Influence of Cardiac CT based disease severity and clinical symptoms on the diagnostic performance of myocardial perfusion.

We aimed to identify factors influencing the sensitivity of perfusion imaging after an initial positive coronary computed tomography angiography (CCTA) using invasive coronary angiography (ICA) with conditional fractional flow reserve (FFR) as reference. Secondly we aimed to identify factors associated with revascularisation and to evaluate treatment outcome after ICA. We analysed 292 consecutive patients with suspected significant coronary artery disease (CAD) at CCTA, who underwent perfusion imaging with either cardiac magnetic resonance (CMR) or myocardial perfusion scintigraphy (MPS) followed by ICA with conditional FFR. Stratified analysis and uni- and multiple logistic regression analyses were performed to identify predictors of diagnostic agreement between perfusion scans and ICA and predictors of revascularisation. Myocardial ischemia evaluated with perfusion scans was present in 65/292 (22%) while 117/292 (40%) had obstructive CAD evaluated by ICA. Revascularisation rate was 90/292 (31%). The overall sensitivity for perfusion scans was 39% (30-48), specificity 89% (83-93), PPV 69% (57-80) and NPV 68% (62-74). Stratified analysis showed higher sensitivities in patients with multi-vessel disease at CCTA 49% (37-60) and typical chest pain 50% (37-60). Predictors of revascularisation were multi-vessel disease by CCTA (OR 3.51 [1.91-6.48]) and a positive perfusion scan (OR 4.69 [2.49-8.83]). The sensitivity for perfusion scans after CCTA was highest in patients with typical angina and multiple lesions at CCTA and predicted diagnostic agreement between perfusion scans and ICA. Abnormal perfusion and multi vessel disease at CCTA predicted revascularisation.

Diagnosing coronary artery disease after a positive coronary computed tomography angiography: the Dan-NICAD open label, parallel, head to head, randomized controlled diagnostic accuracy trial of cardiovascular magnetic resonance and myocardial perfusion scintigraphy.

Aims: Perfusion scans after coronary computed tomography angiography (CCTA) in patients with suspected coronary artery disease (CAD) may reduce unnecessary invasive coronary angiographies (ICAs). However, the diagnostic accuracy of perfusion scans after primary CCTA is unknown. The aim of this study was to determine the diagnostic accuracy of cardiac magnetic resonance (CMR) and myocardial perfusion scintigraphy (MPS) against ICA with fractional flow reserve (FFR) in patients suspected of CAD by CCTA. Methods and results: Included were consecutive patients (1675) referred to CCTA with symptoms of CAD and low/intermediate risk profile. Patients with suspected CAD based on CCTA were randomized 1:1 to CMR or MPS followed by ICA with FFR. Obstructive CAD was defined as FFR ≤ 0.80 or > 90% diameter stenosis by visual assessment. After initial CCTA, 392 patients (23%) were randomized; 197 to CMR and 195 to MPS. Perfusion scans and ICA were completed in 292 patients (CMR 148, MPS 144). Based on the ICA, 117/292 (40%) patients were classified with CAD. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for CMR were 41%, 95% CI [28-54], 84% [75-91], 62% [45-78], and 68% [58-76], respectively. For the MPS group 36% [24-50], 94% [87-98], 81% [61-93], and 68% [59-76], respectively. Conclusion: Patients with low/intermediate CAD risk and a positive CCTA scan represent a challenge to perfusion techniques indicated by the low sensitivity of both CMR and MPS with FFR as a reference. The mechanisms underlying this discrepancy need further investigation.

The North Jutland County Diabetic Retinopathy Study (NCDRS) 2. Non-ophthalmic parameters and clinically significant macular oedema.

BACKGROUND: The influence of non-ophthalmic parameters on the prevalence of clinically significant macular oedema has not been unambiguously established. The present study was initiated with the aim of clarification. METHODS: This cross-sectional study comprised 656 type 1 and 328 type 2 diabetic subjects undergoing retinopathy screening in the county of North Jutland. The association between the presence of clinically significant macular oedema and blood pressure, HbA1c, BMI, age, onset of diabetes, duration of diabetes, blood-pressure-reducing medication, lipid-lowering medication, neuropathy and urinary albumin excretion was explored using multiple logistic regression analysis. RESULTS: We found no significant association between the presence of clinically significant macular oedema and any of the examined parameters in type 1 diabetic subjects. In type 2 diabetic subjects, the duration of diabetes, HbA1c, neuropathy and increased urinary albumin excretion was significantly associated with the presence of clinically significant macular oedema. CONCLUSIONS: The risk factors for clinically significant macular oedema differ in type 1 and type 2 diabetic subjects and can account only in part for this manifestation.

The North Jutland County Diabetic Retinopathy Study: population characteristics.

BACKGROUND: Several population-based studies have reported blood glucose levels and blood pressure to be risk factors for the development of diabetic retinopathy. These studies were initiated more than two decades ago and may therefore reflect the treatment and population composition of a previous era, suggesting new studies of the present population with diabetes. AIM AND METHODS: This cross-section study included 656 people with type 1 diabetes and 328 with type 2 diabetes. Crude prevalence rates of proliferative diabetic retinopathy, clinically significant macular oedema and several specific retinal lesions were assessed, together with their association to a simplified and internationally approved retinal grading. RESULTS: The point prevalence of proliferative retinopathy was found to be 0.8% and 0.3% for type 1 and type 2 diabetes. Equivalent prevalence rates of clinically significant macular oedema were 7.9% and 12.8%, respectively. The most frequently occurring retinal manifestations increased in number until retinopathy level 3, and then decreased. CONCLUSION: The point prevalence of proliferative retinopathy is lower than that found in previous studies, whereas it is increased for clinically significant macular oedema. These data suggest different risk factors for these clinical entities.

Diabetes and risk of acute infectious conjunctivitis--a population-based case-control study.

AIMS: To examine whether diabetes mellitus is associated with an increased risk of acute infectious conjunctivitis (AIC) in adults, as measured by treatment with topical ocular antibiotics. METHODS: A population-based, case-control study in North Jutland County, Denmark. Incident cases of AIC were defined as persons aged more than 15 years redeeming a first-time prescription for a topical ocular antibiotic during 1999 in the County Prescription Database. Five gender- and age-matched population control subjects per case were selected using a unique personal identifier, the Civil Registry Number. Diabetes prior to the ocular antibiotic prescription was determined by record-linkage with the Prescription Database and Hospital Discharge Registry in the county. Odds ratios (ORs) for acute infectious conjunctivitis among diabetic individuals and control subjects were estimated, adjusting for a range of potential risk factors. RESULTS: Among 16 193 adults treated with topical ocular antibiotics, 3.1% had diabetes as compared with 2.5% of the control subjects. The overall adjusted OR for acute infectious conjunctivitis in patients with diabetes was 1.24 [95% confidence interval (CI): 1.13-1.38]. Risk estimates of acute infectious conjunctivitis in individuals with diabetes were consistently increased for both women and men, for all age groups, and for different types of ocular antibiotics prescribed. CONCLUSIONS: This study suggests that diabetes is a risk factor for acute infectious conjunctivitis.

Can a cilio-retinal artery influence diabetic maculopathy?

AIM: To explore the influence of a cilio-retinal artery on diabetic maculopathy. METHODS: In the county of North Jutland 481 diabetic subjects underwent examination for diabetic retinopathy during the period 1 June 2000 to 30 June 2001. A unilateral cilio-retinal artery was observed in 104 patients among which 29 revealed variation in right and left eye maculopathy. A bilateral cilio-retinal artery was observed in 15 diabetic subjects. The influence of a cilio-retinal artery on diabetic maculopathy was explored in a paired study. RESULTS: Diabetic maculopathy was found to be more severe in 26 of 29 eyes with a cilio-retinal artery (p<0.01) compared to eyes without it. The number of red dots (p<0.0001) and hard exudates (p=0.0002) were found to be significantly increased in eyes with a cilio-retinal artery, as also the number of eyes with central photocoagulation (p<0.05). In addition, clinically significant macular oedema was found to be significantly increased in eyes with a cilio-retinal artery compared to eyes without it (0.01

Bedside coagulometry during intravenous heparin therapy after coronary angioplasty.

UNLABELLED: In order to assess the applicability of a bedside coagulometer for measurement of b-APTT, serial blood samples were obtained from 20 patients receiving intravenous heparin treatment following PTCA, and from 5 healthy volunteers. B-APTT was analysed bedside on the Hemochron coagulometer; p-APTT and p-heparin, measured as factor anti-Xa activity, were analysed ex-vivo in the laboratory. B-APTT values, determined by the Hemochron coagulometer, were closely correlated to p-heparin (r=0.83, p<0.001, SD=52 seconds (sec), n=89), and duplicate determinations of b-APTT on the Hemochron coagulometer showed an acceptable repeatability. However, an APTT ratio of 1.5-2.5 was not related to a therapeutic p-heparin level, neither as measured by the Hemochron device nor in the laboratory. BACKGROUND: When administering intravenous heparin during angioplasty procedures, a quick and reliable method for safe and effective monitoring of anticoagulation is necessary. OBJECTIVE: To assess the applicability of a bedside coagulometer, measuring the activated partial thromboplastin time (APTT) in patients receiving intravenous heparin treatment after percutaneous transluminal coronary angioplasty (PTCA). METHODS: In patients with stable angina pectoris, receiving intravenous heparin treatment following PTCA, serial blood samples were obtained by venipuncture and from the arterial sheath for analysis of whole blood APTT (b-APTT), and plasma heparin concentration (p-heparin). Additionally, in healthy volunteers blood samples were obtained after a single bolus injection of heparin. B-APTT was analysed bedside on the Hemochron coagulometer; p-APTT and p-heparin, measured as factor anti-Xa activity, were analysed ex-vivo in the laboratory using conventional analytical methods. RESULTS: In 20 patients a total of 94 venous and 69 arterial blood samples were analysed, and in five healthy volunteers analyses were performed in 20 venous blood samples. B-APTT values, determined by the Hemochron coagulometer, were closely correlated to p-heparin (r=0.83, p<0.001, SD=52 seconds (sec), n=89). An APTT ratio of 1.5-2.5 was not related to a therapeutic p-heparin level, however, neither when using APTT assessed by the Hemochron device nor APTT measured in the laboratory. Duplicate determinations of b-APTT on the Hemochron coagulometer showed an acceptable repeatability; the mean difference between duplicate measurements was 4 sec (coefficient of variation (c.v.)=6%, p<0.05, n=163). CONCLUSIONS: In patients receiving intravenous heparin after PTCA treatment, b-APTT values measured by the Hemochron method showed an acceptable repeatability and were significantly correlated to p-heparin.

Ocular fluorescein kinetics before and after vitrectomy on swine.

PURPOSE: To study the quantitative effects of vitrectomy on fluorescein transport kinetics across the ocular barriers. METHODS: Thirty-six domestic swine were used in this study. Twenty anesthetized swine were given a standardized fluorescein intravenous injection immediately after unilateral vitrectomy. This was followed by one single central sample aspiration from the vitreous and the anterior chamber of both eyes in individual animals at increasing intervals up to 24 h after the injection. Fluorescein concentrations in the samples were determined by high-pressure liquid chromatography (HPLC). Eight swine underwent unilateral vitrectomy followed by anterior chamber and vitreous fluorophotometry on both eyes 1 month later. The fluorescein concentrations determined using this method were followed for 24 h. Similar examinations were performed in a control group of eight swine that did not undergo vitrectomy. Anterior chamber, vitreous, and plasma fluorescein concentration/time courses were analyzed kinetically by iterative nonlinear regression analysis. RESULTS: The barrier surrounding the anterior chamber of the eye was immediately impaired after vitrectomy, as evidenced by an increased area under the fluorescein concentration versus time curve, but the transport kinetics were restored within 1 month after surgery. The blood-retinal barrier was, however, persistently altered following vitrectomy. Transport rate and extent of drug penetration into the vitreous were increased, while drug elimination from the vitreous remained unchanged. CONCLUSION: Vitrectomy led to persistent kinetic fluorescein transport changes in the blood-retinal barrier resulting in faster and increased drug penetration to the vitreous, whereas similar alterations in the anterior chamber barrier transport were only transitory.

Can vitreous fluorophotometry predict the necessity for photocoagulation? A 5-year follow-up study.

PURPOSE: To examine the long-term outcome of vitreous fluorophotometry including the predictability of retinopathic proliferative development in diabetic subjects. METHODS: 21 diabetic subjects were examined by long-term kinetic vitreous fluorophotometry and their barrier properties, as revealed by a permeability-index, were compared to a group of normal subjects. 13 diabetics were classified as having a high permeability-index, while 8 diabetics were classified as having a low permeability-index. The two groups were followed for 5 years with regard to development of proliferative retinopathy. RESULTS: 6 of 13 diabetics with a high permeability-index developed proliferative retinopathy within the 5-year follow-up period. This was in contrast to the low permeability-index group where none of 8 diabetics developed proliferative retinopathy. CONCLUSION: An increased permeability-index points towards an increased risk of development of proliferative retinopathy.

Anterior chamber fluorescein kinetics compared with vitreous kinetics in normal subjects.

PURPOSE: Describe and compare barrier properties in various parts of the eye. METHODS: Fluorophotometric measurements of the anterior chamber, vitreous and plasma fluorescein concentrations were performed and subjected to a kinetic two-compartment analysis. RESULTS: The overall barrier properties as revealed by a permeability-index was found to be 12.2% (anterior chamber) and 3.5% (vitreous). The apparent rate constant of permeation into the anterior chamber (Kin=1,59 h(-1)) was found to be significantly higher than into the vitreous (Kin=0,66 h(-1)) and into the apparent peripheral body compartment (Kin=0,23 h(-1)). The terminal rate constant of fluorescein disposition from the anterior chamber (Kout=0,21 h(-1)) was in agreement with the terminal disposition rate constant for plasma fluorescein (P=0,23 h(-1)), whereas elimination from the vitreous (Kout=0,072 h(-1)) was significantly slower. CONCLUSION: Compartment analysis of ocular fluorescein kinetics is suitable for the study of anterior and posterior barrier properties in the eye. In this study fluorescein elimination from the anterior chamber was restricted by terminal plasma fluorescein decay rather than by ocular tissue.

Anterior chamber and vitreous fluorescein kinetics in normal and diabetic subjects.

PURPOSE: Describe and compare drug exchange between various parts of the eye. METHODS: Fluorophotometric measurements of the anterior chamber, vitreous and plasma fluorescein concentrations were performed and subjected to a kinetic two-compartment analysis. RESULTS: The overall barrier properties as revealed by a permeability-index were found to be 12.2% and 3.5% for the anterior chamber and the vitreous, respectively. The apparent rate constant of permeation into the anterior chamber was found to be significantly higher than into the vitreous and the apparent peripheral body compartment. The terminal rate constant of fluorescein disposition from the anterior chamber was in agreement with the terminal disposition rate constant for plasma fluorescein, whereas elimination from the vitreous was significantly slower. CONCLUSION: Compartment analysis of ocular fluorescein kinetics is suitable for the study of anterior and posterior barrier properties in the eye. In this study fluorescein elimination from the anterior chamber was restricted by terminal plasma fluorescein decay rather than by ocular tissue.

Fluorometric evaluation of panretinal photocoagulation in diabetic subjects.

The effect of panretinal photocoagulation on the blood-retinal barrier was examined by long-term kinetic vitreous fluorophotometry in eight insulin treated diabetic subjects, before and one month after unilateral panretinal photocoagulation. The fluorophotometric investigations revealed an increased permeability-index following this treatment. A further analysis based upon a two-compartment fluorescein kinetic model revealed a decreased penetration rate constant together with increased zero-time concentration coefficients for fluorescein following panretinal photocoagulation. No alterations were observed in kinetic parameters in the group of untreated eyes. This points towards a delayed but increased fluorescein penetration to the vitreous following panretinal photocoagulation, probably indicating an increased net flux of fluorescein across the entire retina. In patients with unilateral proliferative retinopathy the permeability-index obtained from eyes with classified proliferative retinopathy was 18.1%, whereas the permeability-index from eyes without proliferative retinopathy was 15.4%. This relatively small difference seems to indicate that the main part of vitreous fluorescence comes from an increased penetration across the entire retina, whereas a direct leakage from the proliferations themselves is less in magnitude. This increased retinal penetration might possibly be caused by affected transport processes for fluorescein within the retina.

[Femoral head necrosis treated with total hip alloplasty]. / Nekrose af caput femoris behandlet med total hoftealloplastik.

One hundred and three patients with non-traumatic osteonecrosis of the femoral head had 144 primary total hip replacements performed. Average age was 47 (22-73) years. In 85 cases a cemented prosthesis, and in 45 cases an uncemented prosthesis was used, while 14 cases had a cemented femoral stem and an uncemented cup. At follow up, 25 patients had died, 13 patients had had a revision of the prosthesis, and two patients were lost to follow-up, leaving 63 patients (92 hips) for clinical and radiological evaluation. Kaplan-Meier plots for survival of the prosthesis were constructed, showing a total risk of failure of 8% at five years, increasing to 16% at seven years. In 89% of the patients without concomitant diseases, the clinical result was excellent or good. There was no difference in the clinical or radiological result in patients with cemented and uncemented prostheses. It is concluded, that the result after total hip replacement due to non-traumatic osteonecrosis of the femoral head is comparable to that of total hip replacement due to osteoarthrosis, and that an uncemented prosthesis can be expected to yield a result comparable to a cemented prosthesis.

Contrast enhanced computed tomography and magnetic resonance imaging in the diagnosis of recurrent disc herniation.

A positive result of re-operation in patients with recurrent symptoms after lumbar disc surgery is likely only if a new disc herniation is present. An improved ability to differentiate between recurrent disc herniation and scar tissue by contrast enhanced CT and MRI is suggested in earlier studies. In a prospective study 29 patients were selected for operation for suspected recurrent disc herniation. The inclusion of the patients was based on clinical symptoms and signs and myelography or non-enhanced CT. All patients were examined by CT and MRI both with and without intravenous contrast pre-operatively. The examinations were evaluated blind on a five point scale and statistical analysed by a regret function. Intravenous contrast improved the diagnostic power of both CT and MRI. MRI was superior to CT in both non-enhanced and enhanced examinations. MRI with intravenous contrast enhancement is proposed as the primary examination in patients with suspected recurrent disc herniation.

Heterogeneous cerebral glucose metabolism in normal pressure hydrocephalus.

The regional cerebral metabolic rate for glucose (rCMRglu) has never been investigated in large consecutive groups of patients with normal pressure hydrocephalus (NPH), a potentially treatable form of dementia with an unpredictable outcome after shunt surgery. Using PET and 18F-2-fluorodeoxyglucose, rCMRglu was studied in 18 patients who fulfilled hydrodynamic criteria for NPH and in whom a biopsy of the frontal cortex was obtained. When compared with an age matched group of 11 healthy subjects, the patients with NPH showed a significant rCMRglu reduction in all cortical and subcortical regions of interest. Individual metabolic patterns, however, disclosed a large topographical heterogeneity. Furthermore, histopathological examination identified Alzheimer's disease or cerebrovascular disease in six cases, and no parenchymal disease or non-specific degenerative processes in the remaining 12. After separating the patients according to the histological diagnosis, the rCMRglu patterns were still heterogeneous, the abnormalities ranging from focal to diffuse in both subgroups. After shunt operation, 11 patients did not improve or worsened clinically. Six patients improved; of those, two had Alzheimer changes and two cerebrovascular changes in their biopsy. The metabolic pattern of these six patients did not differ from the rest of the NPH group. The results indicate that the NPH syndrome may be non-specifically associated with different degenerative disorders. The metabolic heterogeneity, together with the heterogeneous histopathological findings, indicate the necessity of reevaluating the pathogenesis of the NPH syndrome, and may account for the high variability in the success rate of shunt surgery series.

Dofetilide reduces the incidence of ventricular fibrillation during acute myocardial ischaemia. A randomised study in pigs.

OBJECTIVE: The aim was to investigate whether dofetilide, a new selective cardiac potassium channel blocker, would reduce the incidence of ischaemia induced ventricular fibrillation in closed chest pigs. METHODS: A randomised, blinded, and placebo controlled study was performed in 32 closed chest pigs with a body weight of 70-90 kg. The animals were given a dofetilide/placebo bolus of 25 micrograms.kg-1 over a 10 min period followed by a maintenance dose of 12.5 micrograms.kg-1.h-1 for the next 130 min. Electrocardiograms were recorded during sinus rhythm and during atrial pacing, before (t0) and 20 min (t20) after the beginning of drug treatment. Twenty minutes after the start of drug treatment, acute myocardial ischaemia was induced by inflation of a percutaneous transluminal coronary angioplasty (PTCA) balloon placed in the left anterior descending coronary artery proximal to the first diagonal branch. If ventricular fibrillation occurred during the 2 h ischaemia period the balloon was deflated and defibrillation attempted by dc shocks (360 joules) up to a maximum of 10 shocks. RESULTS: Basal characteristics for the dofetilide group (n = 16) and the placebo group (n = 16) were similar: body weight 76.1(SD 5.4) kg v 75.4(4.4) kg; heart weight 296(29) g v 302(43) g; and heart rate (RR interval) 854(261) ms v 800(307) ms. During atrial pacing 100 beats.min-1 the paced QT interval (QTp) measured at t0 in the dofetilide group and the placebo group were similar, at 335(36) ms v 330(31) ms, respectively. During drug treatment (t20) the QTp interval increased to 412(38) ms in the dofetilide group (p < 0.001) whereas a much smaller increase to 341(32) ms was observed in the placebo group (p < 0.05). The heart rate and ST elevation in the two groups were similar during coronary artery occlusion. During the 2 h ischaemic period, ventricular fibrillation occurred in 6/16 (38%) of the dofetilide treated pigs, and in 13/16 (81%) of the placebo treated pigs (p < 0.01). Defibrillation was successful in 5/6 (83%) and 6/13 (46%) of the animals, respectively (p = 0.3). CONCLUSIONS: Dofetilide significantly reduces the incidence of ischaemia induced ventricular fibrillation in closed chest pigs.

Catheter-implanted prosthetic heart valves. Transluminal catheter implantation of a new expandable artificial heart valve in the descending thoracic aorta in isolated vessels and closed chest pigs.

A new expandable artificial heart valve was developed for implantation by a transluminal catheter technique without using thoracotomy or extracorporeal circulation. The aim of this study was to implant the valve in isolated vessels of the descending thoracic aorta as well as in closed chest pigs, and furthermore to study the prosthesis' mechanical stability and the valve function. The artificial valve was made by mounting a porcine aortic valve on an expandable stent. Before implantation, the stent-valve was compressed on a deflated balloon catheter and mounted inside an introducer sheath. After intravascular introduction to the descending thoracic aorta the stent-valve was discharged from the sheath. Implantation was performed by balloon inflation which expanded the stent-valve to a diameter exceeding the internal vessel's diameter. After balloon deflation the stent-valve maintained an expanded configuration ensuring a stable fixation against the vessel wall. In vitro implantations were performed in 36 isolated descending thoracic aorta specimens obtained from 80 kg pigs. Mechanical stability was evaluated by applying a downing load to the prosthesis. No displacement occurred at loads < or = 1 kg when a large balloon (31 mm) was used for implantation. Transvalvular pressure differences between 11-47 mmHg (median) were obtained at antegrade flowrates between 5-8 l/min. Furthermore, only moderate leakage flows were measured during retrograde perfusion. In vivo implantations were performed in six 80 kg pigs. Implantation was safe and easy, and angiograph and haemodynamic evaluations revealed essentially no stenosis or regurgitation. No complications in migration, perforation, hemorrhage or thrombosis were observed. This study indicates a good mechanical stability and valve function of the new expandable artificial valves.

Long-term kinetic vitreous fluorophotometry.

Fluorophotometric measurements of vitreous and plasma fluorescence were performed in 14 normal subjects up to 24 h after injection of a single intravenous dose of sodium fluorescein. The data were subjected to a kinetic two-compartmental analysis, including the determination of the transfer rate constants between the central and the peripheral compartment (K12 and K21) as well as between the central and vitreous compartment (K(in) and K(out)). In the central compartment (plasma) a mean terminal disposition rate constant (beta) of free fluorescein of 0.23 h-1 was found, corresponding to a half-life of 3.01 h. The vitreous fluorescence reached a maximum 2-5 h after the injection and then declined monoexponentially and very slowly (t1/2 = 9.6 h). The rate constant of permeation into the eye (K(in)) was found to be 0.66 h-1, while the rate constant of elimination of fluorescein from the vitreous was 0.072 h-1 (K(out)). Kin was found to be significantly higher than K12, presumably indicating an active transport mechanism for fluorescein located at the blood-ocular barrier. K(out) was significantly lower than K21, reflecting a slow vitreous elimination of fluorescein. A permeability index defined as the percentage ratio between the areas under the vitreous and the plasma concentration curves was found to be 3.5%, illustrating the poor penetration of fluorescein into the vitreous. Kinetic long-term fluorophotometry appears to be a promising new tool in the study of the blood-ocular barrier.

Long-term kinetic vitreous fluorophotometry in normal and diabetic subjects.

Nine normal and 24 diabetic subjects were examined by long-term vitreous and plasma fluorescein fluorophotometry and the observed concentration profiles were described by biexponential time courses. The rate constant of elimination of fluorescein from the body (K10) was significantly decreased in diabetics with background and proliferative retinopathy, presumably caused by affection of the liver and possibly representing alterations in membranes of liver cells. Increased kidney albumin excretion was observed with increasing degree of retinopathy. The apparent rate constant of fluorescein penetration into the eye (Kin) was found significantly decreased in background as well as in proliferative retinopathy; while the permeability index, calculated as areas under vitreous and plasma fluorescein curves, was significantly increased. In the normal subjects Kin was significantly higher than the rate constant of fluorescein transfer (K12) from the apparent central to the peripheral tissue compartment, whereas in the diabetics this difference was only found in the group with background retinopathy. The findings seem compatible with the concept that the breakdown of the blood-ocular barrier could be caused at least partly by affection of an active transport system for fluorescein, but thickening and compositional changes of the basement membranes in the eye might also be of importance.

Fluorescein and fluorescein glucuronide in plasma.

The evaluation of the blood-ocular barrier for fluorescein requires the measurement of free and unconjugated fluorescein in plasma. This study introduces a new and simple method for the determination of free fluorescein in plasma on the basis of determined total free plasma fluorescence and the free fraction of fluorescence. An excellent good correlation between differential spectrofluorophotometry and this new method is demonstrated. After intravenous administration of sodium fluorescein, the contribution of fluorescein glucuronide to total free plasma fluorescence was evaluated on basis of the areas under the plasma concentration/time curves for fluorescein and fluorescein glucuronide, respectively. After 1 h 8.2% of total free fluorescence in plasma was found to originate from fluorescein glucuronide and after 24 h 18.3% originated from this metabolite. It was concluded that although plasma fluorescein glucuronide measurements are important in the exact evaluation of the blood-ocular barrier, the contribution of fluorescein glucuronide to vitreous fluorescence after intravenous fluorescein administration seems to be of minor magnitude.