Increasing evidence suggests that elevated immune activation is associated with poor outcome in HIV-1 pathogenesis. However, the basis of this association remains unclear. Through ex vivo analysis of virus-specific CD8(+) T-cells and the use of an in vitro model of naïve CD8(+) T-cell priming, we show that the activation level and the differentiation state of T-cells are closely related. Acute HIV-1 infection induces massive activation of CD8(+) T-cells, affecting many cell populations, not only those specific for HIV-1, which results in further differentiation of these cells. HIV disease progression correlates with increased proportions of highly differentiated CD8(+) T-cells, which exhibit characteristics of replicative senescence and probably indicate a decline in T-cell competence of the infected person. The differentiation of CD8(+) and CD4(+) T-cells towards a state of replicative senescence is a natural process. It can be driven by excessive levels of immune stimulation. This may be part of the mechanism through which HIV-1-mediated immune activation exhausts the capacity of the immune system.
Aging↗
Use of serial maternal urine cytomegalovirus PCR to detect primary CMV infection in seronegative pregnant women.
The aim of the study was to determine if serial maternal urine polymerase chain reaction (PCR) tests can detect primary CMV infection during pregnancy. This was a prospective study conducted from 1 January 1999 to 31 December 1999 in an antenatal clinic setting of a teaching hospital. The study group included women who were CMV IgG negative and aged <30 years or had a pre-school child. They were invited to self-collect urine samples monthly and send them to the laboratory by post. Cord bloods were tested for CMV IgG to detect seroconversion. An anxiety questionnaire was sent to all study participants. At first attendance, 1549 (42%) women were CMV IgG negative. Of the 696 eligible women, 609 (88%) participated in the urine PCR study. PCR was performed on 2263 urine samples (median of 4/pregnancy). Primary CMV infection was identified in one woman by urine PCR at 36 weeks (baby CMV negative). Cord blood samples were available from 152/609 infants (25%). Seroconversion was noted in only one woman. Replies to the questionnaire were received from 264/609 women (43%): 214 (81%) had little or no anxiety, and 220 (83%) felt reassured by their study participation. Serial urine PCR is a feasible method of detecting primary maternal CMV infection during pregnancy which has potential for evaluation in further studies.
Adolescent↗
Genes: philosophical analyses put to the test.
This paper describes one complete and one ongoing empirical study in which philosophical analyses of the concept of the gene were operationalized and tested against questionnaire data obtained from working biologists to determine whether and when biologists conceive genes in the ways suggested. These studies throw light on how different gene concepts contribute to biological research. Their aim is not to arrive at one or more correct 'definitions' of the gene, but rather to map out the variation in the gene concept and to explore its causes and its effects.
Attitude↗
Cytomegalovirus infection of the central nervous system.
Studies report that 40-100% of the general population are infected with cytomegalovirus (CMV), a virus associated with severe neurological conditions, such as CMV encephalitis, and which may have a role in some cases of Guillain-Barre syndrome. CMV infection is a particular concern among individuals with HIV, as almost all are co-infected with it. The introduction of highly active antiretroviral therapy (HAART) has provided a means of reconstituting the immune system of those with HIV/AIDS in such a way as to allow CMV infection to be controlled. In doing so, HAART has done much to reduce the mortality rate associated with CMV disease in such patients. Despite this, response to treatment in these patients remains suboptimal and many do not have access to such therapy, so, efforts to improve the treatment of CMV have been a priority. The International Herpes Management Forum (IHMF) has developed management guidelines to promote the improved diagnosis and treatment of CMV disease of the central nervous system (CNS). It is recommended that polymerase chain reaction (PCR) for viral DNA should be performed on CSF as a means of diagnosing CMV infection of the CNS. As CMV disease is always preceded by viraemia, treatment should be directed toward the prevention of CMV disease. However, if CMV disease develops, ganciclovir is recommended as therapy and continued in a maintenance fashion, which can be discontinued should CD4 count remain above 100 cells/mm3 for 6 months. In many circumstances, valganciclovir may be preferred, depending on the level of function in the patient, their ability to take oral therapy and the severity of disease. Use of foscarnet should be limited to ganciclovir-resistant cases due to the high level of toxicity associated with the drug and its intravenous mode of administration.
Acyclovir↗
Is viral shedding a surrogate marker for transmission of genital herpes? A discussion document.
While the concept linking herpes simplex virus (HSV) shedding to transmission is plausible, few data support shedding as a surrogate marker. If shedding is to be used as a surrogate marker in future clinical studies, it must be clear how far shedding must be reduced, and what the shape of the transmission:viral load curve (or transmission:detection frequency curve) is before transmission is reduced. It remains unclear whether peak virus load, frequency of detection of virus, or the area under curve of the time:virus load plot is the critical parameter in the transmission of HSV. This paper reports on an international meeting of experts and a debate at the International Herpes Management Forum (IHMF) Annual Meeting (2004), convened to examine whether a surrogate marker for HSV transmission is necessary, and whether there is any evidence, either in studies involving HSV or other viral infections, to suggest that viral shedding could be used as such a surrogate.
2-Aminopurine↗
Minimizing respondent attrition in longitudinal research: practical implications from a cohort study of adolescent drinking.
The methods used to maximize retention in a longitudinal study of adolescent drinking are discussed. Data were collected at three time points: at recruitment to the study, after nine months and at 18 months. Strategies to minimize attrition included the collection of detailed contact information, incentives for participation, postcard and telephone reminders and telephone interviews. Ninety-six percent of the original sample completed the first follow-up questionnaire, 92% completed the second and the study lost contact with just 3% of participants. The success of the current project is notable as this type of population is notoriously difficult to retain in longitudinal studies.
Adolescent↗
The monitoring of drug trends in Australia.
Recently, there has been increased recognition of the importance of drug information systems (DIS), highlighting the need for an internationally coordinated approach to data collection and advocating the regular assessment of a range of areas. Accurate information provides policy makers with the evidence to evaluate current strategies and to plan future strategies. An effective drug information system (DIS) must collect comprehensive, detailed and in-depth data, while also being sensitive to emergent trends and placing these changes into the context of longer-term trends. An integrated and comprehensive system combines both sensitive (or lead) and slower but more reliable lag indicators. This article reviews conceptual frameworks for DIS and developments in international systems. It then considers the range of DIS in Australia and then describes two integrated monitoring systems with an early warning function: the Illicit Drug Reporting System (IDRS) and the Drug Use Monitoring Australia (DUMA) Programme. Both systems collate sensitive lead indicators, and provide timely information about emerging drug trends in Australia. Together, these two systems are best-placed to provide effective early warning of new trends in illicit drug markets, and constitute an important component of the overall approach to the monitoring of drug use and associated harms in Australia.
Australia↗
Developing a global perspective on drug information systems.
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Drug Information Services↗
Cytomegalovirus (CMV) polymerase chain reaction profiles in individuals with advanced human immunodeficiency virus infection: relationship to CMV disease.
Cytomegalovirus (CMV) disease is a common complication of patients with advanced human immunodeficiency virus infection. The aim of the present study, based on a case-cohort design, was to determine the predictive value of follow-up and baseline qualitative plasma CMV polymerase chain reaction (PCR) values for CMV end-organ disease in 378 patients (158 who progressed to CMV end-organ disease and 220 who did not develop CMV disease). These patients are part of the full AIDS Clinical Trials Group 204 multinational study (1227 patients), a randomized, controlled trial that compared the effects of valacyclovir with those of acyclovir for CMV disease prevention. Baseline PCR positivity was a significant risk factor for CMV disease progression (relative risk [RR], 1.81; 95% confidence interval [CI], 1.09-3.00). In multivariate analyses, time-updated PCR positivity was strongly associated with progression to CMV end-organ disease (RR, 4.42; 95% CI, 2.87-6.81). Change in cumulative PCR status was informative for the risk of subsequent CMV disease.
AIDS-Related Opportunistic Infections↗