Investigation of BAK, BAX and MAD2L1 gene expression in human aneuploid blastocysts.

Maintaining genomic stability is crucial for normal development. At earlier stages of preimplantation development, as the embryonic genome activation is not fully completed, the embryos may be more prone to abnormalities. Aneuploidies are one of the most common genetic causes of implantation failure or first-trimester miscarriages. Apoptosis is a crucial mechanism to eliminate damaged or abnormal cells from the organism to enable healthy growth. Therefore, this study aimed to determine the relationship between the expression levels of genes involved in apoptosis in human aneuploid and euploid blastocysts. In total, 32 human embryos obtained from 21 patients were used for this study. Trophectoderm biopsies were performed and next-generation screening was carried out for aneuploidy screening. Total RNA was extracted from each blastocyst separately and cDNA was synthesized. Gene expression levels were evaluated using RT-PCR. The statistical analysis was performed to evaluate the gene expression level variations in the euploid and aneuploid embryos, respectively. The expression level of the BAX gene was significantly different between the aneuploid and euploid samples. BAX expression levels were found to be 1.5-fold lower in aneuploid cells. However, the expression levels of BAK and MAD2L1 genes were similar in each group. This study aimed to investigate the possible role of genes involved in apoptosis and aneuploidy mechanisms. The findings of this investigation revealed that the BAX gene was expressed significantly differently between aneuploid and euploid embryos. Therefore, it is possible that the genes involved in the apoptotic pathway have a role in the aneuploidy mechanism.

Improved clinical utility of preimplantation genetic testing through the integration of ploidy and common pathogenic microdeletions analyses.

STUDY QUESTION: Can chromosomal abnormalities beyond copy-number aneuploidies (i.e. ploidy level and microdeletions (MDs)) be detected using a preimplantation genetic testing (PGT) platform? SUMMARY ANSWER: The proposed integrated approach accurately assesses ploidy level and the most common pathogenic microdeletions causative of genomic disorders, expanding the clinical utility of PGT. WHAT IS KNOWN ALREADY: Standard methodologies employed in preimplantation genetic testing for aneuploidy (PGT-A) identify chromosomal aneuploidies but cannot determine ploidy level nor the presence of recurrent pathogenic MDs responsible for genomic disorders. Transferring embryos carrying these abnormalities can result in miscarriage, molar pregnancy, and intellectual disabilities and developmental delay in offspring. The development of a testing strategy that integrates their assessment can resolve current limitations and add valuable information regarding the genetic constitution of embryos, which is not evaluated in PGT providing new level of clinical utility and valuable knowledge for further understanding of the genomic causes of implantation failure and early pregnancy loss. To the best of our knowledge, MDs have never been studied in preimplantation human embryos up to date. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort analysis including blastocyst biopsies collected between February 2018 and November 2021 at multiple collaborating IVF clinics from prospective parents of European ancestry below the age of 45, using autologous gametes and undergoing ICSI for all oocytes. Ploidy level determination was validated using 164 embryonic samples of known ploidy status (147 diploids, 9 triploids, and 8 haploids). Detection of nine common MD syndromes (-4p=Wolf-Hirschhorn, -8q=Langer-Giedion, -1p=1p36 deletion, -22q=DiGeorge, -5p=Cri-du-Chat, -15q=Prader-Willi/Angelman, -11q=Jacobsen, -17p=Smith-Magenis) was developed and tested using 28 positive controls and 97 negative controls. Later, the methodology was blindly applied in the analysis of: (i) 100 two pronuclei (2PN)-derived blastocysts that were previously defined as uniformly euploid by standard PGT-A; (ii) 99 euploid embryos whose transfer resulted in pregnancy loss. PARTICIPANTS/MATERIALS, SETTING, METHODS: The methodology is based on targeted next-generation sequencing of selected polymorphisms across the genome and enriched within critical regions of included MD syndromes. Sequencing data (i.e. allelic frequencies) were analyzed by a probabilistic model which estimated the likelihood of ploidy level and MD presence, accounting for both sequencing noise and population genetics patterns (i.e. linkage disequilibrium, LD, correlations) observed in 2504 whole-genome sequencing data from the 1000 Genome Project database. Analysis of phased parental haplotypes obtained by single-nucleotide polymorphism (SNP)-array genotyping was performed to confirm the presence of MD. MAIN RESULTS AND THE ROLE OF CHANCE: In the analytical validation phase, this strategy showed extremely high accuracy both in ploidy classification (100%, CI: 98.1-100%) and in the identification of six out of eight MDs (99.2%, CI: 98.5-99.8%). To improve MD detection based on loss of heterozygosity (LOH), common haploblocks were analyzed based on haplotype frequency and LOH occurrence in a reference population, thus developing two further mathematical models. As a result, chr1p36 and chr4p16.3 regions were excluded from MD identification due to their poor reliability, whilst a clinical workflow which incorporated parental DNA information was developed to enhance the identification of MDs. During the clinical application phase, one case of triploidy was detected among 2PN-derived blastocysts (i) and one pathogenic MD (-22q11.21) was retrospectively identified among the biopsy specimens of transferred embryos that resulted in miscarriage (ii). For the latter case, family-based analysis revealed the same MD in different sibling embryos (n = 2/5) from non-carrier parents, suggesting the presence of germline mosaicism in the female partner. When embryos are selected for transfer based on their genetic constitution, this strategy can identify embryos with ploidy abnormalities and/or MDs beyond aneuploidies, with an estimated incidence of 1.5% (n = 3/202, 95% CI: 0.5-4.5%) among euploid embryos. LIMITATIONS, REASONS FOR CAUTION: Epidemiological studies will be required to accurately assess the incidence of ploidy alterations and MDs in preimplantation embryos and particularly in euploid miscarriages. Despite the high accuracy of the assay developed, the use of parental DNA to support diagnostic calling can further increase the precision of the assay. WIDER IMPLICATIONS OF THE FINDINGS: This novel assay significantly expands the clinical utility of PGT-A by integrating the most common pathogenic MDs (both de novo and inherited ones) responsible for genomic disorders, which are usually evaluated at a later stage through invasive prenatal testing. From a basic research standpoint, this approach will help to elucidate fundamental biological and clinical questions related to the genetics of implantation failure and pregnancy loss of otherwise euploid embryos. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. S.C., M.F., F.C., P.Z., I.P., L.G., C.P., M.P., D.B., J.J.-A., D.B.-J., J.M.-V., and C.R. are employees of Igenomix and C.S. is the head of the scientific board of Igenomix. A.C. and L.P. are employees of JUNO GENETICS. Igenomix and JUNO GENETICS are companies providing reproductive genetic services. TRIAL REGISTRATION NUMBER: N/A.

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

Psychiatric comorbidities of children with elimination disorders.

Enuresis and encopresis can be stressful for children and parents. We investigated the comorbid psychiatric disorders and the emotional and behavioral symptoms associated with elimination disorders. A total of 97 children and adolescents (aged 4-17 years) with an elimination disorder participated in this study. The elimination disorder group consisted of three subgroups: 50 subjects with enuresis nocturna, 26 with encopresis, and 21 subjects with enuresis+encopresis. The control group with no elimination disorder comprised 50 healthy subjects. All children were interviewed by a child and adolescent psychiatrist. Comorbid psychiatric disorders were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL). Parents completed the Strengths and Difficulties Questionnaire. The most common diagnosis was attention-deficit/hyperactivity disorder, followed by oppositional defiant disorder. The highest rate of psychiatric comorbidity was observed in the enuresis+encopresis subgroup, followed by the enuresis nocturna and encopresis subgroups. All the subgroups had higher total difficulties scores than the control group. Screening for psychiatric disorders should be performed for all children with incontinence.

Investigating the level of DNA double-strand break in human spermatozoa and its relation to semen characteristics and IVF outcome using phospho-histone H2AX antibody as a biomarker.

BACKGROUND: Sperm DNA fragmentation and its relation to conventional semen parameters are well studied. However, there is limited information regarding the rate of DNA double-strand breaks (DSBs) and its correlation to basic semen parameters and IVF outcome. OBJECTIVES: The present study aimed to investigate the rate of DNA DSBs in human spermatozoa and its correlation to basic semen parameters and IVF outcome. MATERIALS AND METHODS: The prospective study includes 60 assisted reproductive treatment cycles (52 autologous and eight donors) in which the semen profiles and sperm DNA DSBs have been assessed. The level of sperm DNA DSBs in each sample has been evaluated by using a method to detect histone H2AX phosphorylation. The results were compared with basic semen values and IVF outcomes. RESULTS: No significant correlation was observed between phospho-histone H2AX (γH2AX) levels and basic semen parameters such as semen volume (p = 0.129), sperm count (p = 0.454), total motility (p = 0.934), progressive motility (p = 0.314) and normal sperm morphology (p = 0.720). Similarly, the mean values of γH2AX did not differ with regard to the age of male participants (p = 0.300). However, cycles that resulted in live birth exhibited lower levels of γH2AX (p = 0.007). Accordingly, the level of γH2AX (p < 0.004) and rate of normal sperm morphology (p = 0.015) were found to be variables that affect the live birth outcomes. DISCUSSION AND CONCLUSION: The low levels of γH2AX in sperm cells may be an indicator to IVF outcome independently from the conventional semen parameters and male age.

Etiology of first-ever ischaemic stroke in European young adults: the 15 cities young stroke study.

BACKGROUND AND PURPOSE: Risk factors for IS in young adults differ between genders and evolve with age, but data on the age- and gender-specific differences by stroke etiology are scare. These features were compared based on individual patient data from 15 European stroke centers. METHODS: Stroke etiology was reported in detail for 3331 patients aged 15-49 years with first-ever IS according to Trial of Org in Acute Stroke Treatment (TOAST) criteria: large-artery atherosclerosis (LAA), cardioembolism (CE), small-vessel occlusion (SVO), other determined etiology, or undetermined etiology. CE was categorized into low- and high-risk sources. Other determined group was divided into dissection and other non-dissection causes. Comparisons were done using logistic regression, adjusting for age, gender, and center heterogeneity. RESULTS: Etiology remained undetermined in 39.6%. Other determined etiology was found in 21.6%, CE in 17.3%, SVO in 12.2%, and LAA in 9.3%. Other determined etiology was more common in females and younger patients, with cervical artery dissection being the single most common etiology (12.8%). CE was more common in younger patients. Within CE, the most frequent high-risk sources were atrial fibrillation/flutter (15.1%) and cardiomyopathy (11.5%). LAA, high-risk sources of CE, and SVO were more common in males. LAA and SVO showed an increasing frequency with age. No significant etiologic distribution differences were found amongst southern, central, or northern Europe. CONCLUSIONS: The etiology of IS in young adults has clear gender-specific patterns that change with age. A notable portion of these patients remains without an evident stroke mechanism according to TOAST criteria.

Cerebral venous thrombosis in Behçet's disease compared to those associated with other etiologies.

Cerebral venous thrombosis (CVT) is caused by various etiologies. In Mediterranean and Middle Eastern countries, Behçet's disease (BD) is one of the leading causes of CVT. We aimed to evaluate any differences in CVT patients with and without BD. All registered patients with CVT were evaluated retrospectively. Clinical, neuroradiological findings and follow-up data were compared between patients with BD and patients with other etiologies. There were 36 patients with CVT and BD, and 32 patients with CVT related to other etiological causes. BD patients were younger (median age at onset 26 vs. 39 years; P < 0.001), and there was a male preponderance (28 males, 8 females) as compared to the non-BD group (10 males, 22 females; P < 0.001). Onset was frequently acute in the non-BD group, and it was subacute or chronic in the BD group. Hemi/quadriparesis, aphasia and seizures were significantly more common (P < 0.001) in the non-BD group. In the BD group 94% of the patients presented with symptoms of isolated intracranial hypertension (P < 0.001). Venous infarcts were observed in 63% of the patients with other causes and in 6% of the patients with BD (P < 0.001). At admission 97% of the patients in the BD group and 41% of the patients in the non-BD group had a modified Rankin score of 0-2. Outcome was good in all of the patients with BD and in 91% of patients with other causes. Clinical recurrences were seen in six patients with BD and in one patient without BD. CVT associated with BD has a subacute onset, mostly presents with signs of isolated intracranial hypertension and venous infarction rarely develops; these features distinguish CVT due to BD from those with other causes.

Effect of barn ventilation on blood gas status and some physiological traits of dairy cows.

Twenty Holstein friesian and Brown swiss cows were used to investigate the effect of insufficient in barn ventilation on blood gas status and some physiological traits of the cows. Animals were kept in mechanically ventilated barn in stall barn (I); and the ventilation funnels of the barn were closed to simulate traditional habits of the region's breeders (II); then cows were transfered open-shed barn (III). For each experimental of 10 days period, respiration and pulse rates and blood gas of animals were measured. Temperature, relative humidity, CO2 and NH3 concentrations were recorded in each barns. In mechanically ventilated barn, climatic and atmospheric gas was in normal ranges for the cows but in unventilated barn they were at the upper levels. In experiment II, blood pH was decreased without pCO2 change. The highest blood pO2 and HCO3(-) levels were found when the animals were kept in open-shed barn (III). Measured parameters were not influenced by breed of the cows. Blood pH, pO2 HCO3(-), respiration and pulse rates of the cows were significantly affected by barn types (p < 0.05 and p < 0.01). Respiration and pulse rates were higher in inadequate (II) barn conditions than those of open-shed. Higher levels of gases, especially carbon dioxide, in the unventilated barn significantly influenced biological parameters of cows. It is concluded that poor ventilation caused considerable changes in physiologic parameters of the cows and can potentially affect animal health and production.

Stroke unit versus neurology ward--a before and after study.

INTRODUCTION: Few studies have tested the hypothesis of whether the beneficial effect of Stroke Units (SUs) can be reproduced in routine clinical practice and whether SU are also superior to neurological wards [NWs]. We aimed to compare the outcomes of patients of a newly implemented SU to the outcomes of patients hospitalized in a NW. METHODS: We made a before-after comparison of 352 SUs and 352 NWs patients after adjusting for case-mixes by the multivariate method. Subgroup analyses were also performed to evaluate which patient groups benefit the most. In-hospital case-fatality, proportion of independent patients at discharge, length of hospital stay (LOHS), medical complication rate were the main outcome measures. RESULTS: Adjusted in-hospital case fatality was significantly reduced in the SUs (OR: 0.44, 95 % CI: 0.26-0.76; p = 0.003). The proportion of independent patients at discharge and patients having medical complications was not different. Length of hospital stay was shorter in SU patients (13.76 days vs. 16.72 days, p = 0.003). Treatment in the SUs decreased case fatality in many subgroups [men, elderly, early admitted, severe stroke, co-morbidity present and ischemic stroke groups]. DISCUSSION: The results of randomized trials in favor of SUs can be reproduced in routine clinical practice. The benefit of SU care seems to be more apparent with advancing age and increasing stroke severity. Stroke Unit seems to be a better alternative to an experienced NW.

Cranial MRI in Behçet's disease: 134 examinations of 98 patients.

Two observers, blinded to the patient's neurological status, reviewed 134 MRI studies of 98 consecutive patients with Behçet's disease (BD), to define imaging patterns and to look for any relationship between the MRI findings and the timing of the examination in patients with differing courses of disease. There were 43 patients with overt parenchymal central nervous system (CNS) involvement, 22 with attacks and remissions, 15 with secondary progressive and six with primary progressive disease; 14 had raised intracranial pressure (RICP). Of the remaining 41 patients without specific neurological complaints, 16 had abnormalities on examination (silent CNS involvement) and 25 did not. During an acute CNS attack, the most common finding was a large lesion in the brain-stem or basal ganglia, extending to the diencephalon. On MRI performed after remission of an acute attack or during secondary progression, the same sites were affected, but the lesions were smaller or scattered, with less clearly defined margins. In primary progressive disease or silent CNS involvement, the cerebral white matter was most commonly involved, but almost half the MRI studies were normal. The brain parenchyma was abnormal in only one of the patients with RICP. MRI was normal in all but three patients without clinical CNS involvement, in whom it showed a few millimetric white-matter lesions. Brain-stem atrophy was seen in 15 patients examined >1 year after an initial parenchymal CNS episode, with secondary progressive cases predominating.

Internuclear ophthalmoplegia and cerebellar ataxia: report of one case.

Deep hemispheric or brainstem small infarcts can lead to atypical lacunar syndromes. Unilateral internuclear ophthalmoplegia (INO) and cerebellar ataxia has not been reported previously. A 57-year-old hypertensive female presented with bilateral appendicular and left truncal cerebellar ataxia and right INO. Cranial MRI showed a right paramedian infarct of lacunar size located in the tegmentum of caudal mesencephalon. At this level the involvement of medial longitudinal fascicle (MLF) led to right INO and the lesion of brachium conjunctivum caused the bilateral cerebellar ataxia. Ipsilateral involvement of both cerebellofugal fibers, before and after decussation, was responsible for bilateral cerebellar ataxia.

Venous infarction of brainstem and cerebellum.

The authors describe 2 cases of posterior fosa venous infarction. A 56-year-old woman with essential thrombocytemia presented with fluctuating complaints of headache, nausea, vomiting, left-sided numbness-weakness, and dizziness and became progressively stuporous. Cranial magnetic resonance imaging (MRI) showed bilateral parasagittal fronto-parietal and left cerebellar contrast-enhancing hemorrhagic lesions. On magnetic resonance venography, the left transverse and sigmoid sinuses were occluded. The second patient, a 39-year-old woman, presented with acute onset of diplopia, numbness of the tongue, vertigo, and right-sided weakness following a gestational age stillbirth. MRI revealed lesions in the right half of midbrain and pons and in the superior part of the right cerebellar hemisphere. Digital subtraction angiography showed right transverse and sigmoid sinus occlusion. The authors suggest that one should investigate the possibility of venous infarction in the presence of posterior fossa lesions that are often hemorrhagic and are not within any arterial territory distribution but respect a known venous drainage pattern. Recognition of the observed clinical and neuroimaging features can lead to earlier diagnosis and, potentially, more effective management.

Cerebral vasculitis and ischaemic stroke in Behçet's disease: report of one case and review of the literature.

INTRODUCTION: Behçet's disease (BD) is a multisystemic, recurrent, inflammatory disorder. Neurological involvement is well-known but cerebral vasculitis and ischaemic stroke are unusual. CASE DESCRIPTION: A 43-year-old male patient presented with acute left hemiparesis, he had recurrent oral aphthae and scrotal ulcerations. Two episodes of transient brainstem ischaemia and an episode of right hemiparesis were reported in the past 2 years. Cranial magnetic resonance (MR) imaging showed a right striatocapsular infarction and multiple segmental stenosis, fusiform enlargement and beading of the arteries of the polygone of Willis were seen on angiography. Cerebro-spinal fluid (CSF) examination disclosed lymphocytic pleocytosis. Skin pathergy test was positive. A diagnosis of BD with cerebral vasculitis was made and immunosuppressive therapy was started. Some improvement of the arterial lesions on MR angiography and normalization of CSF were observed after 1 year of treatment. DISCUSSION: Low grade chronic meningo-encephalitis is the core neuropathological process in neuro-Behçet's disease. Nevertheless BD is a systemic disease known to cause vasculitis and can exceptionally lead to cerebral vasculitis and brain infarction. While BD is usually not part of the differential diagnosis of cerebral vasculitis, it should be borne in mind especially in endemic areas of the disease and in patients from these areas.

Masked assessment of MRI findings: is it possible to differentiate neuro-Behçet's disease from other central nervous system diseases? [corrected].

Two neuroradiologists reviewed MRI studies of 34 patients with neuro-Behcet's disease (NBD), 22 with multiple sclerosis (MS) and 7 with systemic lupus erythematosus (SLE) with central nervous system involvement, masked to the clinical diagnosis, age and sex of the patients. Of the patients with NBD 12 were in an acute attack; the others had chronic disease. MRI was assessed using a set of criteria, looking at atrophy, the site of discrete parenchymal lesions, regions of predominant involvement and the extent of the lesion(s). The observers also made a guess at the clinical diagnosis. The brain stem and/or basal ganglia were the most predominantly involved sites in all patients with acute NBD; 75% of these lesions were large and confluent, mainly extending from the brain stem to the diencephalon and basal ganglia. However, in chronic cases, the predominant involvement was in the brain stem and/or basal ganglia in only 36%, and in cerebral hemisphere white matter in another 36%; 27% of these patients showed no parenchymal lesion. Hemisphere white-matter lesions were equally distributed between periventricular and other areas in NBD, while in MS more were periventricular, and in SLE more were nonperiventricular. Brain-stem atrophy was seen in 21% of patients with NBD, with a specificity of 96.5%. In the absence of cortical atrophy, its specificity was 100%. The attempt at making a radiological diagnosis was successful in all cases of acute NBD and 95.5% of patients with MS, but in only 40% of patients with chronic NBD. Most of this latter groups MRI studies were interpreted as MS. An extensive lesion involving the brain stem and basal ganglia seemed to be diagnostic of acute NBD. However, hemisphere white-matter lesions could not be differentiated from those in MS.

Protein C and protein S activities in Behçet's disease as risk factors of thrombosis.

BACKGROUND: In Behçet's disease (BD), there is a marked increase in vascular complications. Approximately 30% of patients with BD suffer from thrombosis of the arteries and veins, varices, aneurysms, and thrombophlebitis of superficial or deep veins. Protein C and Protein S are major inhibitors of coagulation, and it is well known that the deficiency of Protein C and Protein S causes thrombotic disorders. METHODS: Protein C and Protein S activities were measured in 23 patients with BD and in a control group consisting of 23 age- and sex-matched healthy volunteers. Patients who had received anticoagulant or oral contraceptive drugs, or who had liver disease or active thrombosis, were not included in the study. RESULTS: Of the 23 patients with BD (age, 13-55 years), the mean Protein S activities (94.2 +/- 11.3%) were slightly lower than the means of the control group (109.1 +/- 8.4%), but not statistically significant differences could be demonstrated (p > 0.05). Compared with the means of the control group (103.5 +/- 6.9%), the Protein C activities were not lower in BD (106.3 +/- 8.4%). No statistical difference was determined. CONCLUSIONS: Protein C and Protein S deficiencies are not a probable cause of thrombotic manifestations in BD. We do not recommend the measurement of these activities routinely in BD unless thrombosis is the major and primary manifestation of BD.

A controlled study of reliability and validity of MRI findings in neuro-Behçet's disease.

Our aim was to test the reliability of interpreting MRI studies in neuro-Behçet's disease (NBD) and to determine the sensitivity and specificity of different MRI findings. We prospectively studied 50 patients: 24 had chronic NBD, 12 multiple sclerosis, 5 vasculitis other than Behçet's disease (BD) and 9 patients had BD without neurological involvement. MRI studies were performed according to a standard protocol with a 0.2 T imager. Two neuroradiologists, blinded to the diagnosis, age and sex of the subjects, reviewed the films independently, twice. Separate assessments were made for a set of items: dural sinus pathology, widening of ventricles and sulci, brain stem atrophy, lesions of the cerebral cortex, discrete lesions of deep white matter, basal ganglia, brain stem and cerebellum and the presence of smooth periventricular high-signal foci. Intraobserver agreement was substantial or better, and interobserver agreement moderate to substantial for most items. In these patients with chronic NBD we found low sensitivity on all assessed items. Dural sinus pathology or brain stem atrophy were highly specific, but parenchymal lesions in different sites had uniformly low specificity.

[Lipoid proteinosis in 2 sisters]. / Lipoidproteinose bei zwei Schwestern.

Lipoid proteinosis was diagnosed in two daughters of a consanguinous marriage on the basis of genetic, clinical, light microscopic and ultrastructural findings. Hyaline material accumulation, thickening of the basal laminae and the resulting typical onion skin phenomenon were observed. In addition to the pathognomonic cutaneous mucosal findings, unusual manifestations such as persistence of deciduous teeth (in one case), oligodontia and intracerebral calcifications were observed. In one patient, the intracerebral calcifications caused epileptic seizures.

Spontaneous dissection of the extracranial vertebral artery with spinal subarachnoid haemorrhage in a patient with Behçet's disease.

A 40-year-old man with known definite Behçet's disease (BD) was admitted with confusional state which had started 4 days before admission with an acute headache and vomiting. Neurological examination revealed confusion, stiff neck, right facial weakness, left hemiparesis, dysartria and truncal ataxia. CSF was haemorrhagic and xanthochromic. Cranial CT scans were negative, but MRI showed a right pontine hyperintense lesion on T2-weighted images. Bilateral carotid angiograms were normal. Right vertebral angiogram showed findings consistent with a dissection at the V2 segment of the artery. At the level of the fifth cervical vertebra, a radiculomedullary branch of the vertebral artery with an aneurysmal dilatation in its intradural portion was notable. This case shows that, in BD, aneurysm formation can also occur in a spinal artery and spontaneous vertebral artery dissection can be seen.