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Biomedical subjects

M R Dana

Publications and source records attributed to M R Dana.

At least 19 recordsLinked to original sources
PubMed2003

[Angiogenesis and lymphangiogenesis in the cornea. Pathogenesis, clinical implications and treatment options].

BACKGROUND: Whereas the normal cornea is devoid of blood and lymphatic vessels,both can invade the cornea secondary to a variety of corneal diseases and after surgery. This not only reduces visual acuity, but also renders such a cornea high-risk, if subsequent corneal transplantation is performed. METHODS: A PUBMED-based literature search was carried out. RESULTS: Current knowledge on pathogenesis, clinical implications and treatment modalities for corneal neovascularization is discussed. CONCLUSIONS: Novel anti-angiogenic and antilymphangiogenic therapeutic strategies should reduce blindness associated with corneal neovascularization and subsequent graft rejection.

Angiogenesis Inhibitors↗
PubMed2003

Nutrient intake in women with primary and secondary Sjögren's syndrome.

OBJECTIVE: Recently, it has been proposed that dietary factors may contribute to the etiology and progression of Sjögren's syndrome, and that nutritional intervention may modify the severity of pathological abnormalities. The objective of this study was to determine whether the nutrient intake of women with primary (1 degrees SS) or secondary (2 degrees SS; ie with systemic lupus erythematosus (2 degrees SS/SLE) or rheumatoid arthritis (2 degrees SS/RA) Sjögren's syndrome is significantly different than that of age- and gender-matched controls. DESIGN: Women with Sjögren's syndrome were asked to complete the 97 General Purpose Semi-Quantitative Food Frequency Questionnaire, which consists of a list of 147 separate food items that represent the major sources of multiple nutrients. Nutritional data were evaluated in terms of absolute and energy-adjusted nutrient amounts and analyzed by ANOVA. RESULTS: Our results showed: (a) greater intake of energy, glutamate, carbohydrates, lactose, phosphorus, caffeine and unsupplemental thiamin and riboflavin in 1 degrees SS, as well as supplemental calcium in 2 degrees SS/SLE, compared with controls; (b) greater nutrient intake of energy, protein, glutamate, methionine, tryptophan, carbohydrates, lactose, supplemental calcium and phosphorus, sodium, caffeine and unsupplemental calcium, riboflavin and thiamin in 2 degrees SS/RA, relative to 1 degrees SS and/or 2 degrees SS/SLE; (c) higher energy-adjusted values for supplemental calcium in 2 degrees SS/SLE, and for vitamin A and supplemental iron and zinc in 2 degrees SS/RA, compared with other groups; and (d) higher energy-adjusted intake of supplemental calcium, and a lower energy-adjusted intake of unsupplemental vitamin C, polyunsaturated fat, linoleic acid, omega-3 fatty acid, and specific other unsaturated fatty acids, in the Sjögren's syndrome group as a whole, relative to controls. CONCLUSIONS: Our findings demonstrate that nutrient intake is altered in Sjögren's syndrome.

Analysis of Variance↗
PubMed2001

Hormone replacement therapy and dry eye syndrome.

CONTEXT: Postmenopausal hormone replacement therapy (HRT) use is common in the United States. Some research suggests that estrogen may have detrimental effects on the tear film and could influence the development of dry eye syndrome, but few data are available on this relationship. OBJECTIVE: To determine the relationship of HRT and dry eye syndrome. DESIGN, SETTING, AND PARTICIPANTS: The Women's Health Study, a large cohort study in which 25 665 postmenopausal women provided information about use of HRT at baseline (1992), 12, and 36 months and dry eye syndrome at 48 months. MAIN OUTCOME MEASURES: (1) Clinically diagnosed dry eye syndrome, as reported by participants; (2) severe symptoms (both ocular dryness and irritation either constantly or often); and (3) either clinically diagnosed dry eye syndrome or severe symptoms, compared between women who used HRT vs those who did not. RESULTS: For the combined end point of either clinically diagnosed dry eye syndrome or severe symptoms, the multivariable-adjusted odds ratios were 1.69 (95% confidence interval [CI], 1.49-1.91) for estrogen use alone and 1.29 (95% CI, 1.13-1.48) for estrogen plus progesterone/progestin use compared with no HRT use. Each 3-year increase in the duration of HRT use was associated with a significant 15% (95% CI, 11%-19%) elevation in risk of clinically diagnosed dry eye syndrome or severe symptoms. Results were similar for the combined end point of clinically diagnosed dry eye syndrome and severe symptoms. CONCLUSIONS: These data suggest that women who use HRT, particularly estrogen alone, are at increased risk of dry eye syndrome. Physicians caring for women who are taking or considering HRT should be apprised of this potential complication.

Aged↗
PubMed2001

Role of CD4+ and CD8+ T cells in allorecognition: lessons from corneal transplantation.

Corneal transplantation represents an interesting model to investigate the contribution of direct vs indirect Ag recognition pathways to the alloresponse. Corneal allografts are naturally devoid of MHC class II+ APCs. In addition, minor Ag-mismatched corneal grafts are more readily rejected than their MHC-mismatched counterparts. Accordingly, it has been hypothesized that these transplants do not trigger direct T cell alloresponse, but that donor Ags are presented by host APCs, i.e., in an indirect fashion. Here, we have determined the Ag specificity, frequency, and phenotype of T cells activated through direct and indirect pathways in BALB/c mice transplanted orthotopically with fully allogeneic C57BL/6 corneas. In this combination, only 60% of the corneas are rejected, while the remainder enjoy indefinite graft survival. In rejecting mice the T cell response was mediated by two T cell subsets: 1) CD4+ T cells that recognize alloantigens exclusively through indirect pathway and secrete IL-2, and 2) IFN-gamma-producing CD8+ T cells recognizing donor MHC in a direct fashion. Surprisingly, CD8+ T cells activated directly were not required for graft rejection. In nonrejecting mice, no T cell responses were detected. Strikingly, peripheral sensitization to allogeneic MHC molecules in these mice induced acute rejection of corneal grafts. We conclude that only CD4+ T cells activated via indirect allorecognition have the ability to reject allogeneic corneal grafts. Although alloreactive CD8+ T cells are activated via the direct pathway, they are not fully competent and cannot contribute to the rejection unless they receive an additional signal provided by professional APCs in the periphery.

Animals↗
PubMed2001

Efficacy and tolerability outcomes after punctal occlusion with silicone plugs in dry eye syndrome.

PURPOSE: Silicone punctal plugs are widely used to conserve moisture in tear-deficient eyes. We studied the efficacy and tolerability of punctal plugs in symptom reduction and improvement of ocular surface disease parameters in dry eye syndrome. METHODS: We reviewed the records of 50 consecutive patients with dry eye syndrome who were symptomatic despite maximally tolerable lubricant therapy and had bilateral lower punctal plug insertion. After plug insertion, all patients (41 women and nine men) had 6 months or more of follow-up. The subjects ranged in age from 22 to 57 years (mean, 30 years). We recorded subjective and objective improvement of ocular surface disease, frequency of lubricant use, need for upper punctal occlusion, and occurrence of complications after plug insertion. We determined plug retention rates using Kaplan-Meier analyses and assessed associated factors using Cox proportional hazards models. RESULTS: Six months after initial plug placement, 43 of 50 patients (86%) were symptom free, 28 of them (56%) with plugs alone, and 38 patients (76%) had stopped using lubricants on a daily basis. Spontaneous loss of plugs was common, especially in the initial 3 months of follow-up. Considering all plugs, the estimated probability of plug retention was 63% after 6 months of follow-up. Puncta refitted after initial plug loss were twice as likely to lose the replacement plug (P =.02). Upper punctal plugs showed a 4.3-fold higher risk of loss compared with plugs inserted in lower puncta (P <.0001). CONCLUSIONS: There is both a reduced dependency on artificial lubricants and relief of symptoms of dry eye after punctal plugs. However, spontaneous plug loss occurs in a substantial minority of patients. Patient education and close follow-up, particularly in the first 3 months, is recommended to detect plug loss and ensure adequate control of the disease.

Adult↗
PubMed2001

Phacoemulsification in patients after allogeneic bone marrow transplantation.

OBJECTIVE: To study the outcomes of phacoemulsification in allogeneic bone marrow transplant (allo-BMT) recipients. DESIGN: Retrospective, noncomparative, interventional case series. METHODS: Retrospective study of 34 eyes of 19 consecutive patients who had visually significant cataracts after allo-BMT and subsequently underwent phacoemulsification. MAIN OUTCOME MEASURES: Best-corrected vision at the last follow-up visit and development of postoperative complications. RESULTS: Surgery was done at a mean interval of 37 months after BMT, and the mean postoperative follow-up was 13 months. Twenty-one eyes (62%) had subnormal Schirmer I scores as a result of graft-versus-host disease (GVHD) involving the lacrimal gland. Of these, 71% (15 eyes) additionally had significant ocular surface epitheliopathy because of conjunctival GVHD. Frequent lubrication (95%), punctal occlusion (76%), topical steroids (33%), and other topical immunosuppressive therapies (14%) were used to manage GVHD-induced ocular surface disease before cataract surgery. Twelve patients (63%) also received systemic steroids and immunosuppressives. Patients proceeded to surgery only after their ocular surface disease was well controlled. Early postoperative complications included intraocular pressure elevation (three eyes), worsening of dry eye syndrome (two eyes), and corneal thinning (one eye). Posterior capsular opacification (PCO) requiring laser capsulotomy occurred in 44% of eyes. In eyes with preoperative conjunctival GVHD, 47% had recurrence with cessation of immunosuppressive therapy after surgery. Visual acuity at last follow-up visit was 20/30 or better in 33 (97%) eyes. CONCLUSIONS: Phacoemulsification is an effective procedure in restoring vision in patients who have cataracts develop after BMT. However, coexisting ocular disease must be recognized and aggressively treated both before and after surgery to ensure good visual outcomes.

Adult↗
PubMed2001

Immune response to intragraft antigen in draining lymph nodes after corneal transplantation is mediated by interleukin-12.

To examine the molecular basis of immunity generated to intragraft antigens and determine whether it differs between acceptor and rejector hosts, we used a novel in vitro system to assay the T cell response to a specific antigen, ovalbumin (OVA), in the graft. OVA-containing corneas were orthotopically grafted into syngeneic or allogeneic hosts. Draining cervical lymph nodes (cLN) were assayed for OVA-specific T cell proliferation and cytokine production. In addition, cytokine production was assayed in cultures of antigen-presented cells (APC) isolated from cLN cultured with OVA-specific DO11.10 T cells and OVA. OVA-specific immunity was detected only in the draining cLN of mice following allogeneic, but not syngeneic, grafting, and this immunity was evident well before any demonstrable alloresponse in the graft. In addition, cLN cells from mice that accepted their corneal allografts produced significantly less interferon-gamma (IFN-gamma) when stimulated in culture than cells harvested from cLN of rejector hosts. Moreover, APC isolated from cLN of acceptor hosts produced significantly lower levels of IL-12. These data suggest that the induction of immunity to corneal antigens in the draining cLN occurs via an interleukin-12 (IL-12) and IFN-gamma-dependent mechanism. Targeting this process may serve as an effective immunomodulatory strategy in corneal transplantation.

Animals↗
PubMed2001

Blockade of CD40-CD154 costimulatory pathway promotes survival of allogeneic corneal transplants.

PURPOSE: To determine the effect of systemic anti-CD154 monoclonal antibody on the survival of orthotopic murine corneal transplants. METHODS: BALB/c mice were used as recipients of syngeneic, multiple minor histocompatability (H)-disparate, or major histocompatibility complex MHC-mismatched corneal transplants. Recipient beds were either avascular (normal risk) or neovascularized (high risk). Mice were randomized to receive either anti-CD154 antibody or control immunoglobulin by intraperitoneal injection at surgery and once weekly after surgery. After orthotopic corneal transplantation, all grafts were evaluated for signs of rejection by slit lamp biomicroscopy over 8 weeks. The high-risk transplants were continuously observed until week 18 after the therapy was discontinued at week 8. Allospecific delayed-type hypersensitivity (DTH) was evaluated after transplantation in high-risk graft recipients. Frequency of interferon (IFN)-gamma-secreting T cells in the hosts was measured by enzyme-linked immunospot (ELISPOT) assay. RESULTS: In normal-risk transplantation, the 8-week survival rate improved from 25% in control mice to 88% in anti-CD154-treated hosts of minor H-disparate grafts (P = 0.0087) and from 78% in control mice to 100% in anti-CD154-treated recipients of MHC-mismatched transplants (P = 0.177). Of particular significance, in high-risk transplantation, anti-CD154 therapy dramatically enhanced the survival of both minor H- and MHC-disparate corneal transplants to 100% (P = 0.0001) and 92% (P = 0.0002), respectively. In addition, the anti-CD154-treated mice did not exhibit allospecific immunity. However, termination of anti-CD154 led to some loss in graft survival, especially among high-risk minor H-disparate grafts. The frequency of IFN-gamma-producing T cells was significantly reduced in anti-CD154-treated hosts. CONCLUSIONS: Continuous suppression of the CD40-CD154 costimulatory pathway promotes the acceptance of corneal transplants, regardless of the degree of allodisparity or preoperative risk. The beneficial effect of anti-CD154 treatment may be due in part to inhibition of Th1-mediated responses.

Animals↗
PubMed2001

The critical role of lymph nodes in corneal alloimmunization and graft rejection.

PURPOSE: To elucidate the role of draining cervical lymph nodes (CLNs) in corneal alloimmunity. METHODS: Fully mismatched orthotopic corneal transplantation was performed in BALB/c hosts that had their CLNs excised before transplantation (CLN(-)). Normal hosts (CLN(+)), splenectomized mice (Sp(-)), and those without either CLNs or spleen (CLN(-)/Sp(-)) served as comparison groups. To determine the contribution of CLNs to alloimmunity more directly, CLN(-) mice were reconstituted by grafting LNs from other BALB/c mice to their cervical lymphatic chains, thus deriving CLN(-/+) mice. Tetramethyl rhodamine isothiocyanate's (TRITC) flow to draining CLNs was used as a measure of afferent lymph flow. Graft survival and allospecific delayed-type hypersensitivity (DTH) were used as measures of alloreactivity. RESULTS: Fifty percent of normal control and 12% of Sp(-) hosts accepted the allografts. In contrast, 100% of CLN(-) and 88% of CLN(-)/Sp(-) hosts accepted allografts indefinitely (P < 0.01). Additionally, all CLN(-) hosts failed to demonstrate allospecific DTH (P < 0.001). CLN(-/+) mice reconstituted with LN from naïve animals showed graft survival rates and DTH responses that were indistinguishable from those of naïve CLN(+) mice. Of particular interest, however, is that mice reconstituted with CLNs from hosts with rejected corneal grafts had swift rejection of subsequent corneal grafts and exhibited strong donor-specific DTH. In contrast, mice reconstituted with CLNs from hosts with accepted corneal grafts showed rejection of subsequent corneal grafts in a manner that was indistinguishable from rejection in naïve CLN(+) hosts. CONCLUSIONS: Draining CLNs play a critical role in allosensitization and rejection. In contrast to the spleen, draining CLNs do not appear to play a critical role in tolerance induction in corneal transplantation.

Animals↗
PubMed2000

ICAM-1 deficiency suppresses host allosensitization and rejection of MHC-disparate corneal transplants.

BACKGROUND: We used a murine model of orthotopic corneal transplantation to determine whether host deficiency in ICAM-1 promotes survival of corneal grafts with different degrees of allodisparity. METHODS: ICAM-1-/- and wild-type C57BL/6 (ICAM-1+/+) received corneal grafts from the following strains of mice: BALB/c (fully mismatched), BALB.b (mismatched at multiple minor H only), or B10.D2 [including major histocompatibility complex (MHC) mismatch]. Graft rejection, induction of allospecific delayed-type hypersensitivity (DTH) responses, and leukocytic infiltration of grafts were measured. RESULTS: There were no differences in long-term survival of allografts that were either fully mismatched or had only minor H disparity in ICAM-1+/+ vs. ICAM-1-/-hosts. However, whereas B10.D2 grafts were accepted in only 58% of the ICAM-1+/+ hosts, graft survival in ICAM-1-/- recipients was 100% (P=0.006). Moreover, none of the ICAM-1-/- mice receiving B10.D2 grafts developed allospecific DTH. CONCLUSIONS: Prolonged survival seen in MHC-mismatched grafts in ICAM-1-/- mice, along with a suppressed DTH response to donor alloantigens after transplantation, suggest that ICAM-1 is associated with recipient sensitization to MHC alloantigens.

Animals↗
PubMed2000

Topical soluble tumor necrosis factor receptor type I suppresses ocular chemokine gene expression and rejection of allogeneic corneal transplants.

OBJECTIVE: To determine the effect of topical soluble tumor necrosis factor receptor type I (sTNFR-I) on survival of murine orthotopic corneal transplants and on ocular chemokine gene expression after corneal transplantation. METHODS: BALB/c mice (N = 50) were used as recipients of multiple minor H-disparate corneal transplants from B10.D2 donors. After orthotopic corneal transplantation, mice were randomized in a masked fashion to receive either topical sTNFR-I or vehicle 3 times daily, and all grafts were evaluated for signs of rejection and neovascularization by slitlamp biomicroscopy for 8 weeks. Ocular chemokine gene expression in sTNFR-I- and vehicle only-treated groups was determined using a multiprobe ribonuclease protection assay. RESULTS: Hosts treated with topical sTNFR-I experienced significantly enhanced corneal allograft survival compared with animals treated with vehicle alone (P =.01). Moreover, postoperative messenger RNA levels of RANTES and macrophage inflammatory protein-1beta in sTNFR-I-treated eyes were substantially suppressed compared with vehicle-treated eyes. Vehicle-treated eyes bearing rejected allografts expressed higher levels of messenger RNA for both chemokines than control eyes bearing accepted allografts. CONCLUSIONS: Topical treatment with sTNFR-I promotes the acceptance of allogeneic corneal transplants and inhibits gene expression of 2 chemokines (RANTES and macrophage inflammatory protein-1beta) associated with corneal graft rejection. CLINICAL RELEVANCE: Our findings support the feasibility of a topical anticytokine strategy as a means of reducing corneal allograft rejection without resorting to the use of potentially toxic immunosuppressive drugs.

Administration, Topical↗