5′ Region Large Genomic Rearrangements in the BRCA1 Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints

Background: Large genomic rearrangements (LGR) in BRCA1 consisting of deletions/duplications of one or several exons have been found throughout the gene with a large proportion occurring in the 5′ region from the promoter to exon 2. The aim of this study was to better characterize those LGR in French high-risk breast/ovarian cancer families. Methods: DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridization (CGH) array, high-resolution BRCA1 Genomic Morse Codes analysis and Sanger sequencing. Results: The apparent duplication was in fact a tandem triplication of exons 1 and 2 and part of intron 2 of BRCA1, fully characterized here for the first time. We calculated a causality score with the multifactorial model from data obtained from six families, classifying this variant as benign. Among the nine deletions detected in this region, eight have never been identified. The breakpoints fell in six recurrent regions and could confirm some specific conformation of the chromatin. Conclusions: Taken together, our results firmly establish that the BRCA1 5′ region is a frequent site of different LGRs and highlight the importance of the segmental duplication and Alu sequences, particularly the very high homologous region, in the mechanism of a recombination event. This also confirmed that those events are not systematically deleterious.

Emerging orthobunyaviruses associated with CNS disease

The Orthobunyavirus genus comprises a wide range of arthropod-borne viruses which are prevalent worldwide and commonly associated with central nervous system (CNS) disease in humans and other vertebrates. Several orthobunyaviruses have recently emerged and increasingly more will likely do so in the future. Despite this large number, an overview of these viruses is currently lacking, making it challenging to determine importance from a One Health perspective. Causality is a key feature of determining importance, yet classical tools are unfit to evaluate the causality of orthobunyaviral CNS disease. Therefore, we aimed to provide an overview of orthobunyaviral CNS disease in vertebrates and objectify the causality strength of each virus. In total, we identified 27 orthobunyaviruses described in literature to be associated with CNS disease. Ten were associated with disease in multiple host species of which seven included humans. Seven viruses were associated with both congenital and postnatal CNS disease. CNS disease-associated orthobunyaviruses were spread across all known Orthobunyavirus serogroups by phylogenetic analyses. Taken together, these results indicate that orthobunyaviruses may have a common tendency to infect the CNS of vertebrates. Next, we developed six tailor-made causality indicators and evaluated the causality strength of each of the identified orthobunyaviruses. Nine viruses had a ‘strong’ causality score and were deemed causal. Eight had a ‘moderate’ and ten a ‘weak’ causality score. Notably, there was a lack of case-control studies, which was only available for one virus. We, therefore, stress the importance of proper case-control studies as a fundamental aspect of proving causality. This comprehensible overview can be used to identify orthobunyaviruses which may be considered causal, reveal research gaps for viruses with moderate to low causality scores, and provide a framework to evaluate the causality of orthobunyaviruses that may newly emerge in the future.

CARBAMAZEPINE INDUCED SLE-A RARE AND SERIOUS ADR

<p style="line-height: 150%; margin-bottom: 0cm;" align="justify">Carbamazepine is a commonly used antiseizure medication. Carbamazepine-induced SLE (Systemic Lupus Erythematosus) is a very rare phenomenon. Drug-induced SLE is an autoimmune disease caused by long-term use of certain drugs. Carbamazepine is a drug with low risk for causing lupus symptoms. The process that leads to drug-induced SLE are not entirely understood. A very few cases are reported with carbamazepine association with SLE. Herein we report a case of 4 y old girl with SLE induced by carbamazepine showing a causality score of 8 by Naranjo ADR probability scale.</p>

NEONATAL ADVERSE DRUG REACTIONS: ANALYSIS OF PHARMACOVIGILANCE REPORTS AFTER DIRECT DRUG EXPOSURE IN FRANCE

BackgroundTerm and preterm neonates are at higher risk for serious adverse drug reactions than older children and adults. To date, no study has investigated spontaneous reports of adverse drug reactions (ADRs) following direct drug exposure of neonates.MethodsThis is a retrospective study of all spontaneous reports of ADRs registered in the French Pharmacovigilance Database from 1986 to 2012. All reports concerning individuals from birth to ≤30 days, 1 month or 4 weeks were retrieved. ADRs classified as related to ‘pregnancy’ or ‘breastfeeding’ were discarded. Reports were described with regards to characteristics of the infant, the reported ADR(s) (registered according to the Medical Dictionary for Regulatory Activities [MedDRA]) and the reported suspected medicine(s) (registered according to the Anatomical Therapeutic Chemical [ATC] Classification) Causality assessment was performed using the French Causality assessment method.ResultsA total of 1688 unique reports were analysed. More than half of these reports included at least on serious ADR (n=995; 59%). Median age at ADR occurrence was 9 days and a slight predominance of male neonates was observed (male/female ratio of 1.3). Fourteen percent of neonates presented a medical history of preterm birth, infection or genetic and/or congenital abnormality. Overall, 3127 ADRs were described in these reports. The most commonly reported system organ classes (SOCs) were injury, poisoning and procedural complications (16%), general disorders and administration site conditions (12.5%), blood and lymphatic system disorders (12%), gastrointestinal disorders (8%), investigations (8%) and nervous system disorders (8%). In the majority of ADRs reported (n=2279, 73%), infants fully recovered without sequelae but 4% of neonates deceased as a consequence of the reported ADR. Approximately 1/3 of the reported ADRs fell under 10 categories of ADRs the MedDRA classification and 1 out of 5 ADRs was coded as drug maladministration, medication error, overdose or drug maladministration without clinical consequences. A total of 2238 medicinal products out of the 2797 reported were described as suspect or interacting. Therapeutics classes must commonly incriminated were antiinfectives for systemic use and nervous system drugs. Active substances most frequently related to serious adverse reactions were zidovudine, ibuprofen and nevirapine. A total of 4103 drug-ADR pairs were described in the database; the global intrinsic causality score was ‘doubtful/unlikely’ for 35% of them and the extrinsic causality score was ‘never described before’ for only 6% of these pairs. Among the 10 most frequently encountered drug-ADR pairs, 2 active substances were mainly implicated: zidovudine and phytomedione (Vitamin K).ConclusionsWe have provided a unique overview of ADR notifications after direct drug exposure in the neonates. Reporting of ADRs in neonates is scarce. The majority of ADRs are classified as serious and a subsequent proportion is associated to drug administration errors. The number of commonly incriminated drugs is limited and causality assessment is particularly challenging. There is still a need to increase awareness and education of health professionals on neonatal drug safety and to promote detailed ADR reporting in this paediatric population.

How to Diagnose and Exclude Drug-Induced Liver Injury

The diagnosis of drug-induced liver injury (DILI) is largely a diagnosis of exclusion because, with the possible exception of protein:drug adducts in paracetamol overdose, there are no laboratory, biopsy or imaging tests that alone are capable of establishing an unequivocal diagnosis of DILI. However, it is increasingly appreciated that drugs that cause DILI typically have characteristic clinical presentations or ‘signatures' that can be very useful in the diagnosis of DILI. Indeed, knowing a drug's DILI signature (or sometimes signatures) and the incidence rate of DILI during treatment with that drug are perhaps the most useful pieces of historical information in arriving at the diagnosis of DILI. Components of the signature include the typical latency from the onset of treatment, whether there are extrahepatic manifestations, whether the injury is hepatocellular, cholestatic or mixed, and sometimes characteristic features on biopsy or serological testing (e.g. liver autoantibodies). A major advance has been the establishment of the LiverTox website (http://livertox.nih.gov/) which provides open access to standardized entries for over 600 different drugs, including the characteristic clinical presentations of DILI when known. LiverTox will also calculate the causality score for individual cases using the RUCAM instrument and case-specific data entered by the site user. However, the problem with standard diagnostic instruments such as the RUCAM is that DILI signatures are not incorporated into the scoring system. The person entering data must therefore subjectively weigh the RUCAM score with the characteristic DILI signature(s) of the drug to arrive at a diagnosis. In the future, it should be possible to construct improved diagnostic instruments that objectively incorporate DILI signatures, data-based estimates of the incidence rates of DILI from each implicated drug, and perhaps genetic variants associated with the risk of DILI.