Clinical review: Aggressive management and extracorporeal support for drug-induced cardiotoxicity

Poisoning may induce failure in multiple organs, leading to death. Supportive treatments and supplementation of failing organs are usually efficient. In contrast, the usefulness of cardiopulmonary bypass in drug-induced shock remains a matter of debate. The majority of deaths results from poisoning with membrane stabilising agents and calcium channel blockers. There is a need for more aggressive treatment in patients not responding to conventional treatments. The development of new antidotes is limited. In contrast, experimental studies support the hypothesis that cardiopulmonary bypass is life-saving. A review of the literature shows that cardiopulmonary bypass of the poisoned heart is feasible. The largest experience has resulted from the use of peripheral cardiopulmonary bypass. However, a literature review does not allow any conclusions regarding the efficiency and indications for this invasive method. Indeed, the majority of reports are single cases, with only one series of seven patients. Appealing results suggest that further studies are needed. Determination of prognostic factors predictive of refractoriness to conventional treatment for cardiotoxic poisonings is mandatory. These prognostic factors are specific for a toxicant or a class of toxicants. Knowledge of them will result in clarification of the indications for cardiopulmonary bypass in poisonings

Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation

Abstract: Background: Recessive forms of osteogenesis imperfecta (OI) may be caused by mutations in LEPRE1, encoding prolyl 3-hydroxylase-1 (P3H1) or in CRTAP, encoding cartilage associated protein. These proteins constitute together with cyclophilin B (CyPB) the prolyl 3-hydroxylation complex that hydroxylates the Pro986 residue in both the type I and type II collagen alpha 1-chains. Methods: We screened LEPRE1, CRTAP and PPIB (encoding CyPB) in a European/Middle Eastern cohort of 20 lethal/severe OI patients without a type I collagen mutation. Results: Four novel homozygous and compound heterozygous mutations were identified in LEPRE1 in four probands. Two probands survived the neonatal period, including one patient who is the eldest reported patient (17(7/12) years) so far with P3H1 deficiency. At birth, clinical and radiologic features were hardly distinguishable from those in patients with autosomal dominant (AD) severe/lethal OI. Follow-up data reveal that the longer lived patients develop a severe osteochondrodysplasia that overlaps with, but has some distinctive features from, AD OI. A new splice site mutation was identified in two of the four probands, affecting only one of three LEPRE1 mRNA splice forms, detected in this study. The affected splice form encodes a 736 amino acid (AA) protein with a "KDEL'' endoplasmic reticulum retention signal. While western blotting and immunocytochemical analysis of fibroblast cultures revealed absence of this P3H1 protein, mass spectrometry and SDS-urea-PAGE data showed severe reduction of alpha 1(I) Pro986 3-hydroxylation and overmodification of type I (pro) collagen chains in skin fibroblasts of the patients. Conclusion: These findings suggest that the 3-hydroxylation function of P3H1 is restricted to the 736AA splice form

Effect of Supportive Periodontal Therapy on Tooth Loss in Regular and Irregular Compliant Smokers and Non-smokers: A Systematic Review

Aim: The aim of this systematic review is to analyze and compare tooth loss (TL) rates between regular and irregular compliant patients having different smoking habits. Materials and Methods: Electronic and manual literature searches were conducted by one author in several databases, including Medline (PubMed), Embase, Google Scholar. A total of 156 publications were screened. Three reviewers analyzed the articles and extracted the data. A total of 33 studies met the inclusion criteria. Results: A total of 30 articles were eligible for qualitative analysis, and only 3 for quantitative analysis. Compliance and smoking case definition as well as recall intervals during supportive periodontal therapy (SPT) differed widely between studies. A total of 10 publications reported significant differences in TL rates between regular (RC) and irregular compliant (IC) patients, while 25 publications reported significant differences in TL rates between smokers and non-smokers. Conclusion: Regular attendance to SPT visits and non-smoking patients are associated with fewer TL rates. Smoking is considered a major modifiable risk factor for TL

Pectus Carinatum Evaluation Questionnaire (PCEQ): a novel tool to improve the follow-up in patients treated with brace compression

A questionnaire (Pectus Carinatum Evaluation Questionnaire, PCEQ) was developed to be applied in follow-up of patients with Pectus Carinatum (PC). After validation of the PCEQ, we aimed to quantify the compliance to brace compression and to assess factors that could influence this treatment in patients with PC. From July 2008 to July 2014, 56 patients with PC were treated with the Calgary Protocol of compressive bracing at Paediatric Surgery Department of Hospital So Joo. Forty patients (71%) completed the questionnaire. The PCEQ was divided into four sections: (i) compliance; (ii) symptoms; (iii) social influence; (iv) activities. For the validation process of the PCEQ, principal components analysis (PCA), orthogonal varimax or oblimin rotation and Cronbach's alpha coefficient were used. To evaluate the association between compliance and other sections of the questionnaire, we estimated the Pearson's correlation between compliance factor scores ('Compliance Days' and 'Compliance Hours') and the final score of each new questionnaire component identified by PCA ('Chest Pain', 'Dyspnoea', 'Back Pain', 'Parents' Influence', 'Friends' Influence', 'Activities', 'Time To Compliance'). For the sections 'Symptoms', 'Social Influence' and 'Activities', we estimated final scores as the sum of the questions that constitute each component. For the section 'Compliance', the factor scores were estimated by the regression method. After PCA analysis, the PCEQ found nine different components with high reliability. When analysing the compliance of our study group, the final score for 'Activities' revealed a significant correlation with the factor score for 'Compliance Hours' (r = 0.382, P = 0.015). The final score for 'Time To Compliance' showed a significant correlation with both factor scores for 'Compliance Hours' (r = -0.765, P < 0.001) and 'Compliance Days' (r = -0.345, P < 0.029). The PCEQ seems to be an important tool to follow up patients with PC treated by brace compression. Practical steps, such as developing a tight schedule in the early follow-up period or applying the PCEQ in first visits after initiating brace therapy, can be taken in order to increase compliance with brace therapy and improve the quality of life.info:eu-repo/semantics/publishedVersio

Identification de gènes impliqués dans des dysplasies osseuses rares dans des familles libanaises consanguines

La pratique du mariage entre apparentés au sein de la population libanaise, favorisée par des raisons sociales, religieuses, géographiques et aussi politiques, a vu apparaître des sous-groupes de populations de taille plus ou moins réduite, parfois à la limite d isolats génétiques. Ceci a engendré une augmentation de la prévalence des maladies autosomiques récessives fréquentes mais aussi et surtout rares. Parmi ces dernières, les chondrodysplasies ont retenu notre attention. Elles sont caractérisées par un retard statural dû à un défaut du processus d ossification endochondale, qui est responsable de la croissance des os longs. Au cours de ces dernières décennies, plus de 230 gènes responsables d environ 400 maladies osseuses constitutionnelles ont été identifiés. Cependant, les bases moléculaires d'une centaine de dysplasies osseuses restent, à ce jour, inconnues. L identification de gènes codant pour des protéines de nature extrêmement variée a contribué à la compréhension du mécanisme complexe d ossification endochondrale. Mon travail de thèse, réalisé en cotutelle entre l équipe de recherche Bases moléculaires et physiopathologiques des chondrodysplasies de l hôpital Necker enfants-malades, à Paris en France et l Unité de Génétique Médicale (UGM) de l Université Saint-Joseph au Liban, a consisté à identifier des gènes impliqués dans des dysplasies osseuses autosomiques récessives dans quatre familles libanaises consanguines. Dans ce cadre, différentes stratégies ont été adoptées. La première a été une stratégie d intersection des variations détectées par le séquençage de l exome de deux patients, atteints d une forme sévère de dysplasie spondylodysplastique létale et issus de deux familles libanaises consanguines et non apparentées (Familles A et B). Nous avons identifié une mutation homozygote du gène MAGMAS (NM_016069, p.Asn76Asp) (Mitochondria-associated granulocyte macrophage CSF-signaling molecule) à l origine de la maladie dans les deux familles A et B. MAGMAS est une protéine associée à la mitochondrie et impliquée dans la régulation de l import actif des protéines vers la matrice mitochondriale. Par immunohistochimie, nous avons montré que MAGMAS est spécifiquement exprimée au niveau de l os et de la zone hypertrophique du cartilage. MAGMAS, ayant une fonction cruciale pour la survie, est très conservé entre les espèces. Après avoir généré des souches de levures exprimant une copie normale ou mutée du gène humain MAGMAS, nous avons validé l effet délétère de la mutation p.Asn76Asp, i) sur la croissance des levures, en montrant que les souches portant le gène humain muté présentent un caractère thermosensible, ii) sur la fonction d import des protéines vers la matrice mitochondriale, qui est altérée dans les souches mutées et iii) sur la stabilité de la protéine. Nous avons également observé un effet de la mutation sur la morphologie des mitochondries et des peroxysomes des cellules de levures, suggérant une induction de l autophagie dans les souches de levures portant la mutation p.Asn76Asp. L identification de mutations de MAGMAS dans une dysplasie osseuse sévère, permet d attribuer à cette protéine un rôle spécifique dans le processus complexe d ossification endochondrale. La deuxième stratégie a été une combinaison, au sein d une même famille, d une stratégie de cartographie par homozygotie et du séquençage de l exome d un seul patient. Cette approche a été utilisée dans une famille consanguine avec 3 enfants atteints porteurs d une dysplasie rhizomélique (Famille C). Nous avons identifié une mutation homozygote du gène NWD1 (NACHT and WD repeat domain containing 1) (NM_001007525, p.Cys1376Tyr) responsable de la maladie dans cette famille C. Ce gène code pour une protéine ayant des domaines WD répétés qui lui confèrent un rôle dans divers mécanismes comme la transduction de signal, la régulation de la transcription, le transport vésiculaire et le contrôle du cycle cellulaire. (...)Social, religious, geographic and political reasons have favored the consanguineous marriage in the Lebanese population. This led to an increase in the prevalence of autosomal recessive disorders, especially the rare entities including chondrodysplasias. This group of diseases is due to an impairment of the endochondral ossification process. Causative mutations have now been identified in over 230 different genes in more than 400 unique skeletal phenotypes. However, the genetic basis of over 100 different entities remains to be determined. My PhD research project, held between the research group Bases moléculaires et physiopathologiques des chondrodysplasies of Necker enfants-malades hospital (INSERM U781, PARIS, France) and the Medical Genetics Unit of Saint-Joseph University (Lebanon), aims to identify genes involved in autosomal recessive skeletal dysplasias in four consanguineous Lebanese families. Different strategies were carried out: the first consists in overlapping data from whole exome sequencing of two patients affected by a new lethal type of spondylodysplastic dysplasia and issued from two consanguineous unrelated Lebanese families (Families A and B). Here, we report a homozygous missense mutation in the Mitochondria-associated granulocyte macrophage CSF-signaling gene (MAGMAS: NM_016069, p.Asn76Asp) in this severe skeletal dysplasia. MAGMAS, also referred to as PAM16, is a mitochondria-associated protein, involved in pre-proteins import into mitochondria and essential for cell growth and development. We demonstrate that MAGMAS is expressed in trabecular bone and cartilage at early developmental stages underlining its specific role in skeletogenesis. We also give strong evidence of the deleterious effect of the identified mutation on the stability of the protein, its in-vivo activity and the viability of yeast strains. We also show that the mutation is able to induce autophagy in yeast cells. Reporting deleterious MAGMAS mutation in a skeletal dysplasia supports a key and specific role for this mitochondrial protein in ossification. Additional studies would be of interest to further understand the specific role of magmas in ossification. The second strategy was to combine, in a consanguineous family, homozygosity mapping with whole exome sequencing of one of the patients. This strategy was undertaken in family C with 3 patients affected by a rhizomelic dysplasia. It allowed us to identify a homozygous missense mutation in the NWD1 gene (NACHT and WD repeat domain containing 1: NM_001007525, p.Cys1376Tyr) as responsible for the skeletal dysplasia in this family. NWD1 belongs to a large group of WD-repeat domain-containing proteins that are involved in different physiological mechanisms such as signal transduction, transcription regulation, vesicular transport and cell cycle control. (...)PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Effect of different methods of cooling for targeted temperature management on outcome after cardiac arrest : a systematic review and meta-analysis

Background Although targeted temperature management (TTM) is recommended in comatose survivors after cardiac arrest (CA), the optimal method to deliver TTM remains unknown. We performed a meta-analysis to evaluate the effects of different TTM methods on survival and neurological outcome after adult CA. Methods We searched on the MEDLINE/PubMed database until 22 February 2019 for comparative studies that evaluated at least two different TTM methods in CA patients. Data were extracted independently by two authors. We used the Newcastle-Ottawa Scale and a modified Cochrane ROB tools for assessing the risk of bias of each study. The primary outcome was the occurrence of unfavorable neurological outcome (UO); secondary outcomes included overall mortality. Results Our search identified 6886 studies; 22 studies (n = 8027 patients) were included in the final analysis. When compared to surface cooling, core methods showed a lower probability of UO (OR 0.85 [95% CIs 0.75-0.96]; p = 0.008) but not mortality (OR 0.88 [95% CIs 0.62-1.25]; p = 0.21). No significant heterogeneity was observed among studies. However, these effects were observed in the analyses of non-RCTs. A significant lower probability of both UO and mortality were observed when invasive TTM methods were compared to non-invasive TTM methods and when temperature feedback devices (TFD) were compared to non-TFD methods. These results were significant particularly in non-RCTs. Conclusions Although existing literature is mostly based on retrospective or prospective studies, specific TTM methods (i.e., core, invasive, and with TFD) were associated with a lower probability of poor neurological outcome when compared to other methods in adult CA survivors (CRD42019111021).Peer reviewe

Am. J. Hum. Genet.

Thrombocytopenia–absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs. Other frequent associations are congenital heart disease and a high incidence of cow’s milk intolerance. Evidence for autosomal recessive inheritance comes from families with several affected individuals born to unaffected parents, but several other observations argue for a more complex pattern of inheritance. In this study, we describe a common interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR syndrome, detected by microarray-based comparative genomic hybridization. Analysis of the parents revealed that this deletion occurred de novo in 25% of affected individuals. Intriguingly, inheritance of the deletion along the maternal line as well as the paternal line was observed. The absence of this deletion in a cohort of control individuals argues for a specific role played by the microdeletion in the pathogenesis of TAR syndrome. We hypothesize that TAR syndrome is associated with a deletion on chromosome 1q21.1 but that the phenotype develops only in the presence of an additional as-yet-unknown modifier (mTAR)

Am J Hum Genet

Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the γ-subunit gene (CHRNG) of the AChR. Our functional studies show that γ-subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney–cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two α, one β, and one δ subunit are always present. By switching γ to &epsiv; subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the γ subunit were thought to be lethal, as they are in γ-knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because γ expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway