Didanosine-induced retinopathy in adults can be reversible.
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Anti-HIV Agents↗
Biomedical subjects
S M Mitchell
Publications and source records attributed to S M Mitchell.
Cytomegalovirus Retinitis in infancy.
PURPOSE: To describe the presentation of cytomegalovirus retinitis (CMVR) in a series of infants. METHODS: Immunocompromised infants with either HIV or systemic cytomegalovirus (CMV) were examined for CMVR. Ocular involvement was recorded and monitored by digital imaging. RESULTS: Five infants were detected to have CMVR. All the infants demonstrated changes within the macula. One infant progressed from a fine granular pattern to fulminant CMVR. CONCLUSION: Infants under a year with CMVR have a predilection for the disease to present at the macula, in contrast to the presentation in adults, which tends to involve more peripheral parts of the retina.
AIDS-Related Opportunistic Infections↗
Reactivity against Sarcocystis neurona and Neospora by serum antibodies in healthy French horses from two farms with previous equine protozoal myeloencephalitis-like cases.
Sarcocystis neurona is considered a leading cause of equine protozoal myeloencephalitis (EPM), a common infectious neurological disease in horses in the Americas. EPM-like cases associated with S. neurona peptide reactive antibodies in Western blots were recently described in Normandy, France. In this report, antibodies reacting with S. neurona merozoites were detected using an agglutination assay at titers ranging from 50 to 500 in sera from 18/50 healthy horses from two farms with a previous EPM-like case. Higher values were found in older animals. Four out of six horses which traveled or stayed in the US exhibited titers over 50, a higher figure than in the group which did not travel out of France or stayed in an other European country. No correlation was found between anti-S. neurona and anti-Neospora sp. antibody titers. Data prompt further study of significance of anti-S. neurona antibodies in clinically healthy or diseased European horses, and identification of putative immunizing parasite(s) and their host(s).
Animals↗
Prevalence of antibodies to Neospora caninum, Sarcocystis neurona, and Toxoplasma gondii in wild horses from central Wyoming.
Sarcocystis neurona, Neospora caninum, N. hughesi, and Toxoplasma gondii are 4 related coccidians considered to be associated with encephalomyelitis in horses. The source of infection for N. hughesi is unknown, whereas opossums, dogs, and cats are the definitive hosts for S. neurona, N. caninum, and T. gondii, respectively. Seroprevalence of these coccidians in 276 wild horses from central Wyoming outside the known range of the opossum (Didelphis virginiana) was determined. Antibodies to T. gondii were found only in 1 of 276 horses tested with the modified agglutination test using 1:25, 1:50, and 1:500 dilutions. Antibodies to N. caninum were found in 86 (31.1%) of the 276 horses tested with the Neospora agglutination test--the titers were 1:25 in 38 horses, 1:50 in 15, 1:100 in 9, 1:200 in 8, 1:400 in 4, 1:800 in 2, 1:1,600 in 2, 1:3,200 in 2, and 1:12,800 in 1. Antibodies to S. neurona were assessed with the serum immunoblot; of 276 horses tested, 18 had antibodies considered specific for S. neurona. Antibodies to S. neurona also were assessed with the S. neurona direct agglutination test (SAT). Thirty-nine of 265 horses tested had SAT antibodies--in titers of 1:50 in 26 horses and 1:100 in 13. The presence of S. neurona antibodies in horses in central Wyoming suggests that either there is cross-reactivity between S. neurona and some other infection or a definitive host other than opossum is the source of infection. In a retrospective study, S. neurona antibodies were not found by immunoblot in the sera of 243 horses from western Canada outside the range of D. virginiana.
Agglutination Tests↗
Successful treatment of varicella zoster virus retinitis with aggressive intravitreal and systemic antiviral therapy.
AIMS: To describe the successful treatment of varicella zoster virus retinitis (VZVR) using intravenous cidofovir as part of an aggressive management strategy. CASE REPORTS: Two patients with bilateral VZVR were treated with a combination of intravenous cidofovir and ganciclovir with adjuvant intravitreal foscarnet or ganciclovir. Both patients maintained good vision in the less severely affected eye. Retinal detachment did not occur in either patient. CONCLUSIONS: VZVR should be treated aggressively with a combination of intravenous and intravitreal therapy to improve visual prognosis. Intravenous cidofovir, in the absence of contra-indications, should be considered as part of this aggressive therapeutic approach, especially in patients with AIDS in whom the prognosis is particularly poor.
Acquired Immunodeficiency Syndrome↗
A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young.
Maturity-onset diabetes of the young (MODY) is a monogenic, autosomal dominant subtype of early-onset diabetes mellitus due to defective insulin secretion by the pancreatic beta-cell in humans. Five different genes have been identified including those encoding the tissue-specific transcription factors expressed in pancreatic beta-cells, i.e. HNF-4alpha (MODY1), HNF-1alpha (MODY3), IPF-1 (also known as PDX-1, MODY4) and HNF-1beta (MODY5). Analyzing the transcription of the HNF-4alpha gene, we now identify an alternative promoter, P2, which is 46 kb 5' to the previously identified P1 promoter of the human gene. Based on RT-PCR this distant upstream P2 promoter represents the major transcription site in pancreatic beta-cells, but is also used in hepatic cells. Transfection assays with various deletions and mutants of the P2 promoter reveal functional binding sites for HNF-1alpha, HNF-1beta and IPF-1, the other transcription factors known to encode MODY genes. We demonstrate the significance of this alternative promoter in a large MODY family where a mutated IPF-1 binding site in the P2 promoter of the HNF-4alpha gene co-segregates with diabetes (LOD score 3.25). These data suggest a regulatory network of the four MODY transcription factors interconnected at the distant upstream P2 promoter of the HNF-4alpha gene.
Adult↗
Specific affinity depletion of cell adhesion molecules and growth factors from serum.
Serum is a common component of most in vitro cell culture media, particularly of primary cells. Studies of cellular responses to particular adhesion molecules or growth factors are often confounded by the presence of these molecules in the serum supplement. We describe a combined affinity protocol for removing vitronectin and fibronectin from serum. This protocol can also be used to purify these molecules. We also describe the removal of growth-promoting elements using heparin-Sepharose. As vitronectin and fibronectin each bind to heparin, these molecules are removed first and the heparin-Sepharose depletion occurs last in the sequence. This protocol provides a detailed step-by-step guide to achieve quantitative depletion of serum in an optimised format, with additional information on pitfalls and problems. It should be of use to people who wish to accurately determine the relationship between cells, extracellular matrix molecules and growth factors.
Animals↗
Failure of accommodation in patients with HIV infection.
PURPOSE: The principal objective was to test the hypothesis that HIV-positive patients have significantly reduced amplitudes of accommodation compared with controls. The secondary objective was to investigate accommodative impairment in relation to factors such as age of susceptibility, CD4 count, viral load and current antiretroviral therapies. METHOD: The study was a single-center open prospective study involving a subject population of 43 HIV-positive men aged from 26 to 39 years with no previous history of eye problems and 21 age-matched healthy male controls. The main outcome measure was the amplitude of accommodation, as measured monocularly with a standard push-up technique. RESULTS: Amplitudes of accommodation were significantly smaller in the HIV-positive group compared with controls for age groups 25-29 (p = 0.016) and 30-34 years (p = 0.030) but not in the older group. In total, 30% (8/27) of patients aged between 25 and 34 years had reduced amplitudes of accommodation below age-expected norms. Accommodative failure was not related to current or lowest CD4 count, viral load or specific antiretroviral therapies. CONCLUSION: This study has identified accommodative failure in a significant proportion of HIV-positive patients aged between 26 and 35 years. This problem may be under-recognised, and further studies are warranted to investigate possible causes.
Accommodation, Ocular↗
Chronic cocaine-mediated changes in non-human primate nucleus accumbens gene expression.
Chronic cocaine use elicits changes in the pattern of gene expression within reinforcement-related, dopaminergic regions. cDNA hybridization arrays were used to illuminate cocaine-regulated genes in the nucleus accumbens (NAcc) of non-human primates (Macaca fascicularis; cynomolgus macaque), treated daily with escalating doses of cocaine over one year. Changes seen in mRNA levels by hybridization array analysis were confirmed at the level of protein (via specific immunoblots). Significantly up-regulated genes included: protein kinase A alpha catalytic subunit (PKA(calpha)); cell adhesion tyrosine kinase beta (PYK2); mitogen activated protein kinase kinase 1 (MEK1); and beta-catenin. While some of these changes exist in previously described cocaine-responsive models, others are novel to any model of cocaine use. All of these adaptive responses coexist within a signaling scheme that could account for known inductions of genes(e.g. fos and jun proteins, and cyclic AMP response element binding protein) previously shown to be relevant to cocaine's behavioral actions. The complete data set from this experiment has been posted to the newly created Drug and Alcohol Abuse Array Data Consortium (http://www.arraydata.org) for mining by the general research community.
Animals↗
CMVR diagnoses and progression of CD4 cell counts and HIV viral load measurements in HIV patients on HAART.
AIM: To assess the impact of highly active antiretroviral therapy (HAART) on the prevalence and progression of CMV retinitis (CMVR) among AIDS patients with baseline CD4 cell counts <100 cells x 10(6)/l. METHODS: A longitudinal cohort study of 1292 patients. CD4 cell counts and HIV viral load measurements were obtained before commencing therapy, at 3 months, 1 year, 2 years, and at last follow up. The CMVR prevalence rate was measured for the subgroup with baseline CD4 cell counts <100 cells x 10(6)/l. CMVR adverse event (AE) rates per 100 person days at risk were calculated for the subgroup with CMVR and baseline CD4 cell counts <100 cells x 10(6)/l. RESULTS: 1292 patients were started on HAART. 8% of patients had CD4 counts <50 cells x 10(6)/l and 40% had detectable HIV viral load at last follow up. The prevalence of CMVR for the subgroup with baseline CD4 <100 cells x 10(6)/l was 10%. For those with baseline CD4 <100 cells x 10(6)/l, the mean CMVR AE rate was greatest during the first 6 months of follow up after HAART commencement (p <0.003). The mean AE rate per 100 person days at risk was 0.36 (95% CI 0.167 to 0.551) before starting HAART, and 0.14 (95% CI 0.085 to 0.199) after starting HAART (p = 0.03). CONCLUSIONS: HAART significantly prolongs the disease-free intervals in patients with pre-existing disease but recurrences persist within the first 6 months of starting therapy. AE were absent beyond 18 months of follow up in all patients including those with persistently low CD4 counts and detectable HIV viral load indicating clinical immunorestoration. New methods for monitoring the response to therapy are needed to identify those at risk.
Adult↗
Electrophysiological abnormalities following intravitreal vitravene (ISIS 2922) in two patients with CMV retinitis.
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AIDS-Related Opportunistic Infections↗
Prevalence of multiple dideoxynucleoside analogue resistance (MddNR) in a multicenter cohort of HIV-1-infected Italian patients with virologic failure.
We evaluated the prevalence of both Q151M and 6-bp insert at position 69 of RT region responsible for multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 variants in 177 patients who failed to respond to combination therapy. Patients had received protease inhibitors (PI) and/or nonnucleoside reverse transcriptase inhibitors (NNRTIs) after a long-term experience with nucleoside reverse transcriptase inhibitors (NRTIs) (including zidovudine monotherapy). Two of 177 patients (1.1%) showed the specific complex of Q151M mutation, while 4 (2.3%) had the 69 6-bp insert. Mutations that belong to the 151 set in the absence of the pivotal Q151M substitution were detected in as many as 3.9% of the patients. One patient exhibited a 69S [VG] insert that has not been previously phenotypically characterized. This HIV-1 isolate had high levels of resistance to all NRTIs except stavudine. MddNR is an emerging problem after sequential therapy with this class of compounds among HIV-1-infected patients. Either didanosine (ddI) or zidovudine (ZDV) monotherapy allowed the emergence of MddNR variants containing Q151M complex. Monotherapy with ZDV and ddI or subsequent treatments with various NRTI combinations were the common background in the patients with the 69 insert. The overall prevalence of MddNR (3.4%) in Italy is comparable with that observed in several other European countries (3.4%-6.5%). These data suggest that patients failed by NRTI regimens should be analyzed for the presence of both patterns of MddNR.
Acquired Immunodeficiency Syndrome↗
Low density lipoproteins in human plasma make vascular smooth muscle cells resistant to growth inhibition by heparin.
OBJECTIVE: Vascular smooth muscle cell hyperplasia plays a role in atherosclerosis and restenosis. While heparin has shown promise as an inhibitor of smooth muscle cell proliferation in vitro and in some animal models, it has failed to reduce restenosis in clinical trials. We have previously shown that human smooth muscle cells grown in the presence of human serum are heparin resistant, whereas in the presence of bovine serum they are heparin sensitive. In this report, we demonstrate that the heparin resistance factor is present in human plasma as well as serum, and characterise it further. METHODS: Human vascular smooth muscle cells were cultured as explants from the media of redundant adult internal mammary or umbilical cord arteries. They were tested for sensitivity to heparin at 100 microg/ml in the growth medium, in the presence of foetal bovine serum, human-plasma-derived serum, human whole blood serum, or fractions derived from these. RESULTS: In the presence of foetal bovine serum, heparin inhibited cell proliferation, while human-plasma-derived or whole blood sera conveyed heparin resistance. This activity was contained within the fraction of plasma/serum which bound to heparin Sepharose, and the sub-fraction which was retained by a membrane filter of molecular weight cut off of 100000. All the heparin resistance in this latter fraction was supplied by lipoproteins. LDL prepared directly from human plasma conveyed similar heparin resistance to the lipoproteins from the above sub-fraction. CONCLUSION: LDL in human plasma/serum conveys resistance to the anti-proliferative effects of heparin upon vascular smooth muscle cells. This activity may interfere with potential therapeutic effects of heparin as an anti-restenosis agent.
Adult↗
Visual outcome after silicone oil removal and recurrent retinal detachment repair.
PURPOSE: Prospective analysis of the effect of removal of silicone oil (ROSO) in eyes with complicated retinal detachments and evaluation of the visual outcome following recurrent retinal detachment after silicone oil removal. METHODS: We evaluated 62 consecutive cases of ROSO over a 12 month period. All eyes had previously undergone silicone oil placement for complicated retinal detachments. All eyes undergoing scheduled ROSO over the time period of the study were entered and were reviewed post-operatively. RESULTS: Sixty-two eyes were entered into the study. Twenty-one of 62 (34%) developed recurrent retinal detachment following ROSO; 18 of these 21 recurrent detachments were reattached with one additional procedure and only 5 required replacement of the silicone oil. Ten of these 21 eyes (48%) had improvement or stabilisation in final visual acuity compared with the presenting visual acuity. Overall, 39 eyes (63%) had improvement in vision following ROSO and 76% of all eyes had ambulatory visual acuity at the end of the follow-up period. Fourteen eyes required cataract extraction with ROSO to attain this final visual acuity. CONCLUSIONS: Overall, ROSO has a significant rate of recurrent retinal detachment, with a high reattachment rate with one additional procedure. Few of these eyes need the silicone oil replaced. Most eyes will retain ambulatory visual acuity even with multiple procedures in cases of complicated retinal detachments following ROSO even with recurrent retinal detachment.
Adolescent↗
The governance and management of effective community health partnerships: a typology for research, policy, and practice.
Community health partnerships (CHPs) are voluntary collaborations of diverse community organizations that have joined forces in order to pursue a shared interest in improving community health. Although these cross-sectoral collaborations represent a way to address social determinants of health and disease in society, they suffer from governance and management problems associated with interorganizational relationships in general and health care challenges specifically. A typology of effective governance and management characteristics provides a systematic, theoretically based way of addressing dimensions of governance and management and serves as a guide in constructing, maintaining, and measuring successful partnerships. It offers a multidisciplinary perspective for classifying important organizational issues, identifying barriers to successful development and sustainability, and facilitating the attainment of goals.
Community Health Planning↗
Hazards of aspirin withdrawal before transurethral prostatectomy.
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Aged↗
Treatment of immune recovery vitritis with local steroids.
AIMS: To report a series of patients requiring treatment for falling visual acuity associated with immune recovery vitritis, a recently described syndrome of a predominantly vitreous inflammatory reaction in patients with AIDS and cytomegalovirus (CMV) retinitis. METHODS: The medical records of all patients requiring treatment for falling visual acuity associated with immune recovery vitritis were reviewed between March 1996 and March 1998. RESULTS: Nine eyes in seven patients required treatment for falling visual acuity. All patients had inactive CMV retinitis and had received highly active antiretroviral treatment including a protease inhibitor. Vitreous inflammation developed at a mean of 5.5 months (range 1-14) after starting a protease inhibitor. The onset of inflammation correlated with a mean rise in CD4(+) lymphocyte levels of 83 x 10(6)/l (range 30-128). The visual acuity fell by a mean of 2.8 Snellen lines (range 1-4) before treatment, and rose by a mean of 1.9 Snellen lines (range 0-4) after treatment with orbital floor steroids. The mean time interval between treatment with orbital floor steroids and improvement in visual acuity was 3.5 weeks (range 1-8). Following treatment the visual acuity improved or remained stable in all nine eyes, eight eyes returning to within one line of their preinflammation Snellen visual acuity. No eyes developed reactivation or progression of CMV retinitis after treatment, and none developed any other pathology. CONCLUSIONS: Orbital floor steroids appear to be have a useful role in the treatment of persistent immune recovery vitritis where the visual acuity is compromised.
AIDS-Related Opportunistic Infections↗
Cytomegalovirus retinitis after the initiation of highly active antiretroviral therapy: a 2 year prospective study.
BACKGROUND/AIMS: There have been several recent reports suggesting that the natural history of cytomegalovirus retinitis (CMVR) has been significantly modified with the development of highly active antiretroviral therapy (HAART). This 2 year prospective cohort study assesses the effect of HAART on the incidence and progression of CMV retinitis in patients with CD4 cell counts below 50 cells x10(6)/l. METHODS: 63 patients, with CD4 cell counts below 50 cells x10(6)/l, who were recruited to a 2 year prospective cohort study at the commencement of combination antiretroviral therapy including the use of the proteinase inhibitor, indinavir, were reported. The response to HAART was assessed in terms of a rise in the CD4 cell count and fall in HIV viral load. An experienced ophthalmologist performed dilated funduscopy at the time of recruitment and thereafter at 2 weekly intervals and retinal photography was performed at monthly intervals in patients with CMVR. The activity and progression of CMV retinitis was assessed on the basis of the characteristic clinical and photographic findings. RESULTS: 34 patients achieved at least 50 CD4 cells x10(6)/l at 3 months after initiation of therapy. New diagnoses of CMVR were seen only in the non-responder group (p=0. 085). Overall, the relative risk of a new retinitis event in this group was 3.52 (95% CI 1.16, 10.68) at 3 months compared with those patients who were responsive to HAART. 12 of the 63 patients had previous CMVR. Disease progression was associated with non-response to therapy (p=0.182 exact). In patients with CMVR the median time to first progression was 18 days (95% CI 8, 91) in non-responders and 121 days (95% CI 0.59, 3.65) in responders. By the end of the 2 year follow up period all surviving patients had >50 CD4 cells x10(6)/l. No CMV events were seen after 8 months of therapy in either group of patients. CONCLUSIONS: These findings suggest that significant clinical immunorestoration to CMV occurs in response to HAART in patients with CMVR after a lag time of 3-8 months. Initially, a rise in CD4 count is predictive of CMVR response but after the lag period all survivors appear to have developed a clinical immunorestoration to CMV. If HAART is commenced in at risk patients before the development of CMVR the incidence of new disease falls significantly.
AIDS-Related Opportunistic Infections↗