Whole mitochondrial DNA sequencing in Alpine populations and the genetic history of the Neolithic Tyrolean Iceman

The Tyrolean Iceman is an extraordinarily well-preserved natural mummy that lived south of the Alpine ridge ~5,200 years before present (ybp), during the Copper Age. Despite studies that have investigated his genetic profile, the relation of the Iceman´s maternal lineage with present-day mitochondrial variation remains elusive. Studies of the Iceman have shown that his mitochondrial DNA (mtDNA) belongs to a novel lineage of haplogroup K1 (K1f) not found in extant populations. We analyzed the complete mtDNA sequences of 42 haplogroup K bearing individuals from populations of the Eastern Italian Alps – putatively in genetic continuity with the Tyrolean Iceman—and compared his mitogenome with a large dataset of worldwide K1 sequences. Our results allow a re-definition of the K1 phylogeny and indicate that the K1f haplogroup is absent or rare in present-day populations. We suggest that mtDNA Iceman´s lineage could have disappeared during demographic events starting in Europe from ~5,000 ybp. Based on the comparison of our results with published data, we propose a scenario that could explain the apparent contrast between the phylogeographic features of maternal and paternal lineages of the Tyrolean Iceman within the context of the demographic dynamics happening in Europe from 8,000 ybp.This study was financed by the Provincia Autonoma di Bolzano – Alto Adige, Ripartizione Diritto allo studio, università e ricerca scientifica, funds to VCS

Clinical efficacy and safety of ezetimibe on major cardiovascular endpoints: Systematic review and meta-analysis of randomized controlled trials

Background: Randomized clinical trials (RCTs) about Ezetimibe's efficacy on patient-oriented outcomes have given discordant results. The aim of this study was to determine the net effect of Ezetimibe and of the widely marketed combination, Ezetimibe+simvastatin, on mortality and morbidity outcomes. Methods and Findings: We searched for RCT on Ezetimibe using MEDLINE, CCTR, EMBASE, ClinicalTrials.gov databases up to December 2013, Merck and Novartis online registers, and personal communications. Two authors independently selected trials fulfilling these criteria: RCTs comparing Ezetimibe±statin or another lipid-lowering drug against placebo, or against the same lipid-lowering drug at the same dosage, with a follow-up at least 24 weeks and one or more of these outcomes: all-cause mortality, cardiovascular (CV) mortality, stroke, myocardial infarction (MI), cancer, serious adverse events (SAEs); we assessed the risk of bias using the Cochrane checklist. We extracted the data for major clinical events as a dichotomous measure, with the patient the unit of analysis. Pooled analysis was done with random and fixed effect based models. Trials comparing Ezetimibe plus a lipid-lowering drug against the same lipidlowering drug representing the net effect of Ezetimibe, showed a nonsignificant tendency toward damage for cancer, MI, stroke and SAEs. Ezetimibe+simvastatin vs. simvastatin alone showed a stronger tendency towards a higher risk for all-cause death (2.52; 0.65-9.74), CV death (3.04; 0.48-19.21), non-CV death (3.03; 0.12-73.50), MI (1.91; 0.42-8.70), stroke (2.38; 0.46-12.35), cancer (RR 11.11; 0.62-198.29), and SAEs (1.45; 0.95-2.23). Limitations include small numbers of events and inadequate power of the pooling. Trials comparing Ezetimibe+simvastatin vs placebo showed non-significant effects: MI (0.81; 0.66-1.00 p = 0.051), all-cause death (1.02; 0.95-1.09), CV death (0.91; 0.80-1.04), non-CV death (108; 0.99-1.18), stroke (0.86; 0.72-1.04), cancer (1.18; 0.80-1.74), SAEs (1.01; 0.96-1.06). Conclusions: Ezetimibe±simvastatin had inconsistent effects on important outcomes. No firm conclusions are possible, but findings indicative of damage suggest much more selective use of Ezetimibe±simvastatin

Multiple Delayed Verbal Reactions (MDRV) as Vulnerability Indicators for Schizophrenia

Proceedings of the 9th International Multidisciplinary Conference «Stress and Behavior» Saint-Petersburg, Russia, 16–19 May 2005.Multiple Delayed Verbal Reactions (MDRV) methods allow us to identify early cerebral impairments in different phases of brain cognitive functions, such as pre-programming and programming, Working Memory task-independent and task-dependent processes, and transfer between perceptive and executive system and modulation of the final output. MDRV yields information on the two domains of brain function: 1) the processes involved in verbal processing, developing from the language cortical areas to the corresponding phasic motor system, and 2) the general processes of sensomotor integration, programming and attention that are task- independent. The neural substrate involved is the prefrontal network. The brain elementary function is represented by the Central Executive System of Working Memory and more specifically by the delayed reaction.MDRV method: the task stimuli consist of a monosyllable, a dysillabic word and a sentence, all with the same pronounciation, each presented on the screen of the monitor 12 times in random succession. The subject is asked to pronounce the word immediately with a loudspeaker placed near his mouth, while some pairs of surface electrodes record the EMG from oromandibular muscles. In a second series of reactions he is asked to answer only after 0.5–4 s interval has elapsed following the appearance of the task-stimulus; in that moment a go-signal (asterisks) appears on the screen. The main parameters studied were: 1) the latency time of the immediate reaction (tACG at FP = 0). The mean value of tACG at FP = 0 depends on: a) the functional state of the executive systems b) the programming, c) the timing processes. The difference tACG-tEMG as a cue of the relationship between preparatory and timing processes and the duration of ACG (D ACG) as a cue of the timing processes. A further, but not less significant parameter, is represented by the percentage of errors, particularly anticipation-errors. 2) The index of the effects of interfering stimuli. The IF-in, namely tACG at FP = 0.1/ t ACG at FP = 0 depends on lateral inhibition processes and on available cerebral associative channels. 3) The index of the latent learning occurring during the Temporal Bridging (TB) of delayed reactions (TB-in). TB indices, namely the ratios between tACG at FP = 0.5s, or tACG at FP = 1.5 s, or tACG at FP = 4 s as numerators, and tACG at FP = 0 at the denominator, reflect the course of facilitation processes associated with TB. We have examined 80 patients (30 males and 50 females) classified as schizophrenics according to the DSM III-R criteria and 40 normal patients for comparison: all s.p. were treated with atypical anti-psychotic drugs.Results. On the basis of the MDRV we divided the patients in 3 subgroups: 31 with TB-in >1 at FP 0.5 and 4s (paranoid schizophrenics), 16 with TB-in >1 at FP 1.5s (positive syndromes), 33 with TB-in >1 at FP 0.5, 1.5 and 4s (severe cases of disorganized schizophrenia). We have observed the most significance difference in paranoid schizophrenics vs. normal controls in TB-in at FP = 0.5 and at FP = 4s, with a trend to higher values in schizophrenics. We have found that positive syndromes with acute exacerbations shows the highest TB-in increase at FP = 1.5s in a range of 0.90 to 2.4. In severe cases of disorganized schizophrenia TB-in increased at all FPs with highest values at FP = 4s: 1.6 to 2.35.Discussion. A fundamental point inferred from the occurrence of TB-in inversion and impairment in both patients with frank symptoms of schizophrenia and relatives of schizophrenics without clinical symptoms of schizophrenia is that the impairment of WM and delayed reactions associated with a dorso-lateral prefrontal state independent hypoactivity, does not necessarily cause the dysfunctions that lead to the schizophrenic behavior. These prefrontal-dependent impairments could be hardly considered to reflect the cerebral dysfunction that actually produces dysphrenic alterations at the mental level, and dysexecution at the behavioral level. The schizophrenic disorder is in fact a heterogeneous and even the follow-up prognostic criterium of progressiveness adopted by Kraepelin for differentiating dementia praecox from manic-depressive psychosis, is under discussion. A general prefrontal dysfunction that is in itself latent at the level of the general cerebral performance ultimately responsible of the output seems to be a more likely interpretation. The picture in the twins is very interesting from the MDRV point of view because it shows another aspect of schizophrenia. Indeed, obsessive-compulsive symptoms in patients with schizophrenia occur in 8–10 % (Rosen, 1986), and the comorbidity totals 3–25 % (Ingram, 1961), in this case we have an abnormal acceleration in delayed reactions with an impairment of lateral inhibition detected in interfering-stimuli-reactions. These results are in agreement with those obtained by Park et al. (1995) on Working Memory, and Schreiber et al. (1998) on the P3 and N2 components of the Event-Related-Potentials, thus proving that TB-in inversion represent an index of vulnerability for schizophrenia

Testing a biochemical model of human genetic resistance to falciparum malaria by the analysis of variation at protein and microsatellite loci

We recently proposed a biochemical model of genetic resistance to falciparum malaria based on the role of oxidant stress (of parasitic origin) in inducing the irreversible oxidation of hemoglobin and its binding to the erythrocyte membrane (Destro-Bisol et al. 1996). To test the model, we analyzed the relationships between the polymorphisms at the hemoglobin beta chain (HBB) and red cell glutathione peroxidase (GPX1) loci in 18 populations that had been subjected to endemic malaria (Cameroon and Central African Republic). The erythrocytes of GPX1*2 heterozygotes should be more efficient in sheltering the cell membrane from irreversible oxidation and binding of hemoglobin caused by the oxidant stress exerted by Plasmodium falciparum. According to our model, the GPX1*2 allele has an epistatic effect on the HBB*A/*S genotype by lowering its protection against falciparum malaria, In turn, this should decrease the fitness of the HBB*A/*S-GPX1*2/*1 genotype. Our predictions were confirmed, in fact, we observed a clear trend toward a dissociation between the HBB*A/*S and GPX1*2/*1 genotypes in the overall data. To test alternative hypotheses, we also analyzed the genetic variation at 9 protein and 10 autosomal microsatellite loci at both the single- and the 2-locus level, We also discuss the possible relevance of an alternative biochemical pathway, The results further support the conclusions of our study because the dissociation between the GPX1*2/*1 and HBB*A/*S genotypes does not appear to be related either to a general decrease in heterozygosity or to an increased risk of sudden death in HBB*A/*S individuals