Effect on non-vascular outcomes of lowering LDL cholesterol in patients with chronic kidney disease: results from the Study of Heart and Renal Protection.

BACKGROUND: Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of major atherosclerotic events among patients with chronic kidney disease (CKD), with no evidence of an excess risk of cancer or death from any non-vascular cause. However, non-randomized data have suggested that statin therapy may have effects (both adverse and beneficial) on particular non-vascular conditions that do not cause death. METHODS: The Study of Heart and Renal Protection (SHARP) randomized patients with CKD to simvastatin 20 mg plus ezetimibe 10 mg (simvastatin/ezetimibe) daily versus matching placebo. Participants were followed up at least 6 monthly and all post-randomization serious adverse events (SAEs) were recorded. This supplementary analysis reports the effects of treatment on non-vascular SAEs, overall, by system of disease, by baseline characteristics, and by duration of follow-up. RESULTS: During a median of 4.9 years follow-up, similar numbers of participants in the two groups experienced at least one non-vascular SAE (3551 [76.4%] simvastatin/ezetimibe vs 3537 [76.6%] placebo; risk ratio [RR] 0.99, 95% confidence interval [CI] 0.95-1.04). There was no good evidence of any significant effect of simvastatin/ezetimibe on SAEs attributed to any particular nonvascular disease system (of 43 comparisons, only 3 yielded an uncorrected p value < 0.05, of which the smallest was p = 0.02). The relative risk of any nonvascular SAE did not vary significantly among particular prognostic subgroups or by duration of follow-up. CONCLUSIONS: In the SHARP trial, allocation to simvastatin/ezetimibe combination therapy was not associated with any significant non-vascular hazard. TRIALS REGISTRATION: SHARP was retrospectively registered after the first participant was enrolled in 2003 at ISRCTN (ISRCTN54137607 on 31 January 2005: http://www.isrctn.com/ISRCTN54137607) and ClinicalTrials.gov (NCT00125593 on 29 July 2005: https://clinicaltrials.gov/ct2/show/NCT00125593).

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.

BACKGROUND: Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy. METHODS: We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation. FINDINGS: In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11-18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7-19; p<0·0001), in coronary revascularisation of 19% (95% CI 15-24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5-26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76-0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87-0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74-0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81-0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84-1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81-1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92-1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96-1·04; p=0·9), even at low LDL cholesterol concentrations. INTERPRETATION: Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50%. FUNDING: UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.

Development and role of GABA(A) receptor-mediated synaptic potentials during swimming in postembryonic Xenopus laevis tadpoles.

We have investigated the contribution of GABA(A) receptor activation to swimming in Xenopus tadpoles during the first day of postembryonic development. Around the time of hatching stage (37/8), bicuculline (10-50 microM) causes a decrease in swim episode duration and cycle period, suggesting that GABA(A) receptor activation influences embryonic swimming. Twenty-four hours later, at stage 42, GABA(A) receptor activation plays a more pronounced role in modulating larval swimming activity. Bicuculline causes short, intense swim episodes with increased burst durations and decreased cycle periods and rostrocaudal delays. Conversely, the allosteric agonist, 5beta-pregnan-3alpha-ol-20-one (1-10 microM) or the uptake inhibitor, nipecotic acid (200 microM) cause slow swimming with reduced burst durations and increased cycle periods. These effects appear to be mainly the result of GABA release from the spinal terminals of midhindbrain reticulospinal neurons but may also involve spinal GABAergic neurons. Intracellular recordings were made using KCl electrodes to reverse the sign and enhance the amplitude of chloride-dependent inhibitory postsynaptic potentials (IPSPs). Recordings from larval motoneurons in the presence of strychnine (1-5 microM), to block glycinergic IPSPs, provided no evidence for any GABAergic component to midcycle inhibition. GABA potentials were observed during episodes, but they were not phase-locked to the swimming rhythm. Bicuculline (10-50 microM) abolished these sporadic potentials and caused an apparent decrease in the level of tonic depolarization during swimming activity and an increase in spike height. Finally, in most larval preparations, GABA potentials were observed at the termination of swimming. In combination with the other evidence, our data suggest that midhindbrain reticulospinal neurons become involved in an intrinsic pathway that can prematurely terminate swim episodes. Thus during the first day of larval development, endogenous activation of GABA(A) receptors plays an increasingly important role in modulating locomotion, and GABAergic neurons become involved in an intrinsic descending pathway for terminating swim episodes.

A role for slow NMDA receptor-mediated, intrinsic neuronal oscillations in the control of fast fictive swimming in Xenopus laevis larvae.

In larvae of the amphibian, Xenopus laevis, spinal neurons which are active during fictive swimming also display tetrodotoxin-resistant membrane potential oscillations following the coactivation of N-methyl-DL-aspartate (NMDA) and 5-hydroxytryptamine (serotonin or 5-HT) receptors (Scrymgeour-Wedderburn et al., 1997; Eur. J. Neurosci., 9, 1473-1482). The oscillations are slow (approximately 0.5 Hz) compared with swimming (approximately 7-35 Hz) raising doubt over their contribution to the cycle by cycle depolarizations occurring during swimming. We investigated an alternative: that the intrinsic oscillations modulate swimming activity over many consecutive cycles. Bath application of NMDA induced continuous fictive swimming that differed between embryonic and larval preparations. In 81% of larval preparations (n = 36), there was a slow (approximately every 2 s) rhythmic modulation of ventral root activity in which burst durations and intensities increased as cycle periods decreased. This pattern of activity was enhanced rather than abolished following blockade of glycine and gamma-aminobutyric acid (GABA) A receptors and presumably therefore resulted from a periodic increase in the excitation of motor neurons. To determine whether this slow rhythm resulted from intrinsic, 5-HT-dependent membrane potential oscillations, larvae were spinalized to prevent the release of 5-HT from brainstem raphe neurons. The resulting pattern of NMDA-induced activity lacked any slow modulation. The slow modulation could also be enhanced by the bath application of a 5-HT receptor agonist (5-carboxamidotryptamine) and abolished either by the addition of an antagonist (pindobind-5-HT1A) or by removal of magnesium ions, providing more direct evidence for a contribution of intrinsic oscillations. Thus, the 5-HT-dependent intrinsic oscillations modulate NMDA-induced swimming activity over several consecutive cycles.

Development and aminergic neuromodulation of a spinal locomotor network controlling swimming in Xenopus larvae.

In this article we review our research on the development and intrinsic neuromodulation of a spinal network controlling locomotion in a simple vertebrate. Swimming in hatchling Xenopus embryos is generated by a restricted network of well-characterized spinal neurons. This network produces a stereotyped motor pattern which, like real swimming, involves rhythmic activity that alternates across the body and progresses rostrocaudally with a brief delay between muscle segments. The stereotypy results from motoneurons discharging a single impulse in each cycle; because all motoneurons appear to behave similarly there is little scope for altering the output to the myotomes from one cycle to the next. Just one day later, however, Xenopus larvae generate a more complex and flexible motor pattern in which motoneurons can discharge a variable number of impulses which contribute to ventral root bursts in each cycle. This maturation of swimming is due, in part, to the influence of serotonin released from brain-stem raphespinal interneurons whose axonal projections innervate the cord early in larval life. Larval swimming is differentially modulated by both serotonin and by noradrenaline: serotonin leads to relatively fast, intense swimming whereas noradrenaline favors slower, weaker activity. Thus, these two biogenic amines select opposite extremes from the spectrum of possible output patterns that the swimming network can produce. Our studies on the cellular and synaptic effects of the amines indicate that they can control the strength of reciprocal glycinergic inhibition in the spinal cord. Serotonin and noradrenaline act presynaptically on the terminals of glycinergic commissural interneurons to weaken and strengthen, respectively, crossed glycinergic inhibition during swimming. As a result, serotonin reduces and noradrenaline increases interburst intervals. The membrane properties of spinal neurons are also affected by the amines. In particular, serotonin can induce intrinsic oscillatory membrane properties in the presence of NMDA. These depolarizations are slow compared to the cycle periods during swimming and so may contribute to enhancement of swimming over several consecutive cycles of activity.

Voltage oscillations in Xenopus spinal cord neurons: developmental onset and dependence on co-activation of NMDA and 5HT receptors.

The development of intrinsic, N-methyl-D-aspartate (NMDA) receptor-mediated voltage oscillations and their dependence on co-activation of 5-hydroxytryptamine (5HT) receptors was explored in motor neurons of late embryonic and early larval Xenopus laevis. Under tetrodotoxin, 100 microM NMDA elicited a membrane depolarization of around 20 mV, but did not lead to voltage oscillations. However, following the addition of 2-5 microM 5HT, oscillations were observed in 12% of embryonic and 70% of larval motor neurons. The voltage oscillations depended upon co-activation of NMDA and 5HT receptors since they were curtailed by selectively blocking NMDA receptors with D-2-amino-5-phosphonovaleric acid (APV) or by excluding Mg2+ from the experimental saline. 5HT applied in the absence of NMDA also failed to elicit oscillations. Oscillations could be induced by the non-selective 5HT1alpha receptor agonist, 5-carboxamidotryptamine (5CT) and both 5HT- and 5CT-induced oscillations were abolished by pindobind-5HT1, a selective 5HT1alpha receptor antagonist. To test whether 5HT enables voltage oscillations by modulating the voltage-dependent block of NMDA channels by Mg2+, membrane conductance was monitored under tetrodotoxin. Although 5HT caused membrane hyperpolarization of 4-8 mV, there was little detectable change in conductance. NMDA application caused an approximate 20 mV depolarization and an 'apparent' decrease in conductance, presumably due to the conductance pulse bringing the membrane into a voltage region where Mg2+ blocks the NMDA ionophore. 5HT further decreased conductance, which we propose is due to its enhancement of the voltage-dependent Mg2+ block. When the membrane potential was depolarized by approximately 20 mV via depolarizing current injection (to mimic the NMDA-induced depolarization), 5HT increased rather than decreased membrane conductance. Furthermore, 5HT did not affect the increase in membrane conductance following NMDA applications in zero Mg2+ saline. The results suggest that intrinsic, NMDA receptor-mediated voltage oscillations develop in a brief period after hatching, and that they depend upon the co-activation of 5HT and NMDA receptors. The enabling function of 5HT may involve the facilitation of the voltage-dependent block of the NMDA ionophore by Mg2+ through activation of receptors with 5HT1alpha-like pharmacology.

Pre- and postsynaptic modulation of spinal GABAergic neurotransmission by the neurosteroid, 5 beta-pregnan-3 alpha-ol-20-one.

The neuroactive steroid 5 beta-pregnan-3 alpha-ol-20-one (5 beta 3 alpha) modulates GABAA receptor function by potentiating postsynaptic GABA currents. While much is now known about the postsynaptic action of neurosteroids, far less is known about how they affect neurotransmission. We have investigated the synaptic actions of 5 beta 3 alpha in a simple vertebrate model, the embryo of the clawed toad, Xenopus laevis, in which a known GABAergic pathway, activated by the rostral cement gland, terminates swimming when the animal contacts an obstruction. Cement gland stimulation evokes bicuculline-sensitive inhibitory postsynaptic potentials (IPSPs) in motorneurones that terminate swimming and which are greatly enhanced by the presence of (1-5 microM) 5 beta 3 alpha. In the presence of TTX, depolarising inhibitory potentials are recorded with KCl-filled microelectrodes reflecting the spontaneous release of transmitter. The majority are glycinergic with durations of 20-80 ms and are blocked by strychnine while the remainder are GABAergic with durations of 90-200 ms and are abolished by bicuculline. We show here that, in the presence of 5 beta 3 alpha, the spontaneous GABA IPSPs lengthen dramatically in some cases to over 500 ms, but the glycine potentials are unaffected. The steroid has no other detectable postsynaptic effects in that the range of amplitudes of GABA potentials is unaffected and there is no change in the resting membrane potential. However, 5 beta 3 alpha also caused a marked increase in the rate of occurrence of spontaneous GABA potentials. This suggests a novel presynaptic site of action in which the steroid enhances the probability of vesicular GABA release from GABA terminals.

Spontaneous intracerebral hemorrhage following carotid endarterectomy. Experience of 328 operations from 1983-1988.

In a consecutive series of 328 carotid endarterectomies there were two cases of postoperative intracerebral hemorrhage. The patients with transient ischemic attacks and subsequent major cerebral infarction had repair of their very tight carotid stenosis. Each developed intracerebral hemorrhage after a symptom free interval and hypertension was uncontrolled during the postoperative period. Hypertension is a significant complication of carotid endarterectomy and may be a prominent factor in the development of intracerebral hemorrhage after carotid endarterectomy. Also defective cerebrovascular autoregulation in chronic ischemic brain regions may predispose patients to intracerebral hemorrhage.

[Diagnosis and interdisciplinary therapy of spinal cord compression caused by spinal metastases]. / Diagnostik und interdisziplinäre Therapie bei Rückenmarkskompression durch Wirbelsäulenmetastasen.

Metastatic tumours of the bone system occur up to 60% in the spinal cord. The epidural spinal cord compression is also found by metastatic tumour, so patients with metastatic disease in this localisation carry a poor prognosis. From 1986 to 1988 35 patients with symptomatic spine metastasis are operated upon. 43% of these patients recover their capability of walking. 90% from the operated collective show a reduction of pain. The primary tumour is first found from cancer of the lung and second from the kidneys. The most common localisation of metastatic tumour is the thoracic spine. The ratio from male to female is 2:1. If the risk of operation and differential therapy is discussed, the decompression and tumour resection will be the first. The concept for postoperative mobilisation and therapy concludes the stabilisation of spinal cord with internal fixation. Treatment of metastatic tumours takes aim at the improvement of life quality.

[Epidural hematoma following peridural anesthesia]. / Epidurales Hämatom nach Periduralanaesthesie.

Complications of epidural anesthesia are uncommon, but lesions are possible without technical failure. Neurological symptoms increase progressively with spinal cord compression; early recognition and treatment are imperative. Operative decompression is in most cases the only therapeutic option. This case report aims to call attention to the possibility of epidural hematoma following epidural anesthesia.

Risk factors of recurrent disc herniation.

The causes of 100 disc herniation reoperations are analyzed and discussed in a review: we find a recurrence of disc herniation at the same level in 62% of the reoperated cases, a pseudorecurrence in 24% and a closely connected nerve route in 14%. We reoperated on 44% within the first two years and on 69% within the first five years. The interval between the operations is longer, when there is a short painfree interval following surgery and also a long history of pre-operative symptoms. The variables of risk of prolapse recurrence are recorded as a risk score. Retrospectively, 64% belonged to a risk group according to this score. The correlation between operation intervals and scores show, that patients with a short interval have high scores.

[Etiology of the recurrence of lumbar intervertebral disk displacement]. / Atiologie lumbaler Bandscheibenvorfallrezidive.

In a review for reasons of 100 disc prolapses reoperations we found in 62% a recurrence of disc prolapse at the same level, in 24% a recurrence at a different level, whereas in 14% we found that the nerve route was closely connected. We reoperated 44% in the first two years and 69% in the first five years. The time between the operations was prolonged if there was a short period of time for relief of pain after operation and a long period of preoperative symptoms. The variables of risk of a disk prolapse recurrence are recorded in a risk score, in which 64% of the patients belonged retrospectively to a risk group. The correlation between operation interval and score points showed that patients with short interval had high score ratings.