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Biomedical subjects

M J Dolan

Publications and source records attributed to M J Dolan.

At least 19 recordsLinked to original sources
PubMed1999

Dendritic cell (DC)-based anti-infective strategies: DCs engineered to secrete IL-12 are a potent vaccine in a murine model of an intracellular infection.

Infections with intracellular pathogens such as Leishmania donovani and Mycobacterium tuberculosis pose serious health problems worldwide. Effective vaccines for these pathogens are not available. Furthermore, despite optimal therapy, disease progression is often seen with several intracellular infections. For these reasons, we initiated studies to develop novel anti-infective vaccine and treatment strategies that couple the potent Ag-presenting capacity of dendritic cells (DC) with paracrine delivery of potent anti-infective cytokines such as IL-12 to local immune response sites. We tested this strategy in a murine model of visceral leishmaniasis. Adoptive transfer of DCs pulsed ex vivo with soluble L. donovani Ags (SLDA) to naive mice induced the Ag-specific production of IFN-gamma, and increased the percentage of activation markers on spleen lymphocytes. SLDA-pulsed DCs engineered by retroviral gene transfer techniques to secrete high levels of biologically active murine IL-12 augmented this immune response further. In several different vaccination and immunotherapy protocols, compared with sham-treated mice, animals receiving SLDA-pulsed DCs either before or following infection had 1-3 log lower parasite burdens, and this protection was associated with a pronounced enhancement in the parasite-specific IFN-gamma response. The augmentation of this protection by IL-12-engineered DCs was striking. First, live parasites were not detected in the liver of mice vaccinated with IL-12-transduced, SLDA-pulsed DCs. Second, this parasitological response was associated with a nearly normal liver histology. In contrast, parasites and granulomas were found in mice vaccinated with SLDA-pulsed, nontransduced DCs. Collectively, these studies provide the rationale for the development of potent DC-based immunotherapies.

3T3 Cells↗
PubMed1999

A close look at alcohol gel as an antimicrobial sanitizing agent.

BACKGROUND: Hand transmission of microbes by health care workers is a primary cause of nosocomial infections in both long-term and acute care facilities. Compliance with effective handwashing and hand sanitization regimens can break this cycle. METHODS: We investigated the antimicrobial efficacy and irritation potential of 5 handwash product regimens: a nonantimicrobial lotion soap, an antimicrobial lotion soap, an alcohol gel sanitizer, a nonantimicrobial lotion soap with an alcohol gel sanitizer, and an antimicrobial lotion soap with an alcohol gel sanitizer. The regimens were evaluated by using a Healthcare Personnel Handwash procedure, and irritation was assessed by using expert hand evaluation after 25 consecutive washes. RESULTS: The Healthcare Personnel Handwash data showed that the mean log reductions from baseline were greatest for the lotion soaps with alcohol gel sanitizer, less for the alcohol and the antimicrobial soap alone, and least for the bland soap. All of the product regimens showed a low potential for skin irritation. CONCLUSION: In terms of both microorganism reduction and skin irritation, the most effective product regimens were the use of alcohol gel sanitizer in combination with either an antimicrobial or a plain lotion soap.

Adult↗
PubMed1998

CD38 expression on cryopreserved CD8+ T cells predicts HIV disease progression.

Previous studies have revealed that the expression of CD38 on CD8+ T cells is a strong predictor of disease progression in human immunodeficiency virus (HIV)-infected individuals. Those studies were performed using fresh patient samples over an extended trial period. After demonstrating the validity of assay results on cryopreserved cells, we performed a retrospective study using frozen cell samples to determine the predictive value of CD38 expression in patients with CD4 counts above 400 cells/microl. The CD38 expression as measured by antibody binding capacity and the CD38 median channel were shown to be associated with time to new opportunistic infection or death (both P < 0.001). These results suggest that CD38 expression on CD8+ T cells, whether fresh or frozen, provides a useful predictor of HIV disease progression.

ADP-ribosyl Cyclase↗
PubMed1998

HIV-1 infection induces a selective reduction in STAT5 protein expression.

HIV-1 infection is accompanied by qualitative and quantitative defects in CD4+ T lymphocytes. Loss of immune function in HIV patients is usually associated with a profound dysregulation of cytokine production. To investigate whether cytokine signaling defects occur during HIV infection, PHA blasts from healthy human donors were infected with two strains of HIV-1 and screened for the expression of STAT proteins used in cytokine signaling. A selective decrease in STAT5B was seen 8 days after infection with the BZ167 dual-tropic HIV isolate, but not with the Ba-L, M-tropic strain. Based on these findings, purified T cells from HIV-infected patients in different stages of disease were also tested for STAT expression; decreases in STAT5A, STAT5B, and STAT1alpha were observed in all patients. The reduction in STATs seen in vivo and in vitro after HIV infection may contribute to the loss of T cell function in HIV disease.

Cells, Cultured↗
PubMed1998

Bartonella henselae neuroretinitis in cat scratch disease. Diagnosis, management, and sequelae.

OBJECTIVE: This study aimed to report the long-term outcomes of patients treated with an antibiotic drug combination for Bartonella henselae neuroretinitis. DESIGN: The study design was a retrospective case series. PARTICIPANTS: Seven consecutive patients with neuroretinitis and cat scratch disease participated. INTERVENTIONS: Patients underwent medical and ophthalmic evaluations. Blood cultures were obtained, and B. henselae antibody titers were measured. Tuberculosis, Lyme, toxoplasmosis, syphilis, and sarcoidosis were excluded. Patients received oral doxycycline 100 mg and rifampin 300 mg twice daily for 4 to 6 weeks and were observed for an average of 16 months (range, 10-24 months). Formal electrophysiologic testing was performed in three patients after resolution of neuroretinitis. MAIN OUTCOME MEASURES: The changes in ocular inflammation and visual function associated with treatment were recorded. Follow-up examinations and electrophysiologic testing documented sequelae. RESULTS: Patients presented following cat exposure with fever, malaise, and blurred vision. Decreased visual acuity (ranging from 20/40 to counting fingers) frequently was associated with dyschromatopsia and afferent pupillary defects. Ophthalmoscopic analysis showed signs of neuroretinitis, including nerve fiber layer hemorrhages, cotton-wool spots, multiple discrete lesions in the deep retina, and stellate macular exudates. B. henselae infection was confirmed with positive blood cultures or elevated immunofluorescent antibody titers or both. Therapy appeared to promote resolution of neuroretinitis, restoration of visual acuity, and clearance of bacteremia. After 1 to 2 years, two eyes had residual disc pallor, afferent pupillary defects, retinal pigmentary changes, and mildly decreased visual acuity. Electrophysiologic studies showed that when compared to the fellow eye, affected eyes had subnormal contrast sensitivity, abnormal color vision, and abnormal visually evoked potentials. Conversely, electroretinograms were normal in all subjects. CONCLUSIONS: B. henselae is a cause of neuroretinitis in cat scratch disease. Compared to historic cases, doxycycline and rifampin appeared to shorten the course of disease and hasten visual recovery. Long-term prognosis is good, but some individuals may acquire a mild postinfectious optic neuropathy.

Adult↗
PubMed1998

Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression.

Allelic variants for the HIV-1 co-receptors chemokine receptor 5 (CCR5) and CCR2, as well as the ligand for the co-receptor CXCR4, stromal-derived factor (SDF-1), have been associated with a delay in disease progression. We began this study to test whether polymorphisms in the CCR5 regulatory regions influence the course of HIV-1 disease, as well as to examine the role of the previously identified allelic variants in 1,090 HIV-1 infected individuals. Here we describe the evolutionary relationships between the phenotypically important CCR5 alleles, define precisely the CCR5 regulatory sequences that are linked to the CCR5-delta32 and CCR2-641 polymorphisms, and identify genotypes associated with altered rates of HIV-1 disease progression. The disease-retarding effects of the CCR2-641 allele were found in African Americans but not in Caucasians, and the SDF1-3'A/3'A genotype was associated with an accelerated progression to death. In contrast, the CCR5-delta32 allele and a CCR5 promoter mutation with which it is tightly linked were associated with limited disease-retarding effects. Collectively, these findings draw attention to a complex array of genetic determinants in the HIV-host interplay.

Adolescent↗
PubMed1998

Switching curve controller for FES-assisted standing up and sitting down.

A low-level, closed-loop controller for FES-assisted standing up and sitting down is described. If, for able-bodied individuals, when standing up and sitting down, the knee angular velocity is plotted against knee angle, consistent phase-plane trajectories are produced. The bang-bang controller uses a model of this trajectory as a switching curve. The design rationale for the controller was the desire to avoid injuries that might occur if knee-locking on standing up and seat-contact on sitting down are not adequately controlled. This switching curve controller (SCC) was incorporated within a hierarchical, finite state control scheme, with electrical stimulation applied bilaterally to the knee extensors. The SCC was tested in a pilot study on a female volunteer with paraplegia (T5/6 ASIA A) and evaluated against an unramped, open-loop controller (OLC). The vertical hand forces and knee angles were measured. The subject was able to achieve standing up and sitting down safely using both controllers. For standing up, the SCC was not found to offer any quantifiable advantages over the OLC and was found to increase the hand force by 8.4%. In contrast, for sitting down the SCC was found to reduce the knee angular velocities as the subject approached the seat by 27%, demonstrating a safer, softer landing.

Adult↗
PubMed1997

Pneumonia associated with near-drowning.

Drowning and near-drowning can abruptly devastate the lives of both the affected victims and their families. In addition to the complications directly caused by the submersion, several indirect causes of morbidity exist. Infection is one of the complications associated with near-drowning, and pneumonia is the most severe of these infectious complications. The risk factors, microbiological causes, diagnostic approach, and appropriate therapy for pneumonia associated with near-drowning are not well described in the literature. Herein, we review the epidemiology and pathophysiology associated with near-drowning, discuss the potential mechanisms of infection, and describe the likely risk factors for pneumonia related to near-drowning. We also detail the microbiological causes of this entity and provide important clinical and epidemiological information associated with specific pathogens. Finally, we summarize an appropriate diagnostic and therapeutic approach to pneumonia associated with near-drowning.

Adult↗
PubMed1997

Quality framework for force plate testing.

Following work done in C.E.C. project AIM 2002 CAMARC II, a framework of the relevant standards for testing equipment used in laboratories analysing human movement is presented. In particular, gait analysis laboratories may provide a service for a clinical team considering treatment such as surgical intervention or provision of orthoses. In this case the analysis and equipment used in the analysis must have assured quality so that the correct clinical interpretation of the results is possible. The operation of a gait analysis laboratory may be described in quality standards terminology as the operation of a 'special process'. The operation of a special process requires that particular attention be paid to procedures including confirmation of the equipment and regular testing to ensure correct operation of the equipment. In general this is difficult to achieve since equipment manufacturers still have to address this technical requirement. Although difficult, these procedures must be accomplished in the operation of a special process. Passages of the most pertinent standards are presented and a methodology of a periodic confirmation and regular spot checking of equipment suggested to ensure its correct operation. Although force plates are specifically addressed, the framework could be applied to other dynamometers and measurement equipment.

Calibration↗
PubMed1996

Static in situ calibration of force plates.

An in situ calibration protocol for ground-to-foot force measuring platforms is described. The methodology allows verification of the function of the force plate and allows accurate calibration for three force and moment channels. The effect of cross-sensitivity on recorded data is discussed along with the need for improvements in methodology to quantify this property.

Algorithms↗
PubMed1996

Patterns of virus burden and T cell phenotype are established early and are correlated with the rate of disease progression in human immunodeficiency virus type 1-infected persons.

Human immunodeficiency virus (HIV)-1 DNA and RNA levels and T lymphocyte cell surface markers were measured in blood serum and cell fractions from asymptomatic infected patients to find novel virologic and immunologic features in early disease predictive of subsequent clinical disease course. Thirty-two patients with rapid disease progression (rapid CD4+ cell loss and progression to clinical AIDS) were compared with 25 patients with stable infections (constant or rising CD4+ cell counts, no clinical disease manifestations). All HIV-1 burdens measured by polymerase chain reaction were consistently higher in specimens from rapid progressors than slow progressors. For each patient, virus burden remained relatively constant throughout the study period (mean, 42-44 months). Flow cytometry also disclosed stable lymphocyte immunophenotype patterns that correlated strongly with subsequent rapid progression to clinical disease. Thus, in early HIV-1 infection, a constellation of high virus burden and in vivo costimulatory antigen and lymphocyte activation abnormalities is predictive of rapid disease course.

Adult↗
PubMed1996

Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin.

OBJECTIVE: To characterize the mechanism of in vitro antigen-induced apoptotic T-cell death in the peripheral blood mononuclear cells (PBMC) of HIV-1-infected individuals. DESIGN AND METHODS: PBMC from HIV-1 infected and uninfected individuals were unstimulated or stimulated with HIV-1 envelope synthetic peptides (Env) or influenza A virus to determine the extent of antigen-stimulated apoptotic T-cell death, whether this death was limited to the CD4+ subset, and the effects of cytokines on T-cell death. Death was assessed by apoptotic nuclear morphology after 7 days of culture by fluorescence microscopy using a DNA-specific dye. Transwell cultures and supernatant transfers were utilized to test whether a soluble factor produced by HIV-positive PBMC induced death of HIV-negative T cells. Exogenous cytokines [interleukin (IL)-12, interferon (IFN)-gamma, IL-4 and IL-10], as well as antibodies against endogenously produced cytokines (IL-4, IL-10, IL-12, and lymphotoxin) were tested for their ability to modulate death. RESULTS: Antigenic stimulation induced death in PBMC from HIV-positive donors, but not in PBMC from HIV-negative donors. Antigen-stimulated death was seen in CD4+ but not CD8+ T-cell subset from the HIV-positive patients. Apoptotic death was blocked by IL-12, IFN-gamma, anti-IL-4, anti-IL-10, and anti-lymphotoxin, but not by anti-IL-12. Transwell and supernatant transfer experiment indicated that antigen-stimulated HIV-positive PBMC produced a factor that killed T-cell blasts. The factor was inhibited by anti-lymphotoxin, but not by anti-IL-10. CONCLUSIONS: Stimulation of HIV-positive PBMC with CD4-dependent antigens results in selective death of CD4+ T cells that is modulated by cytokines. Our results suggest that apoptotic death is not limited to HIV-infected or HIV-specific T cells, but occurs in bystander cells. Lymphotoxin is a mediator of antigen-stimulated T-cell death in this in vitro model.

Antibodies↗
PubMed1995

Neuroretinitis, aseptic meningitis, and lymphadenitis associated with Bartonella (Rochalimaea) henselae infection in immunocompetent patients and patients infected with human immunodeficiency virus type 1.

Bartonella (Rochalimaea) henselae causes a variety of diseases, including bacillary angiomatosis, peliosis hepatis, lymphadenitis, aseptic meningitis with bacteremia, and cat-scratch disease (CSD). Cases of B. henselae-related disease were collected from September 1991 through November 1993. Patients with suspected CSD, unexplained fever and lymphadenitis, or suspected B. henselae infection who were seen in the Infectious Diseases Clinic at Wilford Hall Medical Center (Lackland Air Force Base, TX) underwent physical and laboratory examinations. In addition to three previously described cases, 23 patients with R. henselae-related infection were identified. The patients included 19 immunocompetent individuals presenting with lymphadenitis (11), stellate neuroretinitis (5), Parinaud's oculoglandular syndrome with retinitis (1), chronic fatigue syndrome-like disease (1), and microbiologically proven adenitis without the presence of immunofluorescent antibodies to B. henselae (1) and four patients infected with human immunodeficiency virus type 1 presenting with isolated lymphadenitis (1), diffuse upper-extremity adenitis (1), neuroretinitis (1), and aseptic meningitis (1). A couple with neuroretinitis and their pet cat, a persistently fatigued patient, and a patient with Parinaud's oculoglandular syndrome were shown to have bacteremia. Tissue cultures were positive for B. henselae in three recent cases of adenitis. Twenty-two patients were exposed to cats. This series further demonstrates the similarities between B. henselae-related diseases and CSD and identifies several new syndromes due to B. henselae.

Adolescent↗
PubMed1995

In vitro T cell function, delayed-type hypersensitivity skin testing, and CD4+ T cell subset phenotyping independently predict survival time in patients infected with human immunodeficiency virus.

Human immunodeficiency virus type 1 (HIV-1)-infected patients (n = 335) in the US Air Force HIV Natural History Program were followed for 3 years (mean) after skin testing, immunophenotyping of CD4+ cell subsets, and measurement of in vitro interleukin-2 production after stimulation by phytohemagglutinin, alloantigens, tetanus toxoid, and influenza A virus. The T cell functional assay predicted survival time (P < .001) and time for progression to AIDS (P = .014). Skin testing for tetanus, mumps, and Candida antigen and the total number of positive tests (P < .001 for each) stratified patients for survival time. In a multivariable proportional hazards model, the T cell functional assay (P = .008), the absolute number of CD4+ T cells (P = .001), the percentage of CD4+ CD29+ cells (P = .06), and the number of reactive skin tests (P < .001) predicted survival time. Thus, cellular immune functional tests have significant predictive value for survival time in HIV-1-infected patients independent of CD4+ cell count.

Acquired Immunodeficiency Syndrome↗
PubMed1995

A chemically defined liquid medium that supports primary isolation of Rochalimaea (Bartonella) henselae from blood and tissue specimens.

Rochalimaea (Bartonella) henselae is a fastidious, slowly growing, gram-negative bacillus that is an etiologic agent of bacillary angiomatosis, cat scratch disease, and related syndromes. Accumulation of direct microbiologic evidence of the relationship between the organism and the syndromes compatible with cat scratch disease has been hindered by the difficulties in the primary isolation of the organism from infected tissue specimens. A chemically defined liquid medium was developed to support the growth of Rochalimaea species to facilitate study of the organism. This medium was also used successfully to isolate R. henselae from clinical specimens from infected patients and a domestic cat. Recovery of R. henselae in this was more successful than when recovery was attempted on solid agar. This cell-free, extract-free, defined medium additionally supported the growth of Rochalimaea quintana and Afipia felis.

Angiomatosis, Bacillary↗