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Biomedical subjects

Paul D Griffiths

Publications and source records attributed to Paul D Griffiths.

At least 19 recordsLinked to original sources
PubMed2003

Enhancement of humoral immune responses to a human cytomegalovirus DNA vaccine: adjuvant effects of aluminum phosphate and CpG oligodeoxynucleotides.

A human cytomegalovirus (HCMV) glycoprotein B (gpUL55) DNA vaccine has been evaluated in BALB/c mice. Intramuscular immunization of these mice with pRc/CMV2-gB resulted in the generation of high levels of gpUL55-specific antibody (geometric mean titer [GMT] 1:8900) and neutralizing antibody (GMT 1:74) after 2 booster doses given 5 and 10 weeks after primary inoculation. Emulsifying the construct with the aluminum phosphate gel adjuvant Adju-Phos before immunization enhanced gpUL55-specific antibody responses (GMT 1:17800, P = 0.04). Co-immunization with CpG oligodeoxynucleotides was shown to enhance levels of neutralizing antibodies generated by immunization of mice with a pRc/CMV2-gB/Adju-Phos emulsion (P = 0.04). The results provide a rationale for evaluating combinations of other HCMV proteins for incorporation into a multi-target DNA vaccine, and for the optimization of adjuvant usage, to elicit enhanced levels of neutralizing antibodies. 2003.

Adjuvants, Immunologic↗
PubMed2003

B1AC-MAMBA: B1 array combined with multiple-acquisition micro B0 array parallel magnetic resonance imaging.

The combination of an in-plane B(1) sensitivity encoding (SENSE) technique with a simultaneous multiple-slice B(0) field step technique (multiple-acquisition micro B(0) array (MAMBA)) has produced high scan time reduction factors (R < or = 8). In this study, two slices were acquired simultaneously in combination with x2 and x4 SENSE in-plane encoding using a MAMBA stepped B(0) field coil inside a four-channel phased-array coil system. Experiments were performed on a 1.5 T Infinion system (Philips Medical Systems, Cleveland, OH). The signal-to-noise ratio (SNR) was reduced with higher R factors, as was expected from the reduced number of acquisitions used to create the unaliased images. The combination of SENSE and MAMBA offers great promise for reducing scan times through parallel acquisition while at the same time reducing the number of RF channels required by a factor equal to the number of field steps employed. The B(1) array combined with MAMBA (B(1)AC-MAMBA) technique is applicable when the length of an object is much greater than its diameter, as in scanning limbs or in whole-body screening for disease.

Artifacts↗
PubMed2003

Dynamic radial projection MRI of inhaled hyperpolarized 3He gas.

A radial projection sliding-window sequence has been developed for imaging the rapid flow of (3)He gas in human lungs. The short echo time (TE) of the radial sequence lends itself to fast repetition times, and thus allows a rapid update in the image when it is reconstructed with a sliding window. Oversampling in the radial direction combined with angular undersampling can further reduce the time needed to acquire a complete image data set, without significantly compromising spatial resolution. Controlled flow phantom experiments using hyperpolarized (3)He gas exemplify the temporal resolution of the method. In vivo studies on three healthy volunteers, one patient with chronic obstructive pulmonary disease (COPD), and one patient with hemiparalysis of the right diaphragm demonstrate that it is possible to accurately resolve the passage of gas down the trachea and bronchi and into the peripheral lung.

Fourier Analysis↗
PubMed2003

Porcine cytomegalovirus in pigs being bred for xenograft organs: progress towards control.

In human medicine, human cytomegalovirus (HCMV) is readily transmitted by organ transplant causing end-organ disease and triggering graft rejection in recipients. Because of a chronic shortage of human organs, pigs transgenic for human complement control proteins are being considered as potential donors. Such xenotransplantation raises concerns about the potential zoonotic transmission of viruses including porcine cytomegalovirus (PCMV), an endemic infection of pigs. Similar to HCMV and PCMV transmission is thought to occur in utero and perinatally. We used quantitative polymerase chain reaction to examine the prevalence, organ distribution and viral load of PCMV in human decay accelerating factor (CD55) transgenic pigs. In animals reared under conventional farm conditions, virus was identified in a wide range of organs including potential xenografts (liver, kidney and heart). The spleen was PCMV DNA positive in all infected pigs. Examination of foetal spleens failed to identify evidence of transplacental infection and prospective monitoring of two litters showed that infection occurred in the postnatal period. This transmission was prevented by hysterotomy derivation and barrier rearing. Our findings demonstrate that PCMV could be eradicated from pig herds being bred for xenotransplantation and argue that the spleen from donor animals should be examined as part of quality control procedures if clinical trials proceed.

Age Factors↗
PubMed2003

Cytomegalovirus, human herpesvirus-6, and human herpesvirus-7 in hematological patients.

The prototype member of the Betaherpesvirinae subfamily, cytomegalovirus (CMV), is the most important infectious pathogen in transplant recipients, including those receiving bone marrow or stem cell grafts. Overt CMV disease such as pneumonitis is notoriously difficult to treat. Antiviral prophylaxis, rapid diagnostic tests to identify CMV infection, and preemptive antiviral chemotherapy are significant improvements in the management of CMV. As the kinetics of the immune response to CMV become better defined, immunotherapeutic approaches should be introduced to complement current management strategies. Two newly identified betaherpesviruses, human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7), are genetically more closely related to each other than to CMV. Both are highly prevalent in the general population and infections post-bone marrow transplantation are common. These viruses are not as pathogenic as CMV but HHV-6 at least can cause disease such as encephalitis, hepatitis, and bone marrow suppression. Both of these newer herpesviruses are potentially susceptible to existing and licensed antiherpesvirus drugs.

Bone Marrow Transplantation↗
PubMed2003

Homology between the human cytomegalovirus RL11 gene family and human adenovirus E3 genes.

A significant proportion of the human cytomegalovirus (HCMV) genome comprises 12 multigene families that probably arose by gene duplication. One, the RL11 family, contains 12 members, most of which are predicted to encode membrane glycoproteins. Comparisons of sequences near the left end of the genome in several HCMV strains revealed two adjacent open reading frames that potentially encode related proteins: RL6, which is hypervariable, and RL5A, which has not been recognized previously. These genes potentially encode a domain that is the hallmark of proteins encoded by the RL11 family, and thus constitute two new members. A homologous domain is also present in a subset of human adenovirus E3 membrane glycoproteins. Evolution of genes specifying the shared domain in cytomegaloviruses and adenoviruses is characterized by extensive divergence, gene duplication and selective sequence loss. These features prompt speculation about the roles of these genes in the two virus families.

Adenovirus E3 Proteins↗
PubMed2003

Two novel spliced genes in human cytomegalovirus.

Two novel spliced genes (UL131A and UL128) flanking UL130 were predicted from sequence comparisons between human cytomegalovirus (HCMV) and its closest known relative, chimpanzee cytomegalovirus (CCMV), and the splicing patterns were confirmed by mRNA mapping experiments. Both genes were transcribed with late kinetics and shared a polyadenylation site. Comparisons with wild-type HCMV in infected human tissues showed that three of five isolates passaged in cell culture contained disruptions of UL128, one was frameshifted in UL131A and one exhibited a deletion affecting UL131A and UL130. CCMV and the Colburn strain of simian cytomegalovirus, which have been passaged in cell culture, also exhibit disruptions of UL128. These observations indicate that expression of either one of UL128 and UL131A is deleterious to growth of primate cytomegaloviruses in cell culture. Although the functions of these genes are unknown, sequence comparisons suggest that UL128 encodes a beta-chemokine.

Amino Acid Sequence↗
PubMed2003

Postmortem MR imaging of the fetal and stillborn central nervous system.

BACKGROUND AND PURPOSE: Changes in the public perception of postmortem procedures in the United Kingdom have led to reduced numbers of autopsies being performed in the fetus and neonate. When autopsy is performed in this group, the brain is now usually studied without being formalin-fixed, which limits the available information. We evaluated the diagnostic accuracy of postmortem MR imaging of the fetal brain and spine when compared with the reference standard, autopsy. METHODS: We obtained high-spatial-resolution T2-weighted images (in-plane resolution approximately 0.4 mm) of the brain and spine in 40 fetuses and stillborn neonates (14-42 weeks gestational age) who were referred for autopsy. The MR findings were compared with those of autopsy, the reference standard, which had been performed independently. RESULTS: In eight cases, the autopsy did not provide structural information of the brain or spine, because assessment of the unfixed tissue was impossible. There was agreement between MR and autopsy findings in 31 (97%) of 32 cases in which comparison could be made. Eleven cases showed normal brain, and 20 cases showed a wide range of developmental and acquired abnormalities. The sensitivity of MR was 100%, specificity 92%, positive predictive value 95%, and negative predictive value 100%. CONCLUSION: MR imaging has a useful role in providing structural information of the central nervous system in fetuses and stillborn neonates.

Autopsy↗
PubMed2003

Contrast-enhanced fluid-attenuated inversion recovery imaging for leptomeningeal disease in children.

BACKGROUND AND PURPOSE: To develop an MR imaging method that improves detection of leptomeningeal disease when compared with the current reference standard, contrast-enhanced T1-weighted imaging. METHODS: We investigated the cases of 10 children who were at high risk of intracranial leptomeningeal disease (Sturge-Weber syndrome and medulloblastoma). The cases of Sturge-Weber syndrome were investigated by using one MR imaging examination, and the cases of medulloblastoma were investigated by using four MR imaging examinations performed over 18 months. In all cases, contrast-enhanced fluid-attenuated inversion recovery (FLAIR) images were acquired in addition to the routine sequences. The parameters of the FLAIR sequence were chosen to maximize the T1 component of the signal intensity, to maximize detection of leptomeningeal enhancement. We made subjective and objective assessments of the presence and extent of leptomeningeal disease as shown on contrast-enhanced T1-weighted images and contrast-enhanced FLAIR images. RESULTS: In three of the four cases of Sturge-Weber syndrome, the T1 and FLAIR sequences showed comparable extent of leptomeningeal enhancement. For one child, FLAIR images showed unexpected bilateral disease and more extensive leptomeningeal enhancement on the clinically suspected side. In four of six cases of medulloblastoma, no leptomeningeal enhancement was shown on any examinations during the 18-month period. In two cases, FLAIR images showed more extensive leptomeningeal enhancement when compared with T1-weighted images. CONCLUSION: Contrast-enhanced FLAIR imaging seems to improve detection of leptomeningeal disease when compared with routine contrast-enhanced T1-weighted imaging. This seems to be partly because of suppression of signal intensity from normal vascular structures on the surface of the brain by FLAIR, which allows easier visualization of abnormal leptomeninges. We think that these findings can be extrapolated to the investigation of leptomeningeal disease of all causes and at all ages.

Cerebellar Neoplasms↗
PubMed2002

Rapid reconstitution of humoral immunity against cytomegalovirus but not HIV following highly active antiretroviral therapy.

OBJECTIVE: To determine the kinetics of reduction in human cytomegalovirus (HCMV) load and specific anti-glycoprotein B (gB) immune responses in patients with concurrent HCMV DNAaemia following the initiation of highly active antiretroviral therapy (HAART). DESIGN: Sequential analysis of eleven patients with HCMV DNAaemia who received HAART and eleven control patients with HCMV DNAaemia. METHODS: HCMV load was measured by quantitative competitive polymerase chain reaction and anti-gB, anti-HIV Env and Gag responses by an end-point dilution immunofluorescence assay using recombinant antigens expressed in insect cells. Estimates of the efficacy of the reconstituting immune system at controlling HCMV replication were based on previous dynamic models. RESULTS: In patients initiating HAART, HCMV DNA levels in blood declined rapidly, with a median half-life of 5.2 days, consistent with an efficacy of the reconstituting immune system at inhibiting HCMV replication of 52.8-85% (median, 61%). Commensurate with this decrease, a significant increase in anti-gB titres was observed in the post-HAART period (corresponding to an average fourfold increase in titre by 1 month rising to an eightfold increase at month 3; = 0.01). No changes in titre were observed in the control group or for anti-HIV Gag antibody levels, while anti-HIV Env antibody levels decreased after HAART. CONCLUSIONS: In patients with HCMV DNAaemia, reconstitution of humoral immunity to HCMV gB occurs rapidly following the initiation of HAART. These changes contrast with the patterns observed for anti-HIV humoral immune responses.

AIDS-Related Opportunistic Infections↗
PubMed2002

Tomorrow's challenges for herpesvirus management: potential applications of valacyclovir.

Controlled trials suggest that acyclovir/valacyclovir can provide significant clinical benefits when used for prophylaxis in the immunocompromised host. These findings implicate herpesvirus(es) in the pathogenesis of complex medical conditions, including graft rejection and death. However, it is not known which of the 8 herpesviruses are important under particular circumstances. Prime candidates for triggering adverse outcomes are cytomegalovirus (CMV) in solid organ transplant recipients (causing rejection), CMV and human herpesvirus type 6 (HHV-6) in bone marrow transplant patients (causing marrow suppression), and herpes simplex virus, HHV-6, and CMV in AIDS patients (accelerating the rate of human immunodeficiency virus disease progression and death). Other diseases that may have a herpesvirus component or trigger susceptible antiviral agents include atherosclerosis and multiple sclerosis. In the future, clinicians should be alert to novel findings of randomized trials that may provide insight into the pathogenesis of these diseases and the contributions made by clinically silent herpesvirus infections.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Valacyclovir provides optimum acyclovir exposure for prevention of cytomegalovirus and related outcomes after organ transplantation.

A meta-analysis of 12 randomized trials (1574 patients) examined herpesvirus and related outcomes following organ transplantation over a range of acyclovir exposures (including valacyclovir). Overall, cytomegalovirus (CMV) infection (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.34-0.57; P<.001), CMV disease (OR, 0.41; 95% CI, 0.31-0.54; P<.001), death (OR, 0.60; 95% CI, 0.40-0.90; P=.01), opportunistic infection (OR, 0.70; 95% CI, 0.53-0.91; P=.009), acute graft rejection (OR, 0.67; 95% CI, 0.52-0.86; P<.001), herpes simplex virus disease (OR, 0.17; 95% CI, 0.12-0.24; P<.001), and varicella-zoster virus disease (OR, 0.06; 95% CI, 0.01-0.25; P<.001) were significantly reduced. Increased acyclovir exposure influenced more end points: Maximum efficacy resulted from valacyclovir (8 g/day). Increasing acyclovir exposure to that achieved with valacyclovir extends benefits of prophylaxis to include impact on graft rejection and opportunistic infections.

Acyclovir↗
PubMed2002

Human cytomegalovirus (HCMV) replication dynamics in HCMV-naive and -experienced immunocompromised hosts.

Human cytomegalovirus (HCMV) can infect both HCMV-naive and -experienced transplant patients. In this study, the growth rate of HCMV in HCMV-naive hosts (1.82 units/day; 95% confidence interval [CI], 1.44-2.56 units/day) was shown to be significantly faster than the growth rate of virus in HCMV-experienced hosts undergoing recurrent infection (0.61 units/day; 95% CI, 0.55-0.7 units/day; P<.0001). The basic reproductive number (R(0)) for HCMV-naive liver transplant patients was 15.1 (95% CI, 8.9-44) but was only 2.4 (95% CI, 2.35-2.8) for HCMV-experienced transplant recipients, corresponding to an anti-HCMV immune efficacy of approximately 84%, despite immunosuppressive therapy. The R(0) values suggest that an anti-HCMV drug or vaccine with an efficacy of >93% (95% CI, 89%-98%) is required to eliminate viral growth during infection of HCMV-naive liver transplant recipients, whereas lower efficacy levels are sufficient to reduce the R(0) value to <1 in hosts with prior HCMV immunity.

AIDS-Related Opportunistic Infections↗
PubMed2002

k-space filtering in 2D gradient-echo breath-hold hyperpolarized 3He MRI: spatial resolution and signal-to-noise ratio considerations.

In this work some of the factors that can influence the signal-to-noise ratio (SNR) and spatial resolution in MR images of inhaled hyperpolarized gases are systematically addressed. In particular, the effects of RF depletion of longitudinal polarization and image gradient diffusion dephasing were assessed in terms of their contribution to a k-space filter. By means of theoretical simulations and a novel method of experimental validation using a variable transverse magnetization of the 1H signal, systematic quantitative and qualitative investigations of the effects of k-space filtering intrinsic to imaging of hyperpolarized gas were made. A 2D gradient-echo image is considered for a range of flip angles with centric, sequential, and half-Fourier Cartesian phase-encoding strategies, and the results are assessed in terms of SNR and spatial resolution in the reconstructed images. Centric phase encoding was found to give the best SNR at higher flip angles, with a trade-off in spatial resolution compared to sequential phase encoding. A half-Fourier approach potentially offers increased SNR through the use of higher flip angles without compromising the spatial resolution, which is comparable to that achieved with sequential encoding.

Fourier Analysis↗
PubMed2002

Study of the effect of CSF suppression on white matter diffusion anisotropy mapping of healthy human brain.

Healthy human brain diffusion anisotropy maps derived from standard spin echo diffusion tensor imaging (DTI) were compared with those using fluid-attenuated inversion recovery (FLAIR) preparation prior to DTI to null the signal from cerebrospinal fluid (CSF). Consistent comparisons entailed development of DTI postprocessing methods, image masking based on fitting quality, and an objective region-of-interest-based method for assessment of white matter extent. FLAIR DTI achieved an extended delineation of major white-matter tracts (genu, splenium, and body of the corpus callosum) close to large CSF-filled spaces (lateral ventricles), but did not affect representation of tracts remote from CSF (internal and external capsules and coronal radiation). This result, which was detectable qualitatively (visual inspection), was verified quantitatively by analyses of the relative anisotropy (RA) distribution over white matter structures for 11 subjects. FLAIR DTI thus suppresses the CSF signal that otherwise masks underlying anisotropic parenchymal tissue through partial volume averaging.

Adult↗
PubMed2002

Interleaved pulsed MAMBA: a new parallel slice imaging method.

A method of acquiring slices in parallel is described which uses interleaved sets of pulsed B(0) field coils to generate discrete regions of uniform field within the main magnetic field known as interleaved MAMBA (multiple acquisition micro B(0) array). Simulations of a number of coil designs were performed using the Biot-Savart law. A six-step coil was built and interfaced to a 0.17 T Niche MRI system and the field steps measured using an imaging technique. Measured field steps were in good agreement with the values predicted by simulation. The coil design was then scaled up by a factor of three, interfaced to a 1.5 T whole-body MRI system, and scans of the hands and arms of volunteers were acquired from up to four field steps using standard spin and gradient echo sequences. Images were also acquired simultaneously from two field steps with no frequency encode aliasing and one excitation. The one-dimensional interleaved pulsed MAMBA step field technique shows great promise for enabling many slices to be acquired simultaneously along the axis of the coil for rapid volumetric studies without the need for multiple shot Hadamard encoding. Extension of interleaved coil design to two or three dimensions is feasible, which could provide full spatial coverage combined with ultra-rapid data acquisition.

Echo-Planar Imaging↗