Biomedical subjects

J C Macdonald

Publications and source records attributed to J C Macdonald.

16 recordsLinked to original sources

PubMed2001

Genetic mapping of a novel X-linked recessive colobomatous microphthalmia.

Colobomatous microphthalmia is a common ocular malformation with a heterogeneous phenotype. The majority of cases without associated systemic abnormalities have an autosomal dominant inheritance pattern [McKusick, 1990: Mendelian inheritance in man]. A few isolated cases with autosomal recessive transmission have been described [Zlotogora et al., 1994: Am J Med Genet 49:261--262]. To our knowledge, no cases of X-linked colobomatous microphthalmia that are not a part of a syndrome or a multisystem disorder have been reported. In this study, we describe a genetic and clinical evaluation of a large pedigree in which colobomatous microphthalmia is segregating in an X-linked recessive fashion. Based on recombination breakpoint analysis, we have determined that the critical interval exists between markers DXS989 and DXS441, placing the disease locus on the proximal short arm or the proximal long arm of the X chromosome. Using linkage analysis, we obtained two-point lod scores of 2.71 at zero recombination with markers DXS1058, DXS6810, DXS1199, and DXS7132. Overlapping multipoint analysis established a broad maximum from marker DXS1068 to marker DXS7132, a region spanning approximately 28 cM. This study provides evidence for the presence of a new locus for colobomatous microphthalmia.

Adolescent↗

PubMed2000

CMV retinitis recurs after stopping treatment in virological and immunological failures of potent antiretroviral therapy.

OBJECTIVES: To determine predictors of clinical relapse of cytomegalovirus (CMV) end-organ disease in a cohort of 17 HIV-infected patients with healed and treated CMV retinitis (CMVR) who responded to HAART with an increase in CD4 cell counts to above 70 cells/mm3 and discontinued CMV maintenance therapy (MT). DESIGN: Seventeen patients were monitored for reactivation of retinitis. The CD4 cell counts, HIV RNA and peripheral blood mononuclear cell (PBMC) lymphoproliferative assays to CMV at 3 month intervals were compared between patients with and without reactivation of CMVR. Positive lymphoproliferative responses were defined as a stimulation index of 3 or greater. RESULTS: Five out of 17 (29%) patients experienced a recurrence of CMVR a mean of 14.5 months after stopping CMV MT and between 8 days and 10 months after CD4 cell counts fell below 50 cells/mm3. Median CD4 cell counts and plasma HIV RNA at reactivation were 37 cells/mm3 and 5.3 log10 copies/ml. Three patients recurred at a previously active site of the retina, one had contralateral CMVR, and one a recurrence of retinitis and pancreatitis simultaneously. Mean lymphoproliferative responses to CMV were 2.4 in patients with reactivation versus 21.0 stimulation index (SI) in patients without reactivation (P= 0.01). A model incorporating four variables (CD4 cell counts and HIV RNA at maintenance discontinuation, highest CD4 cell count, nadir HIV RNA and median lymphoproliferative responses) identified correctly 88% of patients with and without reactivation. CONCLUSION: CMV disease recurs after virological and immunological failure of HAART if CD4 cell counts drop below 50. In this situation, anti-CMV agents should be resumed before clinical reactivation ensues, because of the risk of contralateral retinal involvement and systemic disease.

AIDS-Related Opportunistic Infections↗

PubMed2000

Long-term posterior and anterior segment complications of immune recovery uveitis associated with cytomegalovirus retinitis.

PURPOSE: To identify and describe long-term posterior and anterior segment complications of immune recovery uveitis in patients with inactive cytomegalovirus retinitis who are undergoing highly active antiretroviral therapy-mediated recovery of immune function. METHODS: A prospective cohort study at a university medical center. Twenty-nine eyes of 21 patients with immune recovery uveitis and inactive cytomegalovirus retinitis were followed for 14.5 to 116 weeks (median, 43 weeks) after diagnosis of immune recovery uveitis. RESULTS: Nine eyes of nine patients developed visually important complications involving the posterior segment, anterior segment, or a combination of both. Posterior segment complications included severe proliferative vitreoretinopathy in three eyes and spontaneous vitreous hemorrhage from avulsion of a blood vessel secondary to contraction of the inflamed vitreous in one eye. Proliferative vitreoretinopathy recurred in all cases after surgery, severely compromising the visual outcome. Anterior segment complications included posterior subcapsular cataracts with vision decrease in five eyes and persistent anterior chamber inflammation after cataract extraction, resulting in posterior synechiae and large visually important lens deposits in three eyes. CONCLUSION: Persistent inflammation in immune recovery uveitis may lead to vision-threatening complications, such as proliferative vitreoretinopathy, posterior subcapsular cataracts, and severe postoperative inflammation. Immune recovery uveitis is a chronic inflammatory syndrome that may result in complications months to years after the onset of inflammation.

Adult↗

PubMed2000

Highly active antiretroviral therapy-related immune recovery in AIDS patients with cytomegalovirus retinitis.

OBJECTIVE: To characterize cytomegalovirus (CMV) retinitis in human immunodeficiency virus (HIV)-infected patients who demonstrate immune recovery while receiving highly active antiretroviral therapy (HAART). DESIGN: Consecutive, noncomparative case series. PARTICIPANTS: Twenty-two HIV-positive patients, from two institutions, with a history of CMV retinitis, and with elevated CD4 cell counts after HAART. MAIN OUTCOME MEASURES: Duration of healed CMV retinitis without anti-CMV therapy, CD4 cell count, and HIV viral load. INTERVENTION: Discontinuation of anti-CMV therapy after persistent elevation of CD4 cell count over 50 cell/mm3 (median, 161/mm3; range, 85-408/mm3). RESULTS: The median period of healed CMV retinitis without anti-CMV therapy was 72 weeks (range, 33-116 weeks). Nineteen of 22 patients were still healed without anti-CMV therapy at study end. The three patients with CMV retinitis progression simultaneously had HAART, fail with CD4 cell counts of 37, 35, and 47/mm3. CONCLUSIONS: HIV-positive patients with CMV retinitis, who demonstrate a sustained HAART-induced elevation of CD4 cell count on two consecutive counts 3 months apart and whose retinitis remains healed on anti-CMV therapy for greater than 4 months, are likely to remain healed if the anti-CMV therapy is withdrawn. It is important to monitor these patients with indirect ophthalmoscopy because HAART failure may occur and allow CMV retinitis reactivation.

AIDS-Related Opportunistic Infections↗

PubMed1999

Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy.

This study was conducted to determine the likelihood of the development of a new ocular inflammatory syndrome (immune recovery vitritis, IRV), which causes vision loss in AIDS patients with cytomegalovirus (CMV) retinitis, who respond to highly active antiretroviral therapy (HAART). We followed 30 HAART-responders with CD4 cell counts of >/=60 cells/mm3. Patients were diagnosed with IRV if they developed symptomatic vitritis of >/=1+ severity associated with inactive CMV retinitis. Symptomatic IRV developed in 19 (63%) of 30 patients and in 26 (59%) of 44 eyes over a median follow-up from HAART response of 13.5 months. The annual incidence of IRV was 83/100 person-years. Excluding patients with previous cidofovir therapy did not significantly alter the time course of IRV (P=.79). These data suggest that IRV develops in a significant number of HAART-responders with CMV retinitis and is unrelated to previous cidofovir therapy.

AIDS-Related Opportunistic Infections↗

PubMed1999

Cytomegalovirus (CMV) retinitis activity is accurately reflected by the presence and level of CMV DNA in aqueous humor and vitreous.

To evaluate the potential of ocular and systemic specimens to provide markers of active cytomegalovirus (CMV) retinitis, we examined the relationship between virologic and clinical aspects of CMV infections in AIDS patients with CMV retinitis. CMV polymerase chain reaction (PCR) analysis of 74 aqueous humor and vitreous specimens indicated that ocular specimens can provide accurate markers to differentiate active and inactive CMV retinitis (aqueous or vitreous PCR, P<.001). Moreover, these markers were superior to extraocular measures, including plasma PCR (P=.08) and blood and urine CMV cultures (P=.05). A direct correlation was identified between the quantity of CMV DNA in aqueous humor or vitreous specimens and the corresponding surface area of active CMV retinitis (r2=.69 and.44, respectively). Thus, qualitative and quantitative PCR-based analyses of aqueous humor can provide valuable markers of CMV retinitis activity. Such assays could provide rapid and reliable tools to assist in management of patients with CMV retinitis in whom the view of the retina is obscured.

AIDS-Related Opportunistic Infections↗

PubMed1998

Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy.

The suppression of human immunodeficiency virus (HIV) replication and elevation in CD4 cells observed with protease inhibitor combination regimens known as HAART (highly active antiretroviral therapy) may allow AIDS patients to undergo an immune recovery that allows them to suppress the progression of cytomegalovirus (CMV) retinitis. Eleven AIDS patients receiving HAART with healed CMV retinitis in whom CMV-specific maintenance therapy was discontinued were studied. Median CD4 cell counts were 42 before the initiation of HAART and 183 at discontinuation of anti-CMV therapy. While a median 1.1 log10 drop in plasma HIV-1 RNA was obtained between starting HAART and withdrawal of maintenance therapy for CMV, only 3 of 11 patients maintained plasma HIV RNA below the limits of detection. Reactivation of CMV retinitis after withdrawal of anti-CMV therapy did not occur in any of the patients observed for a median of 156 days (range, 92-558).

AIDS-Related Opportunistic Infections↗

PubMed1998

Cytomegalovirus iritis.

We describe a case of focal cytomegalovirus iritis in a patient with acquired immunodeficiency syndrome (AIDS) who had CMV retinitis. The autopsy showed histologic evidence of focal iritis in the left eye. This iritis was characterized by infiltration of acute inflammatory cells mixed with cytomegalic cells, which was confirmed by CMV-specific immunohistochemical staining. The case suggested that cytomegalovirus could be a direct causative agent of infectious iritis in AIDS patients.

AIDS-Related Opportunistic Infections↗

PubMed1990

L-alpha-glycerophosphate binding to bovine gamma-crystallin: a potential link between metabolism and supramolecular order.

The highly selective nature of protein-ligand interactions provides a sensitive mechanism for the modulation of cellular activity by proteins. In the eye lens the supramolecular order of the lens crystallins, which is expected to be susceptible to protein electrostatic charge, in part defines transparency. The binding of charged ligands to proteins is one way of achieving an alteration in protein electrostatic charge. Evidence is presented that L-alpha-glycerophosphate, a major phosphorus metabolite of eye lens metabolism, binds to the globular protein, gamma-crystallin with moderately high affinity and in a positive cooperative manner. The following binding parameters were obtained from equilibrium measurements: minimum number of binding sites, n = 2; Kassoc = 6.2 +/- 0.5 x 10(3) M-1; cooperativity parameter, alpha H = 1.9 +/- 0.1. Interactive computer graphics display techniques were used to locate putative ligand binding sites, and in turn, to identify the possible molecular interactions responsible for the binding of ligand to protein at one of the sites. One putative binding site was located in the cleft between the two domains of gamma II-crystallin. Arginyl residues 79 and 147 are involved in ligand binding as are the peptide carbonyl oxygens of residues Tyrosyl-50 and Aspartyl-156. Five hydrogen bonds between the ligand and the protein structure are predicted for the binding of L-alpha-glycerophosphate, whereas only 3 occur for the binding of the "unnatural" D-enantiomorph. Modulation of both lens protein supramolecular organization and lens metabolism is predicted to be a consequence of L-alpha-glycerophosphate binding to gamma-crystallin in the lens.

Animals↗

PubMed1989

Impact of cellular and molecular organization on lens metabolism.

The relationship between the metabolic gradient within the ocular lens and its cellular and molecular organization is discussed. The lens shares a number of organizational similarities with other stratified ectodermal tissues. All of these tissues were avascular and therefore, dependent upon the simple diffusion of nutrients from the surrounding medium. They contain non-metabolizing cell layers which are continually produced by an irreversible maturation process. This process is not random aging but a well orchestrated sequence of events dependent upon the physico-chemical properties of specialized proteins typical of each tissue. In the lens, these proteins are the crystallins. The signal for this maturation is decreased metabolism in conjunction with cell dehydration. Metabolism of these maturing cells is decreased by limited nutrient penetration because of barriers to nutrient diffusion and the high rate of utilization of nutrients by the more metabolically active cells near the basement membrane. Additionally, the regulation of anaerobic metabolism is dependent upon the maintenance and dissolution of an organized array of enzymes and the effects of dehydration, i.e. excluded volume effects and modified macromolecular organization. In the lens, the absence of metabolism during the maturation of the inner fiber cell layers is as important as the presence of active metabolism where differentiation and active protein synthesis occur. Therefore, any stress that disrupts tissue organization will have a detrimental effect on lens integrity.

Aging↗

PubMed1975

Biosynthesis of gliotoxin and mycelianamide.

Mycelium of Penicillium terlikowski was permeable to both L-[carboxyl-14C]phenylalanine and cyclo L-[carbonyl-14C]phenylalanyl-L-seryl. The former compound was incorporated well and the latter poorly into gliotoxin produced by stationary cultures of the organism. Mycelium of Penicillium patulum was permeablt to L-[CARBONYL-14C]tyrosyl and cyclo L-alanyl-d-[carbonyl-14C]tyrosyl. These cyclic depeptides were not incorporated into mycelianamide produced by stationary cultures of the organism, but both1carboxyl-14C]tyrosine were incorporated. The latter was incorporated in a specific manner into part of the mycelianamide molecule. The results did not support the postulate that the appropriate cyclic dipeptides, as outlined above, were free intermediates in the biosynthesis of gliotoxin or mycelianamide.

Alanine↗

PubMed1972