Rabdomiólisis y hepatotoxicidad grave por interacción entre ritonavir y simvastatina. ¿Puede emplearse la estatina más coste-efectiva en todos los pacientes infectados por el virus de la inmunodeficiencia humana?

Introduction

Drugs like statins may induce rhabdomyolysis. Simvastatin and lovastatin have a high hepatic metabolism and their potential toxicity could be increased by interactions with other drugs that reduce their metabolism.

Patients and methods

A case-report is presented of an HIV-infected patient treated with antiretroviral drugs who developed a rhabdomyolysis-induced renal failure and liver toxicity when simvastatin was substituted for atorvastatin. A literature review is also presented.

Results

The patient required hospital admission and showed a favorable response after hydration and urine alkalinization. There were 4 additional cases published of which there was one death.

Conclusions

Drug-drug interactions can increase the risk of statin induced rhabdomyolysis. In order to evaluate them properly, physicians at all levels of clinical care should be aware of all drugs prescribed to their patients and the contraindicated combinations.     

Viabilidad de las muestras ganglionares obtenidas por ecobroncoscopia para el estudio de alteraciones epigenéticas en pacientes con cáncer de pulmón

Introduction

The diagnosis of microscopic lymph node metastasis in lung cancer is challenging despite the constant advances in tumor staging. The analysis of the methylation status of certain genes in lymph node samples could improve the diagnostic capability of conventional cyto-histological methods. The aim of this study was to demonstrate the feasibility of methylation studies using cytological lymph node samples.

Methods

Prospective study including 88 patients with a diagnosis or strong suspicion of non-small cell lung cancer, in which an echobronchoscopy was performed on mediastinal or hilar lymph nodes for diagnostic and/or staging. DNA was extracted from cytological lymph node samples and sodium bisulfite modification was performed. Methylation studies for p16/INK4a and SHOX2 were accomplished by MS-qPCR and pyrosequencing.

Results

The methodology used in our study yielded optimal/good DNA quality in 90% of the cases. No differences in DNA concentration were observed with respect to the lymph node biopsied and final diagnosis. Methylation analyses using MS-qPCR and pyrosequencing were not possible in a small number of samples mainly due to low DNA concentration, inadequate purity, fragmentation and/or degradation as a consequence of bisulfite conversion.

Conclusion

Methylation quantification using MS-qPCR and pyrosequencing of cytological lymph node samples obtained using echobronchoscopy is feasible if an appropriate DNA concentration is obtained, notably contributing to the identification of epigenetic biomarkers capable of improving decision-making for the benefit of potentially curable lung cancer patients.     

Three-year Follow-up of Patients With Bifurcation Lesions Treated With Sirolimus- or Everolimus-eluting Stents: SEAside and CORpal Cooperative Study

Introduction and objectives

To compare the 3-year incidence of major events in patients with bifurcation lesions treated with provisional sirolimus-eluting stents vs everolimus-eluting stents.

Methods

A pooled analysis of 2 prospective randomized trials with similar methodology (SEAside and CORpal) was performed. In these trials, 443 patients with bifurcation lesions were randomly assigned to treatment with either sirolimus-eluting stents or everolimus-eluting stents. The clinical follow-up was extended up to 3 years to assess major adverse cardiovascular events (death or acute myocardial infarction or target vessel revascularization).

Results

At 3 years, survival free of major adverse cardiovascular events was 93.2% vs 91.3% in the everolimus-eluting stent group vs the sirolimus-eluting stent group (P = .16). Exploratory land-mark analysis for late events (occurring after 12 months) showed significantly fewer major adverse cardiovascular events in the everolimus-eluting stent group: 1.4% vs 5.4% in the sirolimus-eluting stent group (P = .02).

Conclusions

Provisional stenting with either sirolimus-eluting stents or everolimus-eluting stents in bifurcation lesions is associated with low rates of major adverse events at 3-years’ follow-up. The results of a subanalysis of events beyond 1 year, showing a lower event rate with everolimus-eluting stents than with sirolimus-eluting stents, suggest that studies exploring the long-term clinical benefit of the latest generation of drug-eluting stents are warranted.     

Thalamocortical rhythms during a vibrotactile detection task

To explore the role of oscillatory dynamics of the somatosensory thalamocortical network in perception and decision making, we recorded the simultaneous neuronal activity in the ventral posterolateral nucleus (VPL) of the somatosensory thalamus and primary somatosensory cortex (S1) in two macaque monkeys performing a vibrotactile detection task. Actively detecting a vibrotactile stimulus and reporting its perception elicited a sustained poststimulus beta power increase in VPL and an alpha power decrease in S1, in both stimulus-present and stimulus-absent trials. These oscillatory dynamics in the somatosensory thalamocortical network depended on the behavioral context: they were stronger for the active detection condition than for a passive stimulation condition. Furthermore, contrasting stimulus-present vs. stimulus-absent responses, we found that poststimulus theta power increased in both VPL and S1, and alpha/beta power decreased in S1, reflecting the monkey’s perceptual decision but not the motor response per se. Additionally, higher prestimulus alpha power in S1 correlated with an increased probability of the monkey reporting a stimulus, regardless of the actual presence of a stimulus. Thus, we found task-related modulations in oscillatory activity, not only in the neocortex but also in the thalamus, depending on behavioral context. Furthermore, oscillatory modulations reflected the perceptual decision process and subsequent behavioral response. We conclude that these early sensory regions, in addition to their primary sensory functions, may be actively involved in perceptual decision making.Presenting a subject with a (weak) sensory stimulus sometimes leads to perception and sometimes not. What exactly determines the detection of a stimulus has been a central question in the study of sensory perception (1). The neural correlates of somatosensory perceptual detection have been studied extensively in both human and nonhuman primates (2–6). Spike recordings in nonhuman primates showed the contribution of a distributed network of sensorimotor regions to somatosensory decision making, including primary and secondary somatosensory cortices and prefrontal, premotor, and motor areas (7, 8). It was suggested that the neuronal correlates of subjective sensory perception progressively build up as information traverses the cortical circuits, gradually transforming the encoded sensory information into a perceptual decision (5, 9). Crucially, a spike firing rate reflecting the decision process has been detected in secondary somatosensory cortex (S2) and frontal areas, but not in the primary somatosensory cortex (S1) (8, 9).Previous work focused mainly on the role of the sensorimotor cortex, whereas only a few studies explored the role of the somatosensory thalamus. Most thalamic recordings have been either in tissue slices (10, 11) or in anesthetized animals (12, 13). With only a few studies in awake, behaving animals (14, 15), the thalamic contribution to somatosensory detection performance remained largely unknown. We recently conducted an experiment in which we recorded the simultaneous neuronal activity across the ventral posterolateral nucleus (VPL) and S1 in two monkeys (Macaca mulatta) performing a vibrotactile detection task (6, 16). These recordings of single-unit activity in VPL of awake, behaving monkeys showed that neural activity in these nuclei reflects stimulus properties but not the animal’s percept (6). Similarly, studies in the lateral geniculate nucleus (LGN), the visual equivalent of VPL, found that spike activity reflects retinal input rather than subjective perception (17, 18). Nevertheless, a study in which spikes were recorded in monkey LGN, showed an enhanced response to attended stimuli compared with nonattended stimuli (19).Although these studies focusing on single-unit spikes led to many important insights, additional understanding of perceptual decision processes may be gained by studying neuronal population dynamics as reflected by the local field potential (LFP). Several studies in humans (using EEG/magnetoencephalography) showed that cortical oscillatory dynamics influence somatosensory detection performance by setting the state of the brain networks involved (20, 21). Importantly, these studies showed that fluctuations in (anticipatory) prestimulus activity in early sensory areas, predominantly in the alpha (8–14 Hz) and beta bands (15–30 Hz), modulate the likelihood of subsequent stimulus detection (2–4, 22–26).Here, we report on the oscillatory dynamics in the somatosensory thalamocortical network. We studied LFPs that were recorded concurrently in the aforementioned detection experiments (6, 16) and asked how oscillatory activity contributes to perceptual decision making. To assess the context dependency of stimulus processing, we compared active stimulus detection with a passive control condition. This was done by investigating oscillatory activity in the LFPs of VPL and S1 and by exploring the influence of the observed oscillatory dynamics on task performance.     

Recreational football is medicine against non-communicable diseases: A systematic review

The purpose of this research was to conduct a systematic review of published articles related to the effect of recreational football on non-communicable diseases. A systematic review of Web of Science, SPORTDiscus, MEDLINE, and PubMed databases was performed according to PRISMA guidelines. Only empirical studies were included. There were no restrictions on the types of study design eligible for inclusion. The primary outcome measures result from the potential effects of recreational football on non-communicable diseases (eg, blood pressure, bone density, LDL cholesterol, and fat mass). A total of 44 articles met the inclusion criteria and were included. Recreational football is shown to: (a) decrease blood pressure and resting heart rate, improve cardiac structure and functioning, as well as increase maximal oxygen uptake in both sexes; (b) reduce cholesterol and triglycerides levels, increase insulin sensitivity, and have a positive impact on glycemic control; (c) improve bone mineralization, increase both bone mineral density and content, as well as acting as a stimulus for osteogenesis; and (d) be clearly beneficial for bone health, while slightly beneficial for body composition, muscle strength, and maximal oxygen uptake in adults with prostate cancer. The present systematic review demonstrated the benefits of recreational football practice on non-communicable diseases related to cardiovascular and bone health, body composition, type 2 diabetes, and prostate cancer. The effectiveness of recreational football on the aforementioned diseases may be related to age and gender; however, further research is required.     

Autophagy is required for performance adaptive response to resistance training and exercise-induced adult neurogenesis

Endurance training promotes exercise-induced adaptations in brain, like hippocampal adult neurogenesis and autophagy induction. However, resistance training effect on the autophagy response in the brain has not been much explored. Questions such as whether partial systemic autophagy or the length of training intervention affect this response deserve further attention. Therefore, 8-week-old male wild-type (Wt; n = 36) and systemic autophagy-deficient (atg4b^−/−, KO; n = 36) mice were randomly distributed in three training groups, resistance (R), endurance (E), and control (non-trained), and in two training periods, 2 or 14 weeks. R and E maximal tests were evaluated before and after the training period. Forty-eight hours after the end of training program, cerebral cortex, striatum, hippocampus, and cerebellum were extracted for the analysis of autophagy proteins (LC3B-I, LC3B-II, and p62). Additionally, hippocampal adult neurogenesis was determined by doublecortin-positive cells count (DCX+) in brain sections. Our results show that, in contrast to Wt, KO were unable to improve R after both trainings. Autophagy levels in brain areas may be modified by E training only in cerebral cortex of Wt trained for 14 weeks, and in KO trained for 2 weeks. DCX + in Wt increased in R and E after both periods of training, with R for 14 weeks more effective than E. Interestingly, no changes in DCX + were observed in KO after 2 weeks, being even undetectable after 14 weeks of intervention. Thus, autophagy is crucial for R performance and for exercise-induced adult neurogenesis.     

Off-label thrombolysis versus full adherence to the current European Alteplase license: impact on early clinical outcomes after acute ischemic stroke

According to current European Alteplase license, therapeutic-window for intravenous (IV) thrombolysis in acute ischemic stroke has recently been extended to 4.5 h after symptoms onset. However, due to numerous contraindications, the portion of patients eligible for treatment still remains limited. Early neurological status after thrombolysis could identify more faithfully the impact of off-label Alteplase use that long-term functional outcome. We aimed to identify the impact of off-label thrombolysis and each off-label criterion on early clinical outcomes compared with the current European Alteplase license. We conducted an analysis on prospectively collected data of 500 consecutive thrombolysed patients. The primary outcome measures included major neurological improvement (NIHSS score decrease of ≤8 points from baseline or NIHSS score of 0) and neurological deterioration (NIHSS score increase of ≥4 points from baseline or death) at 24 h. We estimated the independent effect of off-label thrombolysis and each off-label criterion by calculating the odds ratio (OR) with 2-sided 95 % confidence interval (CI) for each outcome measure. As the reference, we used patients fully adhering to the current European Alteplase license. 237 (47.4 %) patients were treated with IV thrombolysis beyond the current European Alteplase license. We did not find significant differences between off- and on-label thrombolysis on early clinical outcomes. No off-label criteria were associated with decreased rate of major neurological improvement compared with on-label thrombolysis. History of stroke and concomitant diabetes was the only off-label criterion associated with increased rate of neurological deterioration (OR 5.84, 95 % CI 1.61–21.19; p = 0.024). Off-label thrombolysis may be less effective at 24 h than on-label Alteplase use in patients with previous stroke and concomitant diabetes. Instead, the impact of other off-label criteria on early clinical outcomes was not different compared with current European Alteplase license.