Individual QT–R‐R Relationship: Average Stability over Time Does Not Rule Out an Individual Residual Variability: Implication for the Assessment of Drug Effect on the QT Interval

Background: Universal QT correction formulae have been shown to under or overcorrect the QT interval duration. Individual QT–R‐R modeling has been proposed as a preferable solution for heart rate correction of QT intervals. However, the QT–R‐R relationship stability over time needs to be evaluated. Methods: The present report is part of randomized, double‐dummy, and placebo‐controlled 4‐way crossover phase 1 study (48 healthy volunteers). Each randomized period included a run‐in placebo day followed the day after by drug administration, with moxifloxacin as a positive control for QT interval measurement. Digital Holter ECG data were analyzed using the “bin” approach. For each period, individual QT–R‐R relationship were calculated using two different models (linear and parabolic log–log models). Results: The mean intrasubject variability for the α coefficient of the linear modeling (SDintra = 0.011 ± 0.005) reached 28.6 ± 10.2%. When the parabolic model was considered, the SDintra was 0.026 ± 0.009 for the α coefficient. The QT–R‐R relationship variability was in part related to long‐term RR changes (R²= 30%, P < 0.05). However, no significant time effect (ANOVA) was evidenced for QT–R‐R coefficients. Moxifloxacin significantly increased the α coefficient of the QT–R‐R relationship from 0.07 ± 0.018 to 0.085 ± 0.019, P < 0.05 (linear model). Conclusions: The individual QT–R‐R relationship shows a residual variability in part related to long‐term autonomic changes. In addition, the QT–R‐R relationship might be modulated by the drug tested. As a consequence, pretherapy QT–R‐R relationship obtained in a given patient cannot be used as a fingerprint throughout a drug trial.     

Human adult bone marrow mesenchymal stem cells repair experimental conduction block in rat cardiomyocyte cultures.

OBJECTIVES: We evaluated whether human adult bone marrow-derived mesenchymal stem cells (hMSCs) could repair an experimentally induced conduction block in cardiomyocyte cultures. BACKGROUND: Autologous stem cell therapy is a novel treatment option for patients with heart disease. However, detailed electrophysiological characterization of hMSCs is still lacking. METHODS: Neonatal rat cardiomyocytes were seeded on multi-electrode arrays. After 48 h, abrasion of a 200- to 450-microm-wide channel caused conduction block. Next, we applied adult hMSCs (hMSC group, n = 8), human skeletal myoblasts (myoblast group, n = 7), rat cardiac fibroblasts (fibroblast group, n = 7), or no cells (control group, n = 7) in a channel-crossing pattern. Cross-channel electrical conduction was analyzed after 24 and 48 h. Intracellular action potentials of hMSCs and cardiomyocytes were recorded. Immunostaining for connexins and intercellular dye transfer (calcein) assessed the presence of functional gap junctions. RESULTS: After creation of conduction block, two asynchronously beating fields of cardiomyocytes were present. Application of hMSCs restored synchronization between the two fields in five of eight cultures after 24 h. Conduction velocity across hMSCs (0.9 +/- 0.4 cm/s) was approximately 11-fold slower than across cardiomyocytes (10.4 +/- 5.8 cm/s). No resynchronization occurred in the myoblast, fibroblast, or control group. Intracellular action potential recordings indicated that conduction across the channel presumably occurred by electrotonic impulse propagation. Connexin-43 was present along regions of hMSC-to-cardiomyocyte contact, but not along regions of cardiomyocyte-to-myoblast or cardiomyocyte-to-fibroblast contact. Calcein transfer from cardiomyocytes to hMSCs was observed within 24 h after co-culture initiation. CONCLUSIONS: Human mesenchymal stem cells are able to repair conduction block in cardiomyocyte cultures, probably through connexin-mediated coupling.     

Capacitative calcium entry and transient receptor potential canonical 6 expression control human hepatoma cell proliferation

Store-operated calcium entry (SOCE) is the main Ca(2+) influx pathway involved in controlling proliferation of the human hepatoma cell lines Huh-7 and HepG2. However, the molecular nature of the calcium channels involved in this process remains unknown. Huh-7 and HepG2 cells express transient receptor potential canonical 1 (TRPC1) and TRPC6, as well as STIM1 and Orai1, and these 4 channels are the most likely candidates to account for the SOCE in these cells. We generated stable TRPC6-overexpressing or TRPC6-knockdown Huh-7 clones, in which we investigated correlations between the presence of the protein, the rate of cell proliferation, and SOCE amplitude. TRPC6-overexpressing Huh-7 cells proliferated 80% faster than did untransfected cells and their SOCE amplitude was 160% higher. By contrast, proliferation rate was 50% lower and SOCE amplitude 85% lower in TRPC6-knockdown clones than in untransfected cells. OAG (olyl acetyl glycerol)-induced calcium entry was similar in all cells, and small interfering RNA (siRNA) against TRPC1 had no effect on SOCE amplitude, highlighting the relationship among SOCE, TRPC6 and cell proliferation in Huh-7 cells. SOCE amplitude was reduced by STIM1 and Orai1 knockdowns, suggesting possible cooperation between these proteins and TRPC6 in these cells. Endothelial growth factor and hepatocyte growth factor increased TRPC6 expression and SOCE amplitude in Huh-7 cells, and cyclin D1 expression was decreased by STIM1, Orai1, and TRPC6 knockdowns. CONCLUSION: TRPC6 was very weakly expressed in isolated hepatocytes from healthy patients and expressed more strongly in tumoral samples from the liver of a cancer patient, strongly supporting a role for these calcium channels in liver oncogenesis.     

Activity distribution of seven digestive enzymes along small intestine in calves during development and weaning

Ten groups of calves were used to study the changes in activity levels and distribution of seven hydrolases in the intestinal mucosa during development and weaning. The calves in the first group were sacrificed at birth while those in the remaining nine groups were either milk-fed until slaughter on days 2, 7, 28, 56, 70, and 119; or weaned between days 28 and 56 and then slaughtered on days 56, 70, and 119, respectively. The small intestine was immediately cut off and divided into five segments, ie, duodenum, proximal jejunum, median jejunum, distal jejunum, and ileum. In the milk-fed animals, the activity levels of aminopeptidases A and N, alkaline phosphatase, lactase, and isomaltase were maximum at 2 days of age, and then declined sharply between days 2 and 7 but did not change significantly thereafter. By contrast, the maltase activity increased between days 7 and 119, while no sucrase activity was detected. Weaning resulted in a decrease in the activity of lactase and an increase in that of aminopeptidase N, maltase, and isomaltase. The distribution of all these enzymes along the small intestine was slightly influenced by age but not at all by weaning.     

Combined Efficacy of Acamprosate and Disulfiram in the Treatment of Alcoholism: A Controlled Study

This study presents the results of a multicenter investigation of the efficacy of acamprosate in the treatment of patients with chronic or episodic alcohol dependence. One hundred eighteen patients were randomly assigned to either placebo or acamprosate, and both groups were stratified for concomitant voluntary use of disulfiram. Treatment lasted for 380 days, with an additional 360-day follow-up period. The primary efficacy parameters evaluated were: relapse rate and cumulative abstinence duration (CAD). Results were analyzed according to Intention-To-Treat principles using χ², t , and multiple regression analyses where appropriate. After 30 days on study medication, 40 of 55 (73%) acamprosate-treated patients were abstinent, compared with 26 of 55 (43%) placebo-treated patients ( p = 0.019). The treatment advantage remained throughout the study medication period and was statistically significant until day 270 ( p = 0.028). Twenty-seven percent of patients on acamprosate and 53% of patients on placebo had a first drink within the first 30 days of the study. The mean CAD was 137 days (40% abstinent days) for the patients treated with acamprosate and 75 days (21% abstinent days) for the placebo group ( p = 0.013). No adverse interaction between acamprosate and disulfiram occurred, and the subgroup who received both medications had a better outcome on CAD than the those on only one or no medication. Acamprosate was well tolerated. Diarrhea was the only significant treatment-induced effect. It was concluded that acamprosate was a useful and safe pharmacotherapy in the long-term treatment of alcoholism. Concomitant administration of disulfiram improved the effectiveness of acamprosate.     

Male <Emphasis Type="Italic">Drosophila melanogaster</Emphasis> flies exposed to hypergravity at young age are protected against a non-lethal heat shock at middle age but not against behavioral impairments due to this shock

Previous studies have shown that exposing flies to hypergravity (3 or 5g) for two weeks at young age slightly increases longevity of male flies and survival time at 37 °C of both sexes, and delays an age-linked behavioral change. The present experiments tested whether hypergravity could also protect flies from a non-lethal 37 °C heat shock applied at young, middle or old age (2, 4 or 6weeks of age). Various durations of exposure at 37 °C had similar deleterious effects on climbing activity, spontaneous locomotor activity and learning in flies that lived or not in hypergravity at young age. Therefore, hypergravity does not protect the behavior of flies from a deleterious non-lethal heat shock. Hypergravity increased longevity of virgin males and decreased that of mated ones; it also increased longevity of virgins at 25 °C, the usual rearing temperature, but not at 30 °C. Thus, the positive effect of hypergravity on longevity is observed only if flies are not subjected to living conditions decreasing longevity, like mating and high temperature. Finally, 4 weeks-old males that lived in hypergravity at young age lived slightly longer (+ 15%) after a non-lethal heat shock (60 or 90 min at 37 °C) than flies that always lived at 1 g, but this positive effect of hypergravity was not observed in females or in older males. Therefore, all these results show that hypergravity exposure can help male middle-aged flies recovering from a heat shock, but does not protect them from behavioral impairments linked to this shock: a mild stress occurring at young age can partially protect from a moderate stress at middle age.     

Myocardial infarction and primary thrombocytosis in a young man

We report the case of a 27-year-old male smoker with simultaneous myocardial infarction (MI) and acute peripheral ischaemia. At the time of his first hospitalization, the platelet count and the coronary angiogram were normal. Two years later, the patient presented again with a leg artery occlusion, followed, a few days later, by a recurrence of MI. At this time, the platelet count was high and the coronary angiogram revealed an occlusion of the right coronary artery. The diagnosis of primary thrombocytosis was made by bone marrow aspiration and biopsy. Different unusual mechanisms of MI in young people are discussed in this report.     

Differential diagnosis on the autism spectrum: Theorizing an “Ordinary Autism”

ObjectivesData on the prevalence of Autism Spectrum Disorder (ASD) reveal several clinical evolutions inducing new psychiatric definitions and diagnostic practices. Thus, autism has shifted from being a rare syndrome with severe clinical forms to a new paradigm: the paradigm of “ordinary” or “invisible” autism, in terms of the frequency and the intensity of the disorders. These changes incorporate new populations into our conception of autism, with new phenotypes that pose theoretical and clinical challenges to clinicians. In response, we propose the hypothesis — based on psychoanalytic theories of psychic structures — of an “ordinary autism” as a definition of a non-prototypical autistic psychic functioning that falls outside the DSM diagnostic framework. This idea seems to provide us new theoretical references that nourish our practices as well as fundamental research.MethodFirst, we will review the nosographic mutations of the DSM-5 and their implications for non-prototypical psychic modes of functioning of autistic people that may not be contained within the autism spectrum's blurry boundaries — especially for the adult population without intellectual delay and in the case of complicated differential diagnosis for clinical and societal reasons. Next, we will discuss the definition of “ordinary” or “invisible” autism in a psychoanalytic structural model, as a possible epistemological orientation for identifying and designing practice with the clinical heterogeneity of autism outside the boundaries of psychiatric ASD.ResultsThe autistic population targeted by the DSM-5 criteria is different from that previously defined by DSM-IV. This leads to two consequences: on the one hand, autistic modes of functioning are not limited to individuals who have been diagnosed with Autism Spectrum Disorders as defined by the DSM-5; thus individuals with autism do not have access to the diagnosis of ASD or are given other diagnoses. The alternative diagnoses proposed by the DSM-5 that attempt to correct this diagnostic exclusion — such as Social (Pragmatic) Communication Disorder — are unsatisfactory. Therefore, there is an entire segment of the autistic population that has subclinical, non-prototypic autistic manifestations or more subtle phenomena discernible in the broader autistic phenotype or sub-threshold autism spectrum that does not have access to the ASD diagnosis and raises differential diagnostic issues. On the other hand, it appears that the autism spectrum brings together extremely different entities and false positives such as schizophrenia and schizophrenic spectrum personality disorders under one diagnostic rubric. Then, the differential problem appears central: both at the theoretical level and in diagnostic practices. The recognition of these limits should encourage us to promote research and clinical applications on this subject. One solution that we envisage is to be found in an extension of Maleval's structural psychoanalytical model: we propose the notion of “ordinary autism” — an echo of ordinary psychosis — to define attenuated or compensated non-prototypical autistic phenotypes, increasingly frequent and with fewer “extraordinary” phenomenological expressions than the classic cases of autism which now call into question the relationship between the normal and the pathological.Discussion“Ordinary autism” seems to offer clinicians the opportunity to formalize the new contemporary and extensive clinical reality of autism. This term situates itself within a theoretical model whose current and future developments might help us respond to clinical and diagnostic issues, but also to therapeutic and societal ones. We propose to continue on the path of the operationalization of these theoretical models in order to identify autistic structural constants that could be found throughout the “ordinary” clinic of autism and could serve as differentiating tools for diagnosis as well as a support in developing and refining therapeutic practices.ConclusionWe conclude that there is an urgent need to conceive of “ordinary autism” to provide us with reference points to respond to new clinical issues, but also to reintroduce respect for the autistic person in his or her subjectivity to the center of our therapeutic practices.