The association between carotid disease, arterial stiffness and diabetic retinopathy in type 2 diabetes: the Fremantle Diabetes Study Phase II.

AIM: To determine whether macrovascular disease assessed by carotid ultrasonography and arterial stiffness by pulse wave velocity are independently associated with diabetic retinopathy in type 2 diabetes. METHODS: A random subgroup of surviving participants with type 2 diabetes from the Fremantle Diabetes Study Phase II were invited to take part in this sub-study in 2018-2019. In addition to standardized questionnaires, a physical examination and fasting biochemical tests, each underwent dilated colour fundus photography, carotid arterial ultrasonography with measurement of the intima-media thickness (IMT) and quantification of the degree of stenosis, and pulse wave analysis calculation of the carotid-femoral pulse wave velocity (cfPWV). The cross-sectional association between arterial disease parameters and diabetic retinopathy was assessed using generalized estimating equation models which enabled both eyes to be included in the analysis. RESULTS: Some 270 participants [mean ± sd age 72 ± 9 years, 153 (57%) men and median (IQR) diabetes duration 15 (11-22) years] were included in analysis. Of 524 assessable eyes, 82 (16%) had diabetic retinopathy. In multivariable analysis, significant independent associates of diabetic retinopathy were age at diabetes diagnosis (inversely), HbA1c , insulin treatment and urinary albumin to creatinine ratio (all P ≤ 0.022), as well as cfPWV [odds ratio (OR) 1.13, 95% confidence interval (CI) 1.03, 1.23 per 1 m/s increase; P = 0.008] and common carotid artery (CCA) IMT ≥1 mm (OR 2.95, 95% CI 1.21, 7.23; P = 0.018). CONCLUSIONS: The association between diabetic retinopathy and CCA IMT suggests that carotid disease may share cardiovascular risk factors with diabetic retinopathy. The association between diabetic retinopathy and cfPWV may reflect the consequences of altered intravascular haemodynamics.

De Novo Donor-Specific HLA Antibodies Are Associated With Rapid Loss of Graft Function Following Islet Transplantation in Type 1 Diabetes.

Outcomes after islet transplantation continue to improve but etiology of graft failure remains unclear. De novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) posttransplant are increasingly recognized as a negative prognostic marker. Specific temporal associations between DSA and graft function remain undefined particularly in programs undertaking multiple sequential transplants. Impact of de novo DSA on graft function over 12 months following first islet transplant was determined prospectively in consecutive recipients taking tacrolimus/mycophenolate immunosuppression at a single center. Mixed-meal tolerance test was undertaken in parallel with HLA antibody assessment pretransplant and 1-3 months posttransplant. Sixteen participants received a total of 26 islet transplants. Five (19%) grafts were associated with de novo DSA. Five (31%) recipients were affected: three post-first transplant; two post-second transplant. DSA developed within 4 weeks of all sensitizing grafts and were associated with decreased stimulated C-peptide (median [interquartile range]) at 3 months posttransplant (DSA negative: 613(300-1090); DSA positive 106(34-235) pmol/L [p = 0.004]). De novo DSA directed against most recent islet transplant were absolutely associated with loss of graft function despite maintained immunosuppression at 12 months in the absence of a rescue nonsensitizing transplant. Alemtuzumab induction immunosuppression was associated with reduced incidence of de novo DSA formation (p = 0.03).

Attainment of metabolic goals in the integrated UK islet transplant program with locally isolated and transported preparations.

The objective was to determine whether metabolic goals have been achieved with locally isolated and transported preparations over the first 3 years of the UK's nationally funded integrated islet transplant program. Twenty islet recipients with C-peptide negative type 1 diabetes and recurrent severe hypoglycemia consented to the study, including standardized meal tolerance tests. Participants received a total of 35 infusions (seven recipients: single graft; 11 recipients: two grafts: two recipients: three grafts). Graft function was maintained in 80% at [median (interquartile range)] 24 (13.5-36) months postfirst transplant. Severe hypoglycemia was reduced from 20 (7-50) episodes/patient-year pretransplant to 0.3 (0-1.6) episodes/patient-year posttransplant (p < 0.001). Resolution of impaired hypoglycemia awareness was confirmed [pretransplant: Gold score 6 (5-7); 24 (13.5-36) months: 3 (1.5-4.5); p < 0.03]. Target HbA1c of <7.0% was attained/maintained in 70% of recipients [pretransplant: 8.0 (7.0-9.6)%; 24 (13.5-36) months: 6.2 (5.7-8.4)%; p < 0.001], with 60% reduction in insulin dose [pretransplant: 0.51 (0.41-0.62) units/kg; 24 (13.5-36) months: 0.20 (0-0.37) units/kg; p < 0.001]. Metabolic outcomes were comparable 12 months posttransplant in those receiving transported versus only locally isolated islets [12 month stimulated C-peptide: transported 788 (114-1764) pmol/L (n = 9); locally isolated 407 (126-830) pmol/L (n = 11); p = 0.32]. Metabolic goals have been attained within the equitably available, fully integrated UK islet transplant program with both transported and locally isolated preparations.

Clinical features at presentation of anterior segment pigment dispersion syndrome.

One hundred and twenty patients with anterior segment pigment dispersion syndrome were reviewed in order to ascertain the features of the condition and form some idea of their significance. Patients were regarded as having pigment dispersion syndrome on the basis of heavy trabecular mesh pigmentation with at least one other feature of the condition. Although common in men, 44 patients, or a little over one-third, were women. Average age at presentation was 47.8 years with women presenting 10 years later than men. Intraocular pressure was very variable at presentation being less than 20 mmHg in 23 patients. Some patients with elevated pressure had no field loss. Variable myopia was recorded in 38 patients: 30 patients were not myopic. Anterior chamber depth was also variable, the average being 3.0 mm, but six patients had a depth of 2.2 mm or less. The syndrome is extremely variable in its features at presentation. The mild hypoplasia and the hypoperfusion of the iris previously described is consistent with the laxity of the iris noted by Ritch and colleagues.

Impact of low birth weight on early childhood asthma in the United States.

OBJECTIVE: To estimate the independent contribution of birth weight to asthma prevalence among children younger than 4 years in the United States and to compare the magnitude of its effect on asthma between African American and white children. DESIGN: Cross-sectional analysis using the 1988 National Maternal-Infant Health Survey and 1991 Longitudinal Follow-up Survey. SETTING: United States. PATIENTS: Eight thousand seventy-one subjects, selected from a randomized, systematic population-based sample and weighted to be nationally representative, who completed both initial and longitudinal follow-up surveys and reported information on asthma diagnosis. MAIN OUTCOME MEASURES: Birth weight and other sociodemographic factors linked to birth outcome were analyzed for independent association with physician-diagnosed asthma by age 3 years. RESULTS: The prevalence of asthma varied by birth weight category: 6.7% in children 2500 g or more at birth, 10.9% in children 1500 to 2499 g at birth, and 21.9% in children less than 1500 g at birth (very low birth weight [VLBW]) (P<.001). Some of the characteristics shown to be independently associated with asthma included: VLBW (odds ratio [OR], 2.9; 95% confidence interval [CI], 2.3-3.6), moderately low birth weight (OR, 1.4; 95% CI, 1.1-1.8), and African American race (OR, 1.9; 95% CI, 1.6-2.4). In stratified analyses, the independent association between VLBW and asthma in white and African American populations was: OR(white), 3.1 (95% CI, 2.2-4.3) and OR(African American), 2.5 (95% CI, 2.0-3.3). The prevalence of VLBW, however, was tripled in African American compared with white children (1.8% vs 0.6%). CONCLUSIONS: These data confirm findings of other studies that identify a strong independent association between low birth weight and asthma. For this 1988 national birth cohort, an estimated 4000 excess asthma cases were attributable to birth weight less than 2500 g. Although the strength of the independent association between VLBW and asthma was smaller in the African American population, the substantially increased prevalence of VLBW in this community may contribute to the disproportionately increased prevalence of asthma among African American children.

Effect of lung fluid composition on type II cellular activity after tracheal occlusion in the fetal lamb.

BACKGROUND/PURPOSE: Fetal tracheal occlusion (TO) causes accelerated lung growth. However, prolonged TO is associated with a decline in the type II cell number. Type II cell function after TO is unclear. Herein, the authors examine type II cell function after TO and the role of tracheal fluid. METHODS: Fetal lambs (term, 145 days) underwent TO at 122 days. Tracheal pressure was recorded daily. In one group of animals (TF; n = 6), lung fluid was aspirated, measured, and reinfused daily. In their respective twins, NS group, lung fluid was replaced milliliter per milliliter with normal saline (NS; n = 6). At death near term, lung weight was obtained, and tissues were processed for stereologic volumetry. Type II cells were quantitated using antisurfactant protein B immunohistochemistry. Surfactant protein B-mRNA expression was studied by Northern analysis. Wilcoxon signed rank test and single factor analysis of variance (ANOVA) were used for statistical analysis (P<.05 was significant). RESULTS: In both experimental groups, intratracheal pressure rose from 1.9+/-1.0 torr to 3.7 to 4.8 torr by day 1, and remained constant thereafter. Lung fluid volume increased from 11.9+/-4.2 on day 0 to 36.8+/-8.0 mL/kg in TF, and to 28.4+/-9.3 mL/kg in NS by day 1 (P<.05). At death, lung weight/body weight ratio was higher in TF (5.45% +/- 0.91%) than in NS (4.40% +/- 0. 67%) or control (3.83%+/-0.58%; P<.05). Type II numerical density was substantially reduced after TO: 57.7+/-12.8 x 10(6)/mL (TF) and 45.0 +/-25.9 x 10(6)/mL (NS), versus 82.3+/-13.6 x 10(6)/mL in controls. Ultrastructurally, remaining type II cells in TF were enlarged and engorged with lamellar bodies; in NS, they were smaller and contained fewer lamellar bodies. Surfactant protein B mRNA expression was significantly decreased in NS, but not in TF, compared with controls. CONCLUSIONS: Type II cell function as well as overall lung growth are stimulated by TO. Lung growth after TO is therefore not unavoidably detrimental to type II cells. After isobaric saline exchange of lung fluid, type II cell function is severely inhibited, confirming the role of tracheal fluid composition in type II stimulating type II cell function.

Study of IgM aggregation in serum of patients with macroglobulinemia.

The effect of solvent conditions on the aggregation of IgM in serum specimens from patients with macroglobulinemia was studied by a turbidimetric procedure. Aggregation of IgM varied considerably among the samples and was affected by a number of experimental parameters. In general, IgM aggregation was more pronounced under acidic conditions and in solvents with low ionic strength. The presence of water-miscible organic solvents also promoted aggregation. Based on these studies, it was concluded that the major force involved in the formation of immunoglobulin aggregates in the serum of patients with macroglobulinemia was electrostatic, rather than hydrophobic, interactions. A number of additives known to prevent protein aggregation were evaluated for their effectiveness in inhibiting IgM aggregation. The only additives that were shown to inhibit or reduce IgM aggregation were charged molecules, such as arginine, sodium chloride, ethylenediamintetraacetic acid and quaternary ammonium beta-cyclodextrin. Some of these charged additives were also effective in dissociating the IgM aggregates once they were formed, even in the presence of detergent.

Fas ligand expression coincides with alveolar cell apoptosis in late-gestation fetal lung development.

Apoptosis plays a central role in the cellular remodeling of the developing lung. We determined the spatiotemporal patterns of the cell death regulators Fas and Fas ligand (FasL) during rabbit lung development and correlated their expression with pulmonary and type II cell apoptosis. Fetal rabbit lungs (25-31 days gestation) were assayed for apoptotic activity by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and DNA size analysis. Fas and FasL expression were analyzed by RT-PCR, immunoblot, and immunohistochemistry. Type II cell apoptosis increased significantly on gestational day 28; the type II cell apoptotic index increased from 0.54 +/- 0.34% on gestational day 27 to 3.34 +/- 1.24% on day 28, P < 0.01 (ANOVA). This corresponded with the transition from the canalicular to the terminal sac stage of development. The day 28 rise in epithelial apoptosis was synchronous with a robust if transient 20-fold increase in FasL mRNA and a threefold increase in FasL protein levels. In contrast, Fas mRNA levels remained constant, suggestive of constitutive expression. Fas and FasL proteins were immunolocalized to alveolar type II cells and bronchiolar Clara cells. The correlation of this highly specific pattern of FasL expression with alveolar epithelial apoptosis and remodeling implicates the Fas/FasL system as a potentially important regulatory pathway in the control of postcanalicular alveolar cytodifferentiation.

Confocal laser scanning ophthalmoscope and spherical harmonics used as a possible aid to detect glaucoma.

We present a procedure whereby the confocal laser scanning ophthalmoscope can be used to extract information about the three-dimensional structure of the central excavated area or the cup of the optic nerve head of the eye. The data are analyzed in terms of spherical harmonics. It is hypothesized that the shape of the cup of the optic nerve head for a normal eye can be parameterized by a specific set of spherical harmonic coefficients and is different from the set of coefficients describing a glaucomatous eye. The sets of coefficients are analyzed by using multivariate statistics and can in turn be used to classify new observations. Preliminary results indicate that there are significant differences in the coefficients and that the procedure might have potential as a diagnostic aid for the detection or the screening of glaucoma.

Management and prognosis of end-stage glaucoma.

PURPOSE: We followed, for a long term, end-stage glaucoma patients as defined by the level of legal blindness. METHODS: Follow up was for 7.7+/-1.8 years (range 2-9) for 22 patients (13 men and nine women) having 32 eyes with functional vision. Age at exit was 74.6+/-15.5 years (range 33-89). Humphrey computerized perimetry and applanation tonometry were used throughout. We attempted to hold intraocular pressure below 15 mmHg using as much medical therapy as required. RESULTS: All visual fields were less than 10 degrees diameter at exit, but at entry seven eyes of six patients still had a field between 10 degrees and 20 degrees, the rest were all less than 10 degrees. Corrected visual acuity at entry was 6/9 to 6/6 in 21 eyes of 6 patients and none had less than 6/60. At exit 16 eyes had 6/9 to 6/6 and five eyes had less than 6/60, but no patient had complete loss of vision. Mean intraocular pressure (IOP) throughout was below 15 mmHg in all but four patients, whose (IOP) were less than 20 mmHg, using multiple medications if necessary. All patients had undergone prior surgery and/or laser trabeculoplasty. CONCLUSIONS: Even though visual loss slowly progressed, most patients with end-stage glaucoma retained functional vision for a long period when intraocular pressure was held below 15 mmHg. More stringent early control of intraocular pressure may avoid the development of end-stage glaucoma.

Comparison of colour Doppler imaging of orbital vessels in elderly compared with young adult patients.

PURPOSE: Colour Doppler imaging provides an estimate of the velocity of blood flow in vessels supplying the eye. METHODS: To assess changes in orbital blood flow with age, we used a method to study peak systolic velocity in 20 young normal patients, mean age 25.2+/-2.4 years and 30 elderly normal patients, mean age 69.5+/-7.9 years. RESULTS: Peak systolic velocity was significantly higher in the central retinal artery and the temporal division of the posterior ciliary artery in elderly patients. There was greater variation in the peak systolic velocity readings in the distal part of the ophthalmic artery in the elderly than in the younger group. There was greater variation in the pulsatility index in the central retinal artery in young subjects. CONCLUSIONS: Though not large, these differences suggest changes in the orbital blood vessels with age which could affect the development of disease processes in elderly patients. These changes should be taken into account when assessing blood flow in elderly patients.