Dietary glycemic index and carbohydrate in relation to early age-related macular degeneration

BACKGROUND: Several dietary factors have been linked to age-related maculopathy (ARM), the early form of age-related macular degeneration, and there is reason to think that dietary carbohydrate may play a role in the development of ARM. OBJECTIVE: The purpose of the present study was to examine the relation between dietary carbohydrate quality, as measured by dietary glycemic index (GI) or total carbohydrate intake, and ARM. DESIGN: From the Nurses' Health Study, 1036 eyes from 526 Boston-area participants without a previous ARM diagnosis were included in the present study. The presence and degree of ARM were classified by the Age-Related Eye Diseases Study system. Long-term dietary information was based on data from an average of 4 food-frequency questionnaires collected over a 10-y period before the assessment of ARM. With eyes as the unit of analysis, we used a generalized estimating approach to logistic regression to estimate the odds ratios for ARM in a manner that accounted for the lack of independence between the 2 eyes from the same subject. RESULTS: After multivariate adjustment, dietary GI was related to ARM (specifically to retinal pigmentary abnormalities), whereas total carbohydrate intake was not. The odds ratio for ARM being in the highest tertile of dietary GI (> or =77.0) versus the lowest (<74.6) was 2.71 (95% CI: 1.24, 5.93; P for trend = 0.01). Neither dietary GI nor total carbohydrate intake was related to drusen. CONCLUSION: Our results suggest that dietary GI may be an independent risk factor for ARM.     

Mid-term follow-up of patients with transposition of the great arteries after atrial inversion operation using two- and three-dimensional magnetic resonance imaging

BACKGROUND: Older patients with transposition of the great arteries who have undergone an atrial inversion procedure (ATRIAL-INV) are difficult to image by echocardiography. The surgical baffles are spatially complex. OBJECTIVE: To test the hypothesis that two- and three-dimensional MRI can elucidate the spatially complex anatomy in this patient population. MATERIALS AND METHODS: Twelve patients with ATRIAL-INV, ages 16+/-4.5 years, underwent routine T1-weighted spin-echo axial imaging to obtain a full cardiac volumetric data set. Postprocessing created three-dimensional shaded surface displays and allowed for multiplanar reconstruction. Routine transthoracic echocardiography was available on all patients. RESULTS: Three-dimensional reconstruction enabled complete spatial conceptualization of the venous pathways, and allowed for precise localization of a narrowed region in the upper limb of the systemic venous pathway found in two patients. This was subsequently confirmed on angiography. Routine MRI was able to image the full extent of the venous pathways in all 12 patients. Routine transthoracic echocardiography was able to visualize proximal portions of the venous pathways in eight (67%), the distal upper limb in five (42%), and the distal lower limb in four (33%) patients, and it was able to visualize the outflow tracts in all patients. CONCLUSION: Three-dimensional reconstruction adds important spatial information, which can be especially important in stenotic regions. Routine MRI is superior to transthoracic echocardiography in delineation of the systemic and pulmonary venous pathway anatomy of ATRIAL-INV patients at mid-term follow-up. Although transesophageal echocardiography is an option, it is more invasive.     

Adverse effects of oral corticosteroids in relation to dose in patients with lung disease

BACKGROUND: The adverse effects of oral corticosteroids are widely recognised but there are few quantitative data on which to base advice to patients. In a two part cross sectional study we compared adverse effects in patients with lung disease taking oral corticosteroids and control subjects and related the adverse effects to corticosteroid dose in the patient group. METHODS: Data on oral corticosteroid use, lifestyle, fractures, and other possible adverse effects were collected by questionnaire and compared between a community based cohort of patients taking continuous or frequent intermittent oral corticosteroids for asthma, chronic obstructive pulmonary disease, or alveolitis and age and sex matched control subjects. Dose related effects were explored in the corticosteroid group using cumulative dose quartiles and multiple logistic regression. RESULTS: A total of 367 patients (> or = 50 years, 48% female) and 734 control subjects completed the questionnaire. The cumulative incidence of fractures since the time of diagnosis was 23% for patients taking oral corticosteroids and 15% in the control group (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.3 to 2.6). Patients were more likely to have had a fracture of the vertebrae (OR 10; 95% CI 2.9 to 34), hip (OR 6; 95% CI 1.2 to 30), and ribs or sternum (OR 3.2, 95% CI 1.6 to 6.6) than control subjects. They also reported a significant increase in cataracts, use of antacids, muscle weakness, back pain, bruising, oral candidiasis, and having fewer teeth. The effects of oral corticosteroids were dose related: the odds ratio for patients in the highest compared with the lowest cumulative dose quartile (median prednisolone dose 61 g versus 5 g) ranged from 2 for all fractures to 9 for vertebral fractures and bruising. CONCLUSIONS: By quantifying the morbidity associated with the use of oral corticosteroids, this study should help to rationalise their long term use.     

Absolute bioavailability and stereoselective pharmacokinetics of doxepin

1. Commercial doxepin contains geometric isomers in the proportions Z:E = 15:85. Z-doxepin and its metabolite Z-N-desmethyldoxepin are both active antidepressants, whereas the corresponding E-isomers are less active therapeutically. 2. The present pharmacokinetic study was a balanced, randomized, two-treatment, two-period, two-sequence crossover design in which 12 healthy male volunteers were given single doses of commercial doxepin intravenously and orally on two occasions separated by a washout period. 3. A two-compartment model with no lag time and first-order elimination fitted the plasma concentration-time curves after intravenous dosing. Pharmacokinetic parameters estimated from the model were comparable with those estimated by non-compartmental methods. 4. All pharmacokinetic parameters displayed a wide between-subject variability. Both isomers of doxepin showed large volumes of distribution and relatively short half-lives in plasma, suggestive of extensive distribution and/or tissue binding. The mean fraction absorbed after oral administration was 0.29 for each isomer. Renal clearances of each isomer were very low after either oral or intravenous dosing, although all four analytes were quantifiable in the urine for prolonged periods. 5. After oral dosing, plasma concentrations of the doxepin isomers remained roughly in the ratio Z:E = 15:85, whereas those of N-desmethyldoxepin were closer to 1:1 in all but two outliers, who had high levels E-N-desmethyldoxepin.     

Cytoskeletal-induced alterations in the adhesion of HT-1080 fibrosarcoma cells to extracellular matrix

We have investigated the adhesion of the human fibrosarcoma cell line, HT-1080, transfected with glial fibrillary acidic protein (GFAP) to a variety of extracellular matrix macromolecules (ECM) including collagen type IV, laminin, and fibronectin. The GFAP-transfectants demonstrated altered adhesiveness to extracellular matrix substrates when compared to controls. GFAP-positive, heavy metal-induced fibrosarcoma cells were more adherent to plastic and collagen type IV than were the parental or uninduced cells. In contrast, GFAP-positive fibrosarcoma cells were less adherent to laminin- or fibronectin-coated dishes than controls. Time course adhesion studies over 9 days showed that the heavy metal-induced fibrosarcoma cells progressively became more adherent to collagen type IV and less adherent to laminin- or fibronectin-coated dishes than did uninduced cells. However, with the removal of heavy metal from the medium, the HT-1080 fibrosarcoma cells were restored to their original adhesive potential. By phase microscopy, uninduced and induced HT-1080 cells demonstrated different morphological features and remained viable in an anchorage-dependent fashion on collagen type IV as a substrate. By way of contrast, GFAP-induced HT-1080 cells were not particularly viable in monolayer culture and readily detached from laminin as a substrate. The expression of beta1 integrin in GFAP-positive fibrosarcoma cells was decreased following heavy metal induction by Western blot analyses. In contrast, the expression of alpha2 integrin was increased whereas alpha5 integrin was unchanged in HT-1080 cells following the induction of GFAP. Gelatin zymography showed that 72 kDa collagenase was less expressed in GFAP-induced clones than in controls. Our data suggest that the forced expression of the intermediate filament, GFAP, in HT-1080 cells may modulate cell adhesion to different ECM substrates through alterations in expression of integrins.     

Phenotypic and functional analysis of T-cell recovery after anti-CD3 immunotoxin treatment for tolerance induction in rhesus macaques

T-cell reduction utilizing specific antibody has been widely used in human transplantation, and is a cornerstone of several tolerance induction strategies in nonhuman primates. We have established a population of long-term tolerant rhesus macaques induced with an anti-CD3epsilon immunotoxin (IT). This treatment effects transient, specific and profound ablation of T cells in blood and lymphoid tissues. In most instances the IT was used in combination with the NF-kappaB inhibitor, 15-Deoxyspergualin. This 2-week long protocol produces a "window of opportunity" for tolerization in which the animal exhibits an enduring quiescent state of unresponsiveness to the allograft, all accomplished without maintenance immunosuppressive drugs. During this induction period, the treated immune system bears some resemblance to that of the neonate, in that T cell numbers are abnormally low and antigen presentation by dendritic cells is precluded by an arrest in their NF-kappaB dependant maturation. In addition, IL-4 production is prominent during and after the tolerance induction interval. For this study we focused on measuring the monkey's ability to repopulate T cells with particular emphasis on the memory T-cell phenotype. Three "memory" phenotypes were utilized; CD3(+)CD45RO(+), CD3(+)CRTH2(+), and CD3(+)CD4(+)CD8(+). All three phenotypes exhibited different patterns of recovery, all of which included transient bursts in their numbers during repopulation. We also estimated thymic activity after T-cell ablation with the use of a newly-described RTE or recent thymic émigré phenotype (a na?ve CD8(+)CD103(+) T cell). This marker revealed production of RTE cells including supranormal levels at approximately 6 months post-transplant, implicating thymic function in the repopulation of T-cells. Finally, we measured antibody responses to a panel of antigens (vaccines, environmental antigen, and foreign proteins) that indicated there was no apparent loss of immunologic function during or after the tolerance induction period. Results of studies of T-cell receptor repertoire expression suggest preservation of the pretreatment repertoire, which is consistent with rapid recovery of immune competence to the test antigens. Taken together, these results suggest that while aggressive, this tolerance induction protocol does not appear to incur a prolonged immunologically-compromised state, if at all.     

Three-year incidence and cumulative prevalence of retinopathy: the atherosclerosis risk in communities study

PURPOSE: To describe the three-year incidence and cumulative prevalence of retinopathy and its risk factors. DESIGN: Population-based, prospective cohort study in four US communities. METHODS: In the Atherosclerosis Risk in Communities (ARIC) Study, 981 participants had retinal photography of one randomly selected eye at the third examination (1993 to 1995) and three years later at the fourth examination (1996). Photographs were graded on both occasions for retinopathy signs (for example, microaneurysm, retinal hemorrhage, and/or cotton-wool spots). Incidence was defined as participants without retinopathy at the third examination who developed retinopathy at the fourth examination, and cumulative prevalence was defined to include incident retinopathy as well as participants who had retinopathy at both the third and fourth examinations. RESULTS: The three-year incidence and cumulative prevalence of any retinopathy in the whole cohort was 3.8% and 7.7%, respectively. In multivariable analysis, incident retinopathy was related to higher mean arterial blood pressure (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.0 to 2.3, per standard deviation increase in risk factor levels), fasting serum glucose (OR 1.6, 95% CI 1.3 to 2.1), serum total cholesterol (OR 1.4, 95% CI 1.0, 2.0), and plasma fibrinogen (OR 1.4, 95% CI 1.1 to 1.9). Among persons without diabetes, the three-year incidence and cumulative prevalence of nondiabetic retinopathy was 2.9% and 4.3%, respectively. Incident nondiabetic retinopathy was related to higher mean arterial blood pressure (OR 1.4, 95% CI 0.9 to 2.3) and fasting serum glucose (OR 1.5, 95% CI 1.0 to 2.3). Among persons with diabetes, the three-year incidence and cumulative prevalence of diabetic retinopathy was 10.1% and 27.2%, respectively. CONCLUSIONS: Retinopathy signs occur frequently in middle-aged people, even in those without diabetes. Hypertension and hyperglycemia are risk factors for incident retinopathy.