Biomedical subjects

L Morris

Publications and source records attributed to L Morris.

At least 19 recordsLinked to original sources

PubMed2006

Bayesian network analysis of resistance pathways against HIV-1 protease inhibitors.

Interpretation of Human Immunodeficiency Virus 1 (HIV-1) genotypic drug resistance is still a major challenge in the follow-up of antiviral therapy in infected patients. Because of the high degree of HIV-1 natural variation, complex interactions and stochastic behaviour of evolution, the role of resistance mutations is in many cases not well understood. Using Bayesian network learning of HIV-1 sequence data from diverse subtypes (A, B, C, F and G), we could determine the specific role of many resistance mutations against the protease inhibitors (PIs) nelfinavir (NFV), indinavir (IDV), and saquinavir (SQV). Such networks visualize relationships between treatment, selection of resistance mutations and presence of polymorphisms in a graphical way. The analysis identified 30N, 88S, and 90M for nelfinavir, 90M for saquinavir, and 82A/T and 46I/L for indinavir as most probable major resistance mutations. Moreover we found striking similarities for the role of many mutations against all of these drugs. For example, for all three inhibitors, we found that the novel mutation 89I was minor and associated with mutations at positions 90 and 71. Bayesian network learning provides an autonomous method to gain insight in the role of resistance mutations and the influence of HIV-1 natural variation. We successfully applied the method to three protease inhibitors. The analysis shows differences with current knowledge especially concerning resistance development in several non-B subtypes.

Bayes Theorem↗

PubMed2006

Persistence of nevirapine-resistant HIV-1 in women after single-dose nevirapine therapy for prevention of maternal-to-fetal HIV-1 transmission.

Single-dose nevirapine (sdNVP) for prevention of mother-to-child transmission of HIV-1 can select nevirapine (NVP)-resistant variants, but the frequency, duration, and clinical significance of this resistance is not well defined. We used a sensitive allele-specific PCR assay to assess the emergence and persistence of NVP-resistant variants in plasma samples from 22 women with HIV-1 subtype C infection who participated in a study of sdNVP for prevention of mother-to-child transmission of HIV-1. The women were categorized into three groups on the basis of detection of NVP resistance by standard genotype analysis. Group 1 (n = 6) had NVP resistance detected at 2 and 6 mo after sdNVP, but not at 12 mo. Group 2 (n = 9) had NVP resistance detected at 2 mo, but not 6 mo. Group 3 (n = 7) had no NVP resistance detected at any time point. Allele-specific PCR analysis for the two most common NVP resistance mutations (K103N and Y181C) detected NVP-resistant variants in most (16 of 21) samples that were negative for NVP resistance by standard genotype, at levels ranging from 0.1% to 20% 1 yr after treatment. The frequency of NVP-resistant mutations decreased over time, but persisted above predose levels for more than 1 yr in > or = 23% of the women. These findings highlight the urgent need for studies assessing the impact of sdNVP on the efficacy of subsequent antiretroviral therapy containing NVP or other nonnucleoside reverse transcriptase inhibitors.

Adult↗

PubMed2006

Laparoscopic application of PGE2 to re-establish oviducal patency and fertility in infertile mares: a preliminary study.

REASONS FOR PERFORMING STUDY: Mares are occasionally encountered that consistently fail to conceive when inseminated, naturally or artificially, with fertile stallion semen in the absence of any identifiable pathology of either the structure or function of their reproductive tract. HYPOTHESIS: Temporary blockage of the oviducts by accumulations of naturally occurring oviducal masses may be preventing oviducal transport of the embryo to the uterus. METHODS: Mares, with known reproductive histories, that had exhibited inexplicable failure of conception were treated by laparoscopically guided administration of PGE2-laced triacetin gel directly onto the surface of their oviducts. RESULTS: Fifteen mares age 10-21 years that had exhibited inexplicable failure of conception during 1-4 years were treated, of which 14 (93%) conceived within the same or subsequent breeding season. CONCLUSIONS: The high success rate of this treatment supports the tentative diagnosis of oviducal obstruction in these mares and indicates that blockage of the mare's oviducts may occur in the form of a moveable accumulation of debris rather than from permanent fibrous adhesions resulting from salpingitis. POTENTIAL RELEVANCE: This laparoscopic application of PGE2 to the oviducts constitutes a sound and practical method of restoring fertility in mares suffering oviducal obstruction and further studies involving the procedure are warranted.

Animals↗

PubMed2005

The process of decision-making by stressed social workers: to stay or leave the workplace.

This paper considers the perception of stress and its impact on social workers, their relationships and decision-making. It begins with an exploration of stress, perception and how perception is utilized to understand stress experiences. It continues with exploration of decision-making processes. Finally it explores themes relating to decision-making based on case study findings of social workers who experienced stress and explores the outcomes of decision-making in relation to the workplace and how this might impact on retention.

Career Mobility↗

PubMed2005

3-D numerical simulation of blood flow through models of the human aorta.

A Spiral Computerized Tomography (CT) scan of the aorta were obtained from a single subject and three model variations were examined. Computational fluid dynamics modeling of all three models showed variations in the velocity contours along the aortic arch with differences in the boundary layer growth and recirculation regions. Further down-stream, all three models showed very similar velocity profiles during maximum velocity with differences occurring in the decelerating part of the pulse. Flow patterns obtained from transient 3-D computational fluid dynamics are influenced by different reconstruction methods and the pulsatility of the flow. Caution is required when analyzing models based on CT scans.

Aged↗

PubMed2005

Injection-moulded models of major and minor arteries: the variability of model wall thickness owing to casting technique.

Cardiovascular disease of major and minor arteries is a common cause of death in Western society. The wall mechanics and haemodynamics within the arteries are considered to be important factors in the disease formation process. This paper is concerned with the development of an efficient computer-integrated technique to manufacture idealized and realistic models of diseased major and minor arteries from radiological images and to address the issue of model wall thickness variability. Variations in wall thickness from the original computer models to the final castings are quantified using a CCD camera. The results found that wall thickness variation from the major and minor idealized artery models to design specification were insignificant, up to a maximum of 16 per cent. In realistic models, however, differences were up to 23 per cent in the major arterial models and 58 per cent in the minor arterial models, but the wall thickness variability remained within the limits of previously reported wall thickness results. It is concluded that the described injection moulding procedure yields idealized and realistic castings suitable for use in experimental investigations, with idealized models giving better agreement with design. Wall thickness is variable and should be assessed after the models are manufactured.

Anatomy, Cross-Sectional↗

PubMed2004

A mathematical model to predict the in vivo pulsatile drag forces acting on bifurcated stent grafts used in endovascular treatment of abdominal aortic aneurysms (AAA).

Endovascular treatment of abdominal aortic aneurysms (AAA) is a promising new alternative to the traditional surgical repair. However, the endovascular approach suffers problems such as stent graft migration, endoleaks and stent mechanism breakage. Fatigue failure is believed to be the major cause of stent graft migration and device breakage. Knowledge of the in vivo forces acting on such devices is a basic requirement for the design of a successful endovascular device. Using a Fourier series trigonometric fit of a typical pressure and flow relationship, a mathematical model, using the control volume method, was developed to predict the pulsatile drag forces acting on various bifurcated stent graft geometries. It was found that for an iliac angle of 30 degrees, a proximal diameter of 24 mm and an iliac diameter of 12 mm, the drag force varied, over the cardiac cycle, between 3.9 and 5.5 N in the axial direction. It was noted that for a specific iliac angle the drag force variation with proximal diameter approximates a quadratic fit, with an increase in proximal diameter producing an increase in drag force. The more compliant the aorta the higher the drag force. Previously published results demonstrated the axial loads (axial drag forces) required for stent graft migration for certain stents types are lower than the drag forces calculated in this study. It is believed that the results of this study can provide guidelines for the quantitative analyses of the in vivo drag forces experienced by stent grafts and could therefore be used as design criteria for such devices.

Aortic Aneurysm, Abdominal↗

PubMed2004

Antibodies against human herpesvirus 8 in South African renal transplant recipients and blood donors.

OBJECTIVE: To examine the seroprevalence of human herpesvirus 8 (HHV-8) antibodies in a selected group of renal transplant recipients and blood donors, in relation to various socio-demographic variables. SUBJECTS: Anonymised serum samples were obtained from 306 black donors attending blood donations at the SA National Blood Transfusion Service, Johannesburg, and 430 recipients of renal transplants at Johannesburg General Hospital, from 1998 to 1999. METHODOLOGY: Serum samples were tested by indirect immunofluorescence assay to detect IgG antibodies against HHV-8. Crude and adjusted seroprevalence, and odds ratios were calculated to examine the relationship between antibodies to HHV-8 and age, sex, population, and risk group. RESULTS: Adjusted HHV-8 seroprevalence at 'medium to high' antibody titres (at least 1:51,200) increased with age, from 2% (age 15-24; 95% CI=0.7-5.2) to 10% (age 45+; 95% CI=6.3-15.2). Whites had the lowest % adjusted seroprevalence (1.8; 95% CI:0.8-4.2), followed by blacks (7.4; 95% CI=5.1-10.8), Asians/Indians (9.5; 95% CI=3.6-22.9), and individuals of mixed race (12.5; 95% CI=4.5-30.2). Seroprevalence was not related to gender, or to occupation of blood donors. HHV-8 seroprevalence did not differ significantly between first-time blood donors, repeat donors, and transplant recipients (P=0.49). Transplant recipients had a greater proportion of persons with high HHV-8 antibody intensity; however, this difference was statistically not significant (P=0.08). CONCLUSIONS: Blood donors and renal transplant patients had relatively high HHV-8 antibody titres. Given the strong association between HHV-8 seropostivity and the risk of developing Kaposi's sarcoma, it may be prudent in settings where HHV-8 seroprevalence is high to screen for HHV-8 in donated blood used for these immunocompromised individuals.

Adolescent↗

PubMed2003

Reduction in visceral slide is a good sign of underlying postoperative viscero-parietal adhesions in children.

BACKGROUND/PURPOSE: Viscera stuck to the anterior abdominal wall from previous surgery risk injury during laparoscopic surgery. A prospective study was conducted to determine if these adhesions are detectable on ultrasound scan by showing a reduction in the normal visceral slide. METHODS: Patients undergoing laparoscopic procedure after a previous laparotomy underwent preoperative real-time ultrasound scan to observe if viscera slides freely under the abdominal wall. A reduction in slide was considered a positive sign of underlying adhesions. These findings were correlated with the operative findings. RESULTS: Anterior abdominal wall scans were performed on 17 children. Reduced visceral slide was seen in 10. Viscero-parietal adhesions were found in 9 of 10 patients. Visceral slide was reduced in a very localized area in 6 patients, and, in these, a loop of bowel (n = 3), liver and bowel (n = 2), or liver (n = 1) was adherent. In 4, reduced visceral slide was seen over a wide area. Extensive adhesions were found in 3 of 4. One renal transplant patient with peritonitis had a false-positive ultrasound scan. At laparotomy there were no adhesions. The peritonitis is thought to have prevented an adequate examination. Seven patients had normal visceral slide. Of these, 4 had no adhesions, but 3 children had flimsy omental adhesions. The sensitivity and specificity of visceral slide in predicting adhesions were 75% and 80%, respectively. CONCLUSIONS: Reduction in visceral slide is a good sign of underlying postoperative viscero-parietal adhesions. Ultrasonographic mapping of the abdominal wall may be useful in selecting an adhesion-free site for trocar insertion in children with previous operations requiring laparoscopic procedures.

Abdominal Wall↗

PubMed2003

Human herpesvirus-8 antibodies and DNA in HIV-1 infected patients in South Africa.

HIV-infected individuals with high levels of IgG antibodies against human herpesvirus-8 (HHV-8) are at increased risk of developing Kaposi's sarcoma. The aim of this study was to measure the association between HHV-8 viraemia and IgG antibody responses (by immunofluorescence) in a group of 201 HIV-infected individuals attending outpatient clinics, 91 in-patients with AIDS and 87 HIV-infected patients admitted with Kaposi's sarcoma. Compared to HIV-infected outpatients, the adjusted odds ratio in relation to Kaposi's sarcoma was 15.4 (95% CI 4.4-54.2) in those with viraemia, 25.1 (95% CI 6.6-95.6) in those with a positive immunofluorescent signal and infinity (lower exact CI 33.6) in those with a high immunofluorescent signal (all P trend < 0.001). Among those without HHV-8 viraemia, 23% were IgG-positive, but only 5.5% had a high immunofluorescent signal. In those who were viraemic, 89.1% were IgG-positive, and 28.2% had a high immunofluorescent signal, suggesting viraemia is associated with high HHV-8 immunofluorescence IgG signal.

Adult↗

PubMed2003

Improved detection of hepatocyte proliferation using antibody to the pre-replication complex: an association with hepatic fibrosis and viral replication in chronic hepatitis C virus infection.

To test the hypothesis that hepatitis C virus (HCV) might induce hepatocyte proliferation directly, thereby predisposing HCV carriers to cirrhosis and hepatocellular carcinoma, we have used a new method to identify proliferating hepatocytes, employing a novel monoclonal antibody to minichromosome maintenance (Mcm) proteins, essential components of the pre-replication complex. Antibody to Ki-67, a conventional marker of cell division, was also studied. Eighty-seven patients with chronic HCV infection and a broad spectrum of histological change were studied. Proliferation was observed rarely in hepatocytes from normal liver from healthy controls (always less than 0.01%). However, proliferating hepatocytes were detected in all HCV-infected patients and the proportion of hepatocytes expressing Mcm-2 (3-40%) always exceeded that expressing Ki-67 (1-14%) and correlated positively with increasing stage of fibrosis (P = 0.0001) and viral replication (P = 0.0004). There were weaker but significant associations between the proportion of hepatocytes expressing Mcm-2 and inflammatory indices including interface hepatitis, portal tract inflammation, lobular inflammation and steatosis. There was no association between the proportion of hepatocytes expressing Mcm-2 and age, gender or past alcohol consumption, but there was a weak association with current consumption of alcohol (P = 0.0067). The proportion of Ki-67 hepatocytes did not correlate with any clinical, laboratory or histological parameter. Mcm-2 was also detected in bile duct cells, sinusoidal lining cells and infiltrating lymphocytes, but at low frequency. These data indicate first, that Mcm-2 is a more sensitive marker of hepatocyte proliferation than Ki-67, second that many hepatocytes in chronic HCV infection have entered the cell cycle and third, suggest that interference with the hepatocyte cell cycle might be an alternative approach to therapy.

Adult↗

PubMed2003

Molecular investigation of two possible cases of accidental HIV-1 transmission in South Africa.

HIV-1 sequences from two possible transmission cases in South Africa were examined for evidence of genetic linkage. HIV-1-seropositive blood samples were obtained from a donor and recipient within 8 months following a blood transfusion and from a healthcare worker and her patient within 10 months following a needle-stick injury. A 700-bp region in env and 550-bp region in gag were analyzed. All sequences were phylogenetically associated with HIV-1 subtype C, the predominant HIV-1 subtype in South Africa. The nucleotide sequences from the blood transfusion case grouped together significantly with a bootstrap value of 100%. These samples were 98% and 100% identical in the predicted amino acid sequences of env and gag, respectively. In contrast, sequences from the needle-stick case showed only 67% and 80% amino acid identity in env and gag, respectively, and were separated on a phylogenetic tree. Molecular analysis suggested that HIV transmission occurred in the blood transfusion case but not in the case of the needle-stick injury. These data emphasize the need for molecular investigation of epidemiologically linked cases of HIV transmission.

Adult↗

PubMed2003

Full-length genome characterization of HIV type 1 subtype C isolates from two slow-progressing perinatally infected siblings in South Africa.

Isolation and characterization of HIV-1 from asymptomatic, slow-progressing individuals are important in studying viral pathogenesis and facilitate the development of vaccines and antivirals. In this study we identified two slow-progressing HIV-1-infected siblings, isolated viruses, and sequenced the full-length genome, to identify virus attenuations that may contribute to their altered rate of disease progression. Proviral DNA from strains 99ZATM10 and 01ZATM45 was isolated from peripheral blood mononuclear cells (PBMC) coculture.Virtually full-length genomes and long terminal repeat (LTR) regions were polymerase chain reaction (PCR) amplified, sequenced, and assembled to generate the complete genomes. Phylogenetic analysis confirmed that both isolates were subtype C throughout their genome. Predicted amino acid sequence analysis for all the HIV-1 proteins showed that both viruses had open reading frames for all genes, and encoded proteins of the expected length, except for the rev gene. The 3' end of rev exon 2 did not have the 16-amino acid (aa) truncation characteristic of subtype C viruses, and in addition, had a three-aa extension (GlyCysCys). Rev is a necessary regulatory factor for HIV expression, and changes in the protein may affect viral replication. These results suggest that slower HIV disease progression in these children may be attributed, at least in part, to an altered Rev protein.

Amino Acid Sequence↗

PubMed2003

On using experimentally estimated wall shear stresses to validate numerically predicted results.

The objective of this investigation was to assess the use of experimentally estimated wall shear stresses to validate numerically predicted results. The most commonly cited haemodynamic factor implicated in the disease initiation and proliferation processes at graft/artery junctions is wall shear stress (WSS). WSS can be determined from the product of the viscosity of the fluid and the wall shear rate. Numerically, the wall shear rate is predicted using velocity values stored in the computational cell near the wall and assuming zero velocity at the wall. Experimentally, the wall shear rate is estimated by applying a curve-fit to near-wall velocity measurements and evaluating the shear rate at a specific distance from the wall. When estimating the wall shear rate from the laser Doppler anemometry (LDA) point velocity measurements, large differences between the experimentally estimated and numerically predicted WSSs were introduced. It was found that the estimated WSS distributions from the experimental results are highly dependent on the curve-fitting method used to calculate the wall shear rate. However, the velocity profiles for both the experimental and numerical investigations show extremely good comparison. It is concluded that numerical models should be validated using unprocessed LDA point velocity measurement and not estimated WSS values.

Anastomosis, Surgical↗

PubMed2003

Integr8: enhanced inter-operability of European molecular biology databases.

OBJECTIVES: The increasing production of molecular biology data in the post-genomic era, and the proliferation of databases that store it, require the development of an integrative layer in database services to facilitate the synthesis of related information. The solution of this problem is made more difficult by the absence of universal identifiers for biological entities, and the breadth and variety of available data. METHODS: Integr8 was modelled using UML (Universal Modelling Language). Integr8 is being implemented as an n-tier system using a modern object-oriented programming language (Java). An object-relational mapping tool, OJB, is being used to specify the interface between the upper layers and an underlying relational database. RESULTS: The European Bioinformatics Institute is launching the Integr8 project. Integr8 will be an automatically populated database in which we will maintain stable identifiers for biological entities, describe their relationships with each other (in accordance with the central dogma of biology), and store equivalences between identified entities in the source databases. Only core data will be stored in Integr8, with web links to the source databases providing further information. CONCLUSIONS: Integr8 will provide the integrative layer of the next generation of bioinformatics services from the EBI. Web-based interfaces will be developed to offer gene-centric views of the integrated data, presenting (where known) the links between genome, proteome and phenotype.

Computational Biology↗

PubMed2001

Conserved domains of subtype C nef from South African HIV type 1-infected individuals include cytotoxic T lymphocyte epitope-rich regions.

We have characterized 43 nef sequences from subtype C HIV-1-infected South Africans and compared deduced amino acid sequences with other subtypes to identify areas of conservation. Our Nef amino acid sequences were aligned with a consensus subtype B, HXB2 reference strain and a consensus subtype C sequence. All were found to be highly homologous to subtype B in the central region of Nef, but more variable at the N and C termini of the molecule. Alignment of a consensus amino acid sequence generated from South African subtype C Nef with subtypes A, B, and D underscores cross-clade conservation in the central domain of the molecule. This domain is also rich in previously described cytotoxic T lymphocyte (CTL) epitopes that are restricted by commonly found HLA molecules in the South African population.

Amino Acid Sequence↗

PubMed2001

Characterization of full-length HIV type 1 subtype C sequences from South Africa.

Four full-length genome subtype C sequences from South Africa, three of which are being used for vaccine development, were characterized. Three isolates were obtained from recently infected individuals in KwaZulu/Natal: Du151, Du422, and Du179. A fourth isolate, CTSc2, was obtained from an individual residing in Cape Town. All four strains used the CCR5 coreceptor, although Du179 also used CXCR4. The four isolates clustered within subtype C, but the three Du isolates formed a subcluster with a bootstrap value of 100%, with CTSc2 outside the subcluster. None of the strains showed evidence of intersubtype recombination, as expected from the predominance of subtype C in South Africa. All 4 isolates had a 16-amino acid truncation on the 3' end of the Rev protein, identified in other subtype C isolates. Like many other subtype C strains, Du151, Du422, and Du179 had three NF-kappa B-binding sites in the LTR; however, CTSc2 had only two.

Genome, Viral↗

PubMed2001

CCR5 is the major coreceptor used by HIV-1 subtype C isolates from patients with active tuberculosis.

Tuberculosis (TB) is the major opportunistic infection of HIV-infected patients in developing countries and is associated with activation of the immune system and increased HIV-1 expression. The aim of this study was to explore the biological properties of HIV-1 isolates from patients with active TB. Ten HIV-1 subtype C isolates were analyzed for biological phenotypes, using MT-2 cells, and for coreceptor usage, using coreceptor-transfected cell lines. All isolates were nonsyncytium inducing (NSI) in the MT-2 assay and replicated in CCR5-expressing cells. None of the isolates used CXCR4 or any of the minor coreceptors (CCR1, CCR2b, or CCR3) efficiently. Analysis of the V3 region showed that all isolates contained the GPGQ motif characteristic of subtype C and also had a sequence profile typical of NSI viruses. These data indicate that despite their advanced disease state, patients with TB harbor viruses that use the CCR5 coreceptor. It is possible that activation of monocytes and macrophages during TB infection results in the expansion of macrophage-tropic isolates that preferentially use CCR5.

AIDS-Related Opportunistic Infections↗