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A letter to the editor is presented in response to the article "About the right facial palsy of Charles Bell. Was Sir Charles Bell himself really affected by facial paralysis?," by S. F. S. Korteweg et al.

Abstract Background Several cases have been reported of patients with a ring chromosome 18 replacing one of the normal chromosomes 18. Less common are patients with a supernumerary ring chromosomes 18. High resolution whole genome examination in patients with multiple congenital abnormalities might reveal cytogenetic abnormalities of an unexpected complexity. Results We report a 24 years old male patient with lower spinal anomalies, hypospadia, bifid scrotum, cryptorchism, anal atresia, kidney stones, urethra anomalies, radial dysplasia, and a hypoplastic thumb. Some of the anomalies overlap with the VACTERL association. Chromosome analysis of cultured peripheral blood lymphocytes revealed an additional ring chromosome in 13% of the metaphases. Both parents had a normal karyotype, demonstrating the de novo origin of this ring chromosome. FISH analysis using whole chromosome paints showed that the additional chromosomal material was derived from chromosome 18. Chromosome analysis of cultured fibroblasts revealed only one cell with the supernumerary ring chromosome in the 400 analyzed. To characterize the ring chromosome in more detail peripheral blood derived DNA was analyzed using SNP-arrays. The array results indicated a 5 Mb gain of the pericentromeric region of chromosome 18q10-q11.2. FISH analysis using BAC-probes located in the region indicated the presence of 6 signals on the r(18) chromosome. In addition, microsatellite analysis demonstrated that the unique supernumerary ring chromosome was paternally derived and both normal copies showed biparental disomy. Conclusions We report on an adult patient with multiple congenital abnormalities who had in 13% of his cells a unique supernumerary ring chromosome 18 that was composed of 6 copies of the 5 Mb gene rich region of 18q11.

A letter to the editor is presented in response to the article "Peripheral Facial Palsy in the Past. Contributions from Avicenna, Nicolaus Friedrich and Charles Bell," by L. A. De Lima Resende and S. Weber in the 2008 issue.

Introduction: Various statistical approaches can be used to deal with unmeasured confounding when estimating treatment effects in observational studies, each with its own pros and cons. This study aimed to compare treatment effects as estimated by different statistical approaches for two interventions in observational stroke care data., Patients and Methods: We used prospectively collected data from the MR CLEAN registry including all patients (n = 3279) with ischemic stroke who underwent endovascular treatment (EVT) from 2014 to 2017 in 17 Dutch hospitals. Treatment effects of two interventions - i.e., receiving an intravenous thrombolytic (IVT) and undergoing general anesthesia (GA) before EVT - on good functional outcome (modified Rankin Scale ≤2) were estimated. We used three statistical regression-based approaches that vary in assumptions regarding the source of unmeasured confounding: individual-level (two subtypes), ecological, and instrumental variable analyses. In the latter, the preference for using the interventions in each hospital was used as an instrument., Results: Use of IVT (range 66-87%) and GA (range 0-93%) varied substantially between hospitals. For IVT, the individual-level (OR ~ 1.33) resulted in significant positive effect estimates whereas in instrumental variable analysis no significant treatment effect was found (OR 1.11; 95% CI 0.58-1.56). The ecological analysis indicated no statistically significant different likelihood (β = - 0.002%; P = 0.99) of good functional outcome at hospitals using IVT 1% more frequently. For GA, we found non-significant opposite directions of points estimates the treatment effect in the individual-level (ORs ~ 0.60) versus the instrumental variable approach (OR = 1.04). The ecological analysis also resulted in a non-significant negative association (0.03% lower probability)., Discussion and Conclusion: Both magnitude and direction of the estimated treatment effects for both interventions depend strongly on the statistical approach and thus on the source of (unmeasured) confounding. These issues should be understood concerning the specific characteristics of data, before applying an approach and interpreting the results. Instrumental variable analysis might be considered when unobserved confounding and practice variation is expected in observational multicenter studies., (© 2022. The Author(s).)

Background: Despite evidence of a quite large beneficial effect of endovascular treatment (EVT) for ischemic stroke caused by anterior circulation large vessel occlusion, many patients do not recover even after complete recanalization. To some extent, this may be attributable to incomplete microvascular reperfusion, which can possibly be improved by antiplatelet agents and heparin. It is unknown whether periprocedural antithrombotic medication in patients treated with EVT improves functional outcome. The aim of this study is to assess the effect of acetylsalicylic acid (ASA) and unfractionated heparin (UFH), alone, or in combination, given to patients with an ischemic stroke caused by an intracranial large vessel occlusion in the anterior circulation during EVT., Methods: MR CLEAN-MED is a multicenter phase III trial with a prospective, 2 × 3 factorial randomized, open label, blinded end-point (PROBE) design, which aims to enroll 1500 patients. The trial is designed to evaluate the effect of intravenous ASA (300 mg), UFH (low or moderate dose), both or neither as adjunctive therapy to EVT. We enroll adult patients with a clinical diagnosis of stroke (NIHSS ≥ 2) and with a confirmed intracranial large vessel occlusion in the anterior circulation on CTA or MRA, when EVT within 6 h from symptom onset is indicated and possible. The primary outcome is the score on the modified Rankin Scale (mRS) at 90 days. Treatment effect on the mRS will be estimated with ordinal logistic regression analysis, with adjustment for main prognostic variables. Secondary outcomes include stroke severity measured with the NIHSS at 24 h and at 5-7 days, follow-up infarct volume, symptomatic intracranial hemorrhage (sICH), and mortality., Discussion: Clinical equipoise exists whether antithrombotic medication should be administered during EVT for a large vessel occlusion, as ASA and/or UFH may improve functional outcome, but might also lead to an increased risk of sICH. When one or both of the study treatments show the anticipated effect on outcome, we will be able to improve outcome of patients treated with EVT by 5%. This amounts to more than 50 patients annually in the Netherlands, more than 1800 in Europe, and more than 1300 in the USA., Trial Registration: ISRCT, ISRCTN76741621 . Dec 6, 2017.

Competing Interests: Competing interests: None declared.

- This review evaluates the safety and efficacy of, smoking cessation interventions.- Behavioural counselling is the cornerstone of smoking cessation programmes.- This counselling can be supplemented with written self-help materials, telephone counselling and e-health tailored to individual patient preferences.- Behavioural counselling may be combined with pharmacotherapy for increased effectiveness. First choice is a combination of a nicotine patch and a nicotine lozenge or chewing gum, mainly because of the favourable side-effect profile.- Furthermore, varenicline, bupropion and nortripyline are effective in smoking cessation; varenicline appears to be the most effective drug. These drugs have, however, more contraindications and potential side effects, which necessitates a correct diagnosis and more intensive monitoring.- The e-cigarette is not recommended as it seems to be equally efficacious as nicotine replacement therapy, but its potential side effects - such as normalising smoking - have not been sufficiently investigated.

- The revised guideline 'Treatment of tobacco addiction and smoking cessation support' offers health professionals a framework to provide evidence-based care to patients who smoke, which should aid in reducing smoking prevalence and smoke-related morbidity and mortality.- Four topics of the guideline have been revised: behavioural interventions, pharmacotherapy, e-health interventions and e-cigarettes. For the other topics, the recommendations from the 2009 version remain unaltered.- It is important that health professionals offer a made-to-measure smoking cessation advice and apply a fit-for-purpose smoking cessation intervention.- Nicotine replacement therapy remains the first-line pharmacotherapy intervention and is most effective when combined with behavioural intervention.- E-health interventions are particularly effective when they are personalised and of an interactive nature, and when text messaging is incorporated.- At present, e-cigarettes are not recommended as an aid to smoking cessation.

Evidence on the clinical effectiveness of probiotics in the prevention of necrotising enterocolitis (NEC) in preterm infants is conflicting and cohort studies lacked adjustment for time trend and feeding type. This study investigated the association between the introduction of routine probiotics (Lactobacillus acidophilus and Bifidobacterium bifidum; Infloran(®)) on the primary outcome 'NEC or death'. Preterm infants (gestational age <32 weeks or birth weight <1500 gram) admitted before (Jan 2008-Sep 2012; n = 1288) and after (Oct 2012-Dec 2014; n = 673) introduction of probiotics were compared. Interrupted time series logistic regression models were adjusted for confounders, effect modification by feeding type, seasonality and underlying temporal trends. Unadjusted and adjusted analyses showed no difference in 'NEC or death' between the two periods. The overall incidence of NEC declined from 7.8% to 5.1% (OR 0.63, 95% CI 0.42-0.93, p = 0.02), which was not statistically significant in the adjusted models. Introduction of probiotics was associated with a reduced adjusted odds for 'NEC or sepsis or death' in exclusively breastmilk-fed infants (OR 0.43, 95% CI 0.21-0.93, p = 0.03) only. We conclude that introduction of probiotics was not associated with a reduction in 'NEC or death' and that type of feeding seems to modify the effects of probiotics.

Background: Ataxia with oculomotor apraxia type 1 is an autosomal-recessive neurodegenerative disorder characterized by a childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. Ataxia with oculomotor apraxia type 1 is caused by bi-allelic mutations in APTX (chromosome 9p21.1)., Case Presentation: Our patient has a clinical presentation that is typical for ataxia with oculomotor apraxia type 1 with no particularly severe phenotype. Multiplex Ligation-dependent Probe Amplification analysis resulted in the identification of a homozygous deletion of all coding APTX exons (3 to 9). SNP array analysis using the Illumina Infinium CytoSNP-850 K microarray indicated that the deletion was about 62 kb. Based on the SNP array results, the breakpoints were found using direct sequence analysis: c.-5 + 1225&#95;*44991del67512, p.0?. Both parents were heterozygous for the deletion. Homozygous complete APTX deletions have been described in literature for two other patients. We obtained a sample from one of these two patients and characterized the deletion (156 kb) as c.-23729&#95;*115366del155489, p.0?, including the non-coding exons 1A and 2 of APTX. The more severe phenotype reported for this patient is not observed in our patient. It remains unclear whether the larger size of the deletion (156 kb vs 62 kb) plays a role in the phenotype (no extra genes are deleted)., Conclusion: Here we described an ataxia with oculomotor apraxia type 1 patient who has a homozygous deletion of the complete coding region of APTX. In contrast to the patient with the large deletion, our patient does not have a severe phenotype. More patients with deletions of APTX are required to investigate a genotype-phenotype effect.

Pathogenic mutations in CYLD can be identified in patients affected with Brooke-Spiegler syndrome, (Familial) Cylindromatosis or multiple familial trichoepithelioma. To date, only technologies which are able to identify small point mutations in CYLD, such as sequence and WAVE analysis, were used. Here we describe the identification of a larger rearrangement identified by Quantitative PCR analysis of CYLD, indicating that a combination of these technologies is necessary when searching for pathogenic mutations in CYLD.

Background: Several cases have been reported of patients with a ring chromosome 18 replacing one of the normal chromosomes 18. Less common are patients with a supernumerary ring chromosomes 18. High resolution whole genome examination in patients with multiple congenital abnormalities might reveal cytogenetic abnormalities of an unexpected complexity., Results: We report a 24 years old male patient with lower spinal anomalies, hypospadia, bifid scrotum, cryptorchism, anal atresia, kidney stones, urethra anomalies, radial dysplasia, and a hypoplastic thumb. Some of the anomalies overlap with the VACTERL association. Chromosome analysis of cultured peripheral blood lymphocytes revealed an additional ring chromosome in 13% of the metaphases. Both parents had a normal karyotype, demonstrating the de novo origin of this ring chromosome. FISH analysis using whole chromosome paints showed that the additional chromosomal material was derived from chromosome 18. Chromosome analysis of cultured fibroblasts revealed only one cell with the supernumerary ring chromosome in the 400 analyzed. To characterize the ring chromosome in more detail peripheral blood derived DNA was analyzed using SNP-arrays. The array results indicated a 5 Mb gain of the pericentromeric region of chromosome 18q10-q11.2. FISH analysis using BAC-probes located in the region indicated the presence of 6 signals on the r(18) chromosome. In addition, microsatellite analysis demonstrated that the unique supernumerary ring chromosome was paternally derived and both normal copies showed biparental disomy., Conclusions: We report on an adult patient with multiple congenital abnormalities who had in 13% of his cells a unique supernumerary ring chromosome 18 that was composed of 6 copies of the 5 Mb gene rich region of 18q11.

The first experiments for bridging peripheral nerve gaps using nerve tubulation emerged in the 19th century. Because Gluck (1853-1942) is said to have performed the first animal experiment of nerve tubulation in 1880, it is interesting to explore the background and veracity of this claim. The original documents on nerve tubulation in the 19th century were studied. We conclude that the conduit that was initially used for nerve tubulation was derived from a resorbable decalcified bone tube developed for wound drainage by Neuber (1850-1932) in 1879. Gluck proposed the use of the bone tube as a guided conduit for regenerating nerves in 1881 but stated briefly that his experiments failed because of scar formation. Vanlair (1839-1914) documented the first successful application of nerve tubulation using a bone tube to bridge a 3 cm sciatic nerve defect in a dog in 1882.

Background: Malformations of cortical development (MCDs) are a major source of handicap. Much progress in understanding the genetic causes has been made recently. The number of affected children in whom a molecularly confirmed diagnosis can be made is unclear., Objective: To evaluate the etiology of MCDs in children and the effect of a combined radiological, clinical, and syndrome classification., Design: A case series of 113 children with a radiological diagnosis of MCD from January 1, 1992, to January 1, 2006., Setting: The Erasmus Medical Center-Sophia Children's Hospital, a secondary and tertiary referral center., Patients: Patients with MCD underwent a complete radiological, clinical, and neurological assessment and testing for known genes involved in the pathogenesis of MCD as appropriate for their phenotype., Results: We established an etiological diagnosis in 45 of 113 cases (40%). For 21 patients (19%), this included molecular and/or genetic confirmation (Miller-Dieker syndrome; LIS1, DCX, FLNA, EIF2AK3, or KIAA1279 mutations; or an inborn error of metabolism). In 17 (15%), a syndrome with an unknown genetic defect was diagnosed. In 7 patients (6%), we found evidence of a gestational insult. Of the remaining 68 patients, 34 probably have a yet-unknown genetic disorder based on the presence of multiple congenital anomalies (15 patients), a family history with multiple affected persons (12 patients), or consanguineous parents (7 patients)., Conclusions: In our cohort, combining diagnostic molecular testing with clinical, radiological, and genetic classification; syndrome identification; and family study provided a diagnosis in 40% of the cases of MCD. This contributes to the possibility of prenatal diagnosis and improved patient treatment and disease management.

Objective: To compare The anatomy lesson of Dr Nicolaes Tulp by Rembrandt (1632) with the findings during dissection of the forearm of a cadaver., Design: Descriptive., Method: The left forearm of a 41-year-old white male cadaver was dissected, photographs being taken at every stage of dissection. The anatomical structures in the original painting and during dissection were described and compared. At dissection, several structures were displaced in an attempt to reproduce the anatomical structures as shown in the painting., Results: Dissection revealed four anatomical differences in comparison with Rembrandt's painting: (a) the muscle belly seen at the proximal ulnar side of the forearm in the painting was not seen on dissection; section of the insertion of the M. flexor carpi radialis and transposition of this muscle to the location of the muscle belly created the possibility of lifting up the M. flexor digitorum superficialis and reproducing the muscle belly; (b) in the painting, Tulp lifted only the M. flexor digitorum superficialis, but the amount of muscle tissue found in the forceps was increased in the painting compared with the dissection; (c) the positions of the bellies of the M. flexor digitorum superficialis to the index finger and 5th digit and to the 3rd and 4th digits were found to be reversed; (d) the longitudinal white structure situated in the ulnar part of the 5th digit in the painting was not found on dissection. This may have been an anatomical variant of the ulnar nerve., Conclusion: The anatomical characteristics of the painting could not be reproduced by dissection of the forearm of a cadaver.

Mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe two Dutch families with familial frontotemporal dementia associated with the novel missense mutation L315R in exon 11 of tau. The age at onset of disease showed a large variation within each family, ranging from 25 to 64 years. Incomplete penetrance was established in an 82-year-old mutation carrier with no signs of dementia and appeared probable in two additional subjects. The brains of two affected subjects were studied and showed extensive tau pathology in neurons (Pick-like inclusions) and astroglial cells, particularly in the frontotemporal cortex and the hippocampal formation. Sarkosyl-insoluble tau extracted from the cerebral cortex showed the presence of straight and twisted tau filaments and a pattern of pathological tau bands similar to that of Pick's disease. Upon dephosphorylation, only five of the six brain tau isoforms were observed, with the shortest isoform being undetectable. All six tau isoforms were present in soluble brain tau. Recombinant tau proteins with the L315R mutation showed a reduced ability to promote microtubule assembly.

Hereditary spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders for which >/=14 different genetic loci have been identified. In some SCA types, expanded tri- or pentanucleotide repeats have been identified, and the length of these expansions correlates with the age at onset and with the severity of the clinical phenotype. In several other SCA types, no genetic defect has yet been identified. We describe a large, three-generation family with early-onset tremor, dyskinesia, and slowly progressive cerebellar ataxia, not associated with any of the known SCA loci, and a mutation in the fibroblast growth factor 14 (FGF14) gene on chromosome 13q34. Our observations are in accordance with the occurrence of ataxia and paroxysmal dyskinesia in Fgf14-knockout mice. As indicated by protein modeling, the amino acid change from phenylalanine to serine at position 145 is predicted to reduce the stability of the protein. The present FGF14 mutation represents a novel gene defect involved in the neurodegeneration of cerebellum and basal ganglia.