Exfoliative glaucoma and primary open-angle glaucoma: associations with death causes and comorbidity.

PURPOSE: To investigate whether type of glaucoma or use of acetazolamide are associated with main cause of death and comorbidity. MATERIAL AND METHODS: The survival data, including date and cause of death, for 1147 patients with capsular or simple glaucoma who were ultimately hospitalized at the Eye Department, National Hospital, Oslo, between 1961 and 1970, were analysed. Binary logistic regression was carried out to investigate the patterns of death causes and comorbidity in subgroup analyses. RESULTS: Patients with exfoliative glaucoma (XFG) and those with primary open-angle glaucoma (POAG) showed no significant differences in rates of death caused by acute cerebrovascular diseases, cardiac diseases and cancer. Interestingly, we found that chronic cerebral diseases such as senile dementia, cerebral atrophy and chronic cerebral ischaemia (n = 81) were more common in patients with XFG than in those with POAG (p = 0.01) and in the group of acetazolamide users (p = 0.03). Patients with XFG had a higher probability of developing an acute cerebrovascular disease than patients with POAG (n = 228, p = 0.03). CONCLUSION: In this retrospective study, we found that comorbidity with acute cerebrovascular disease and chronic cerebral diseases (senile dementia, cerebral atrophy and chronic cerebral ischaemia) were more common in patients with XFG than in patients with POAG. Prospective data are needed in order to conclude upon the associations found in this study.

Comparison of survival of exfoliative glaucoma patients and primary open-angle glaucoma patients: impact of acetazolamide use.

PURPOSE: To compare the survival rates of patients with exfoliative glaucoma (XFG) and those with primary open-angle glaucoma (POAG), and to establish whether the use of acetazolamide has any influence on survival. METHODS: The survival data, including date and cause of death, for 1147 patients with XFG or POAG who were ultimately hospitalized at the Eye Department, National Hospital, Oslo, between 1961 and 1970, were analysed retrospectively. The Cox proportional hazard model was used in the survival analyses. RESULTS: No statistically significant differences in survival were found between patients with XFG and those with POAG (p = 0.85). As expected, female gender and younger age at diagnosis were associated with longer survival periods. Surprisingly, we found that patients with more recent birth dates had relatively lower survival rates than patients with earlier birth dates; when this was included in the analyses, the use of acetazolamide was found to be associated with reduced survival (n = 492, p = 0.02).

Reduced calcium tolerance in rat cardiomyocytes after myocardial infarction.

During ischaemia and reperfusion the intracellular Na+ concentration is elevated in the cardiomyocytes and the cells are depolarized, both favouring reverse mode Na,Ca-exchange loading of the cell with Ca2+. We examined whether cardiomyocytes from rats with congestive heart failure (CHF) and younger rats (HINCX) which both have a high expression of the Na,Ca-exchanger protein (NCX) showed reduced tolerance to extracellular Ca2+. The CHF was induced in Isofluran anaesthetized rats by left coronary artery ligation. Isolated cardiomyocytes were loaded with Fura-2AM and 140 mm Na+ and exposed to 0.05 mm Ca2+. Expression of the Na,Ca-exchanger protein was analysed. Fura-2 340/380 ratio rose more rapidly in HINCX and CHF than in SHAM, and the rise was abolished by Ni2+. Hypercontracture developed more frequently in HINCX and CHF than in SHAM cells. The amount of NCX was 54% higher in HINCX and 76% higher in CHF compared with SHAM. Na+-loaded cardiomyocytes from CHF and HINCX rats are more susceptible to Ca2+ overload than SHAM cells because of the increased capacity for Na,Ca-exchange.

Mechanisms of cardiomyocyte dysfunction in heart failure following myocardial infarction in rats.

Available information regarding the cellular and molecular mechanisms for reduced myocardial function after myocardial infarction (MI) is scarce. In rats with congestive heart failure (CHF), we examined cardiomyocytes isolated from the non-infarcted region of the left ventricle 6 weeks after ligation of the left coronary artery. Systolic left-ventricular pressure was reduced and diastolic pressure was markedly increased in the CHF-rats. The cardiomyocytes isolated from the CHF-hearts had increased resting length, reduced fractional shortening by 31% and a 34% increase in time to 90% relaxation compared to sham cells (P<0.01 for all). Peak L-type calcium currents were not significantly changed, but peak calcium transients measured with fura-2 were reduced by 19% (P<0.01). Moreover, the decline of the calcium transients as measured by the time constant of a monoexponential function was significantly increased by 26% (P<0.01). We also examined the contribution of the Ca2+-ATPase of the sarcoplasmic reticulum (SR) in the removal of cytosolic Ca2+ during relaxation by superfusing cells with 1 microM thapsigargin that effectively inhibits the Ca2+-ATPase. Relaxation time in CHF-cells was significantly less prolonged when this drug was used (P<0.01). This suggests that other mechanisms, probably the Na+-Ca2+ exchanger, contribute significantly to the relaxation rate in CHF. Simultaneous measurements of fura-2 transients and mechanical shortening did not reveal any alteration in the calcium-myofilament sensitivity in CHF. Our study clearly shows reduced shortening and prolonged relaxation in cardiomyocytes isolated from non-infarcted region of the left ventricle in heart failure. Moreover, we were able to relate the observed cardiomyocyte dysfunction to changes in specific steps in the excitation-contraction coupling.

Reduced myocardial Na+, K(+)-pump capacity in congestive heart failure following myocardial infarction in rats.

We examined changes in expression and function of the cardiac Na+, K(+)-pump in a post-infarction rat model of hypertrophy and congestive heart failure (CHF). Myocardial infarction was induced by ligation of the left coronary artery in Wistar rats and hearts were obtained from animals with CHF and from sham operated rats after 6 weeks. In the CHF group the ratio of heart weight to body weight was 70% greater compared to sham (*P < 0.05) and all left-ventricular end-diastolic pressures (LVEDP) were above 15 mmHg. The expression of the alpha 1- and beta 1-subunits (mRNA and protein) of the Na+, K(+)-pump was not significantly different in CHF and sham. As compared to sham the alpha 2 isoform, mRNA and protein levels were lower in CHF hearts by 25 and 55%, respectively, whereas the alpha 3 isoform mRNA was greater by 120% in CHF. The alpha 3 protein was not detectable in sham but a prominent band was seen in CHF. Cell volume of isolated cardiomyocytes was 30% larger in CHF. Cardiomyocytes containing the Na+ sensitive fluorescent dye SBFI were loaded to an intracellular Na+ concentration ([Na+]i] of about 140 mM in a K(+)- and Mg(2+)-free medium (140 mM Na+, free Ca2+ of 10(-8) M). To avoid back leak of Na+ and to ensure no voltage effects on the Na+, K(+)-pump extracellular Na+ was subsequently removed, and 6 mM Mg2+ was added to the superfusate, The Na+, K(+)-pump was then reactivated by 10 mM Rb+. SBFI fluorescence ratio decreased mono-exponentially with a time constant (tau) of 191 +/- 15 s in sham (n = 8) and 320 +/- 38 s in CHF (n = 9) rats (P < 0.01). These changes in fluorescence indicate that the maximum rate of decline of [Na+]i from 100 to 35 mM was 39% (P < 0.005) slower in CHF compared to sham, whereas maximum pump rate per cell was not significantly altered (9.0 +/- 0.7 fmol/s in sham and 7.1 +/- 0.7 fmol/s in CHF cells). The [Na+]i which caused 50% pump activation (k0.5) was also not altered in CHF (40 mM in both groups). We conclude that the number of Na+, K(+)-pumps per cell was maintained in CHF but an isoform switch of the alpha 3-replacing the alpha 2-isoform occurred. However, maximum Na+, K(+)-pump rate in terms of rate of change of [Na+]i was significantly attenuated in CHF, most likely as a result of increased cell size.

A new improved way of making double-barrelled ion-selective micro-electrodes.

The methods published for fabrication of double-barrelled ion-selective micro-electrodes are often difficult to follow and give inconsistent results. We describe here a new improved way of making double-barrelled ion-selective micro-electrodes from theta-style glass capillaries that offers several refinements which improve reproducibility: (1) good control of silanization and (2) dry-bevelling to assure no inter-barrel silane contamination and to minimize the signal-to-noise ratio by increasing the tip diameter, without compromising the sharpness of the tip.

Calcium induced contracture stimulates Na,K-pump rate in isolated sheep cardiac Purkinje fibers.

By keeping intracellular Na+ (aiNa) low, the Na,K-pump can prevent Ca2+ overload of cardiomyocytes. We therefore examined whether Ca2+ stimulates Na,K-pump activity in sheep cardiac Purkinje fibers. By removing Ca2+, Mg2+ and K+, the fibers depolarized and aiNa rose to 70 mM. After addition of 6 mM Mg2+ and lowering extracellular Na2+ to 29 mM, 30mM Rb+ was added, and over 10-15 min aiNa recovered to 3-7 mM. Two load-recovery cycles were conducted in 10 fibers. During one of the cycles Ca2+ (0.1-1.0 mM) was added before Rb+, causing a contracture. During recovery aiNa fell faster during Ca2+ contracture than in control cycles. Between 30 and 20 mM the rates were -10.0+/-1.6 and -5.4+/-0.6 mM/min, respectively (P<0.05). In Ca2+-exposed fibers tension fell almost parallel with aiNa. Na, K-pump reactivation caused membrane potential (Vm) to hyperpolarize transiently to -70 mV. Ca2+ did not affect membrane conductance. For a given aiNa during reactivation, Vm was more negative during Ca2+ contracture and depolarized faster (P<0.05). Intracellular pH (pHi) fell from 7.11+/-0.05 to 6.92+/-0.08 (n.s.) during control load-recovery cycles and was 6.83+/-0.14 at the end of the Ca2+ cycles. ATP content of the fibers did not change significantly through two complete load-recovery cycles, but creatine phosphate (CrP) fell by about 40%. By fitting the data to a model incorporating the Hill equation we show that during Ca2+-induced contracture maximum Na,K-pump rate (Vmax) was increased by about 40% and aiNa that causes 50% pump activation (k0.5) was lowered from 21. 2+/-1.6 to 15.5+/-1.4 mM.

Fuzzy space and control of Na+, K(+)-pump rate in heart and skeletal muscle.

Since intracellular Na+ activity (aiNa) is one important determinant of Na+ K(+)-pump rate as well as excitability and the finely tuned contractility, it is surprising that the relation between aNa and pump rate reported by different authors has kQ5 varying between 10 and 40 mmol L-1. Other data also point to a variable relation between pump rate and aiNa. During stimulation of isolated rat soleus muscles at 2 Hz, ouabain-sensitive 86Rb uptake was increased in spite of the intracellular Na+ remaining unaltered. In isolated cardiomyocytes, a transient Na+. K(+)-pump current was observed upon activation by extracellular K+ in spite of good control of aiNa. Na(+)-loaded, isolated, sheep cardiac Purkinje fibres initially hyperpolarized over a period of up to 1 min upon activation of the Na+, K+ pump with no detectable change of aiNa. These examples are compatible with the existence of a micro-environment close to the membrane where diffusion is slower than in the rest of the cytosol, so that local aiNa may fluctuate or gradients may develop as visualized by Wendt-Gallitelli at al. (1993). We conclude that the reported relationships between Na+, K+, pump rate and aiNa in intact cells probably underestimate the true affinity of the Na+, K+ pump for Na+ due to a functional diffusion barrier beneath the sarcolemma, and also because of incomplete cell dialysis in whole-cell voltage clamp experiments. The Na+, K+ pump seems to be preferentially supplied with Na+ from the outside through neighbouring channels and transporters.

[Chloroquine poisoning]. / Forgiftning med klorokin.

More travel abroad and changes in the prevalence of malaria have made chloroquine more widely prescribed for prophylaxis and treatment. Acute chloroquine poisoning is life threatening, involving high risk of death caused by cardiac arrest, arrhythmia and apnoea within a few hours of ingestion. Rapid absorption of the drug from the gastrointestinal tract, and high toxicity, produce the sudden clinical symptoms after overdose. We describe the case of a 16 year-old woman who ingested 1.95 grams of chloroquine base. After an initially short period of apnoea, she was successfully treated with mechanical ventilation and large doses of diazepam. Plasma chloroquine levels showed an initial peak of 6.7 mumol/l. The pharmacokinetics of the drug and its major metabolite, the clinical features of an overdose of chloroquine and the principles of treatment are discussed.