High risk of ischaemic stroke amongst patients with hereditary haemorrhagic telangiectasia.

BACKGROUND AND PURPOSE: Hereditary haemorrhagic telangiectasia (HHT) is a genetic disease with fragile blood vessels and vascular malformations, potentially causing neurological manifestations, including stroke and cerebral abscesses. The study aimed to investigate neurological manifestations in the Danish HHT database, focusing on pulmonary arteriovenous malformations (PAVMs) as a risk factor for cerebral events. METHODS: Retrospective analysis of the Danish HHT database was conducted, cross-referencing neurological outcomes with the Danish Apoplexy Register for accuracy. Patients were stratified by HHT type. Primary outcomes included ischaemic stroke, transient ischaemic attack and cerebral haemorrhage. Secondary outcomes comprised age, age at HHT diagnosis, age at cerebral ischaemic event, and PAVM and cerebral arteriovenous malformation status. RESULTS: Six hundred and sixty-four HHT patients were included. PAVM was diagnosed in 54% of patients, with higher prevalence in HHT type 1 (70%) compared to HHT type 2 (34%) and juvenile polyposis HHT (66%). Ischaemic stroke or transient ischaemic attack occurred in 12.5%, with a higher risk associated with macroscopic PAVM. Logistic regression showed a nearly 10 times increased risk of ischaemic stroke with macroscopic PAVM. Cerebral abscesses occurred in 3.2% of patients, all with macroscopic PAVM. Incomplete PAVM closure increased cerebral abscess risk. CONCLUSION: This study provides valuable insights into the prevalence of neurological manifestations and vascular events in HHT patients. The presence of PAVM was associated with an increased risk of ischaemic stroke, highlighting the importance of early screening and intervention. The findings emphasize the need for comprehensive management strategies targeting both vascular and neurological complications in HHT patients, especially regarding secondary stroke prevention.

A randomized, double-blind trial comparing the effect of two blood pressure targets on global brain metabolism after out-of-hospital cardiac arrest.

PURPOSE: This study aimed to assess the effect of different blood pressure levels on global cerebral metabolism in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). METHODS: In a double-blinded trial, we randomly assigned 60 comatose patients following OHCA to low (63 mmHg) or high (77 mmHg) mean arterial blood pressure (MAP). The trial was a sub-study in the Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial (BOX). Global cerebral metabolism utilizing jugular bulb microdialysis (JBM) and cerebral oxygenation (rSO2) was monitored continuously for 96 h. The lactate-to-pyruvate (LP) ratio is a marker of cellular redox status and increases during deficient oxygen delivery (ischemia, hypoxia) and mitochondrial dysfunction. The primary outcome was to compare time-averaged means of cerebral energy metabolites between MAP groups during post-resuscitation care. Secondary outcomes included metabolic patterns of cerebral ischemia, rSO2, plasma neuron-specific enolase level at 48 h and neurological outcome at hospital discharge (cerebral performance category). RESULTS: We found a clear separation in MAP between the groups (15 mmHg, p < 0.001). Cerebral biochemical variables were not significantly different between MAP groups (LPR low MAP 19 (16-31) vs. high MAP 23 (16-33), p = 0.64). However, the LP ratio remained high (> 16) in both groups during the first 30 h. During the first 24 h, cerebral lactate > 2.5 mM, pyruvate levels > 110 µM, LP ratio > 30, and glycerol > 260 µM were highly predictive for poor neurological outcome and death with AUC 0.80. The median (IQR) rSO2 during the first 48 h was 69.5% (62.0-75.0%) in the low MAP group and 69.0% (61.3-75.5%) in the high MAP group, p = 0.16. CONCLUSIONS: Among comatose patients resuscitated from OHCA, targeting a higher MAP 180 min after ROSC did not significantly improve cerebral energy metabolism within 96 h of post-resuscitation care. Patients with a poor clinical outcome exhibited significantly worse biochemical patterns, probably illustrating that insufficient tissue oxygenation and recirculation during the initial hours after ROSC were essential factors determining neurological outcome.

Perfusion Computed Tomography as a Screening Tool for Pending Delayed Cerebral Ischemia in Comatose Patients After Aneurysmal Subarachnoid Hemorrhage: A Retrospective Cohort Study.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is frequently complicated by delayed cerebral ischemia (DCI), leading to poor outcomes. Early diagnosis of DCI is crucial for improving survival and outcomes but remains challenging in comatose patients. In this study, we aimed to evaluate computed tomography with angiography and perfusion (P-CT) as a screening modality on postictal days four and eight for impending DCI after aSAH in comatose patients using vasospasm with hypoperfusion (hVS) as a surrogate and DCI-related infarction as an outcome measure. Two objectives were set: (1) to evaluate the screening's ability to accurately risk stratify patients and (2) to assess the validity of P-CT screening. METHODS: We conducted a retrospective review of the records of comatose patients with aSAH from January 2019 to December 2021 who were monitored with P-CT scans on days four and eight. The event rates of DCI-related infarction, hVS, and endovascular rescue therapy (ERT) were analyzed, and the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for DCI were calculated. DCI-related infarction was defined as new secondary cerebral infarction > 48 h < 6 weeks post aSAH not attributable to other causes, and hVS was defined as arterial narrowing with corresponding hypoperfusion on P-CT. RESULTS: Fifty-six comatose patients were included, and 98 P-CT scans were performed. The incidence of DCI-related infarction was 40%. Screening P-CT on days four and eight found vasospasm in 23% of all patients, including 11% with hVS. A positive hVS on day four or eight revealed a relative risk of 2.4 [95% confidence interval (CI) 1.13-5.11, p = 0.03], sensitivity of 23% (95% CI 8-45, p = 0.03), specificity of 95% (95% CI 36-100, p = 0.03), PPV of 0.83 (95% CI 0.36-1.00, p = 0.03), and NPV of 0.65 (95% CI 0.50-0.78). Six positive P-CT scans led to digital subtraction angiography in five patients, three of whom received ERT. All ERT-intervened patients developed DCI-related infarction. CONCLUSIONS: P-CT resulted in few interventions and often resulted in late detection of DCI at an irreversible stage. Although a positive P-CT result accurately predicts impending DCI-related infarction, screening on days four and eight alone in comatose patients with aSAH often fails to timely detect impending DCI. Based on our analysis, we cannot recommend P-CT as a screening modality. P-CT is likely best used as a confirmatory test prior to invasive interventions when guided by continuous multimodal monitoring; however, prospective studies with comparison groups are warranted. The need for a reliable continuous screening modality is evident because of the high rate of deterioration and narrow treatment window.

Virtual magnetic resonance elastography predicts the intraoperative consistency of meningiomas.

BACKGROUND AND PURPOSE: Virtual magnetic resonance elastography (vMRE) is an experimental imaging modality designed to non-invasively predict the haptic properties of tissues. The modality is sensitive to tissue stiffness and fibrosis. Information about meningioma consistency prior to resection is of great interest in neurological surgery as the surgical plan and outcome may be affected by the tumor's stiffness. In this study, we assessed the ability of vMRE to predict the intraoperative consistency and mechanical heterogeneity of intracranial meningiomas. MATERIALS AND METHODS: We included 12 patients scheduled for meningioma resection, of which one patient was found to have a solitary fibrous tumor on histological examination. All participants underwent preoperative vMRE and intraoperative consistency grading. RESULTS AND CONCLUSIONS: Intraoperative qualitative consistency correlated positively with vMRE-based consistency assessment (odds ratio 5.63, 95% CI 1.12-28.30, p = 0.04) at b1000. Mechanically homogenous tumors had significantly lower ∆ mean stiffness than heterogeneous tumors (8.13 vs 18.07 kPa, p = 0.01). This study thus demonstrates a possible clinical application of vMRE in predicting the intraoperative consistency and mechanical heterogeneity of meningiomas.

Novel Homozygous Truncating Variant Widens the Spectrum of Early-Onset Multisystemic SYNE1 Ataxia.

Pathogenic variants in the SYNE1 gene are associated with a phenotypic spectrum spanning from late-onset, slowly progressive, relatively pure ataxia to early-onset, fast progressive multisystemic disease. Since its first description in 2007 as an adult-onset ataxia in French Canadian families, subsequent identification of patients worldwide has widened the clinical spectrum and increased the number of identified pathogenic variants. We report a 20-year-old Faroese female with early-onset progressive gait problems, weakness, dysphagia, slurred speech, orthostatic dizziness, and urge incontinence. Neurological examination revealed mild cognitive deficits, dysarthria, broken slow pursuit, hypometric saccades, weakness with spasticity, hyperreflexia, absent ankle reflexes, ataxia, and wide-based, spastic gait. Magnetic resonance imaging displayed atrophy of the cerebellum, brainstem, and spinal cord. Severely prolonged central motor conduction time and lower motor neuron involvement was demonstrated electrophysiologically. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed hypometabolism of the cerebellum and right frontal lobe. Muscle biopsy revealed chronic neurogenic changes and near-absent immunostaining for Nesprin-1. Next-generation sequencing revealed a previously undescribed homozygous truncating, likely pathogenic variant in the SYNE1 gene. The patient's mother and paternal grandfather were heterozygous carriers of the variant. Her father's genotype was unobtainable. We expand the list of likely pathogenic variants in SYNE1 ataxia with a novel homozygous truncating variant with proximity to the C-terminus and relate it to a phenotype comprising early-onset cerebellar deficits, upper and lower motor neuron involvement and cognitive deficits. Also, we report novel findings of focally reduced frontal lobe FDG-PET uptake and motor evoked potential abnormalities suggestive of central demyelination.

Six generations of CHMP2B-mediated Frontotemporal Dementia: Clinical features, predictive testing, progression, and survival.

OBJECTIVES: Chromosome 3-linked frontotemporal dementia (FTD-3) is caused by a c.532-1G > C mutation in the CHMP2B gene. It is extensively studied in a Danish family comprising one of the largest families with an autosomal dominantly inherited frontotemporal dementia (FTD). This retrospective cohort study utilizes demographics to identify risk factors for onset, progression, life expectancy, and death in CHMP2B-mediated FTD. The pedigree of 528 individuals in six generations is provided, and clinical descriptions are presented. Choices of genetic testing are evaluated. MATERIALS AND METHODS: Demographic and lifestyle factors were assessed in survival analysis in all identified CHMP2B mutation carriers (44 clinically affected FTD-3 patients and 16 presymptomatic CHMP2B mutation carriers). Predictors of onset and progression included sex, parental disease course, education, and vascular risk factors. Life expectancy was established by matching CHMP2B mutation carriers with average life expectancies in Denmark. RESULTS: Disease course was not correlated to parental disease course and seemed unmodified by lifestyle factors. Diagnosis was recognized at an earlier age in members with higher levels of education, probably reflecting an early dysexecutive syndrome, unmasked earlier in people with higher work-related requirements. Carriers of the CHMP2B mutation had a significant reduction in life expectancy of 13 years. Predictive genetic testing was chosen by 20% of at-risk family members. CONCLUSIONS: CHMP2B-mediated FTD is substantiated as an autosomal dominantly inherited disease of complete penetrance. The clinical phenotype is a behavioral variant FTD. The disease course is unpredictable, and life expectancy is reduced. The findings may be applicable to other genetic FTD subtypes.

Early Intrathecal T Helper 17.1 Cell Activity in Huntington Disease.

OBJECTIVE: Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. No disease-modifying therapy exists for the treatment of patients with HD. The purpose of this study was therefore to investigate early disease mechanisms that potentially could be used as a target therapeutically. METHODS: Lymphocyte activity in cerebrospinal fluid (CSF) from 4 cohorts of HTT gene expansion carriers (n = 121 in total) and controls was analyzed by techniques based on flow cytometry and enzyme-linked immunosorbent assays. RESULTS: The data of this study provide evidence of immune abnormalities before motor onset of disease. In CSF of HTT gene expansion carriers, we found increased levels of proinflammatory cytokines, including IL-17, and increased consumption of the lymphocyte growth factor IL-7 before motor onset of HD. In concordance, we observed an increased prevalence of IL-17-producing Th17.1 cells in the CSF of HTT gene expansion carriers, predominantly in pre-motor manifest individuals. The frequency of intrathecal Th17.1 cells correlated negatively with progression of HD and the level of neurodegeneration, suggesting a role of Th17.1 cells in the early disease stage. We also observed a skewing in the balance between proinflammatory and regulatory T cells potentially favoring a proinflammatory intrathecal environment in HTT gene expansion carriers. INTERPRETATION: These data suggest that Th17.1 cells are implicated in the earliest pathogenic phases of HD and suggest that treatment to dampen T -cell-driven inflammation before motor onset might be of benefit in HTT gene expansion carriers. ANN NEUROL 2020;87:246-255.

Kawasaki disease, autoimmune disorders, and cancer: a register-based study.

Kawasaki disease has well-described cardiovascular complications. However, the association to autoimmunity and cancer in the long term is not well described. We investigated theses associations using a registry-based matched cohort follow-up study of patients diagnosed with Kawasaki disease. Patients with Kawasaki disease were included and matched 1:5 to a population control group, matched by birth year, sex and incident month of the Kawasaki disease diagnosis. A total of 820 cases < 21 years of age were identified. Median age at diagnosis was 3 years. Median follow-up time was 12 years. Patients with KD were at higher risk of being diagnosed with ischaemic heart disease at 10 years (HR 39.94 (95% CI 5.00-319.28)) and 30 years (HR 8.33 (95% CI 3.03-22.91)). The 10-, 20- and 30-year risks of developing autoimmune disorders were HR 4.23 (95% CI 3.01-5.94), HR 3.23 (95% CI 2.44-4.29) and 2.83 (95% CI, 2.17-3.68), all p < 0.001. Cancer risk was increased after 30 years (HR 2.42 (95% CI, 1.09-5.34)). All-cause mortality after 35 years was also significantly increased (HR 3.14 (95% CI, 1.03-9.60)). Children with KD have increased long-term risks of ischaemic heart disease also of autoimmune disease and cancer, as well as an increased all-cause mortality. The surprisingly increased risk of autoimmunity must be investigated further. What is known: • Kawasaki disease is characterized by acute vasculitis and inflammation that can affect the coronary arteries. • Anti-inflammatory medicine is effective in the acute stages of the disease. What is new: • Children with Kawasaki disease have an increased risk of developing autoimmune disease in the long term. • Kawasaki disease is associated with a slightly increased mortality rate driven by non-cardiovascular causes.

Paroxysmal Cranial Dyskinesia and Nail-Patella Syndrome Caused by a Novel Variant in the LMX1B Gene.

BACKGROUND: In a Danish family, multiple individuals in five generations present with early-onset paroxysmal cranial dyskinesia, musculoskeletal abnormalities, and kidney dysfunction. OBJECTIVE: To demonstrate linkage and to identify the underlying genetic cause of disease. METHODS: Genome-wide single-nucleotide polymorphisms analysis, Sequence-Tagged-Site marker analyses, exome sequencing, and Sanger sequencing were performed. RESULTS: Linkage analyses identified a candidate locus on chromosome 9. Exome sequencing revealed a novel variant in LMX1B present in all affected individuals, logarithm of the odds (LOD) score of z = 6.54, predicted to be damaging. Nail-patella syndrome (NPS) is caused by pathogenic variants in LMX1B encoding a transcription factor essential to cytoskeletal and kidney growth and dopaminergic and serotonergic network development. NPS is characterized by abnormal musculoskeletal features and kidney dysfunction. Movement disorders have not previously been associated with NPS. CONCLUSIONS: Paroxysmal dyskinesia is a heretofore unrecognized feature of the NPS spectrum. The pathogenic mechanism might relate to aberrant dopaminergic circuits. © 2020 International Parkinson and Movement Disorder Society.

Enhancement of Autophagy and Solubilization of Ataxin-2 Alleviate Apoptosis in Spinocerebellar Ataxia Type 2 Patient Cells.

Spinocerebellar ataxia type 2 (SCA2), a rare polyglutamine neurodegenerative disorder caused by a CAG repeat expansion in the ataxin-2 gene, exhibits common cellular phenotypes with other neurodegenerative disorders, including oxidative stress and mitochondrial dysfunction. Here, we show that SCA2 patient cells exhibit higher levels of caspase-8- and caspase-9-mediated apoptotic activation than control cells, cellular phenotypes that we find to be exacerbated by reactive oxygen species (ROS) and inhibition of autophagy. We also suggest that oligomerization of mutant ataxin-2 protein is likely to be the cause of the observed cellular phenotypes by causing inhibition of autophagy and by inducing ROS generation. Finally, we show that removal of ataxin-2 oligomers, either by increasing autophagic clearance or by oligomer dissolution, appears to alleviate the cellular phenotypes. Our results suggest that oligomerized ataxin-2 and oxidative stress affect autophagic clearance in SCA2 cells, contributing to the pathophysiology, and that activation of autophagy or clearance of oligomers may prove to be effective therapeutic strategies.

Serum Neurofilament Light in Patients with Frontotemporal Dementia Caused by CHMP2B Mutation.

INTRODUCTION: The potential of neurofilament light (NfL) as a blood-based biomarker is currently being investigated in autosomal dominant neurodegenerative disease. This study explores the clinical utility of serum-NfL in frontotemporal dementia due to CHMP2B mutation (FTD-3). METHODS: This cross-sectional study included serum and CSF data from 38 members of the Danish FTD-3 family: 12 affected CHMP2B mutation carriers, 10 presymptomatic carriers, and 16 noncarriers. Serum-NfL levels measured by single-molecule array (Simoa) technology were tested for associations with the clinical groups and clinical parameters. Serum and CSF data were compared, and CSF/serum-albumin ratio was included as a measure of blood-brain barrier (BBB) function. RESULTS: Serum-NfL concentrations were significantly increased in symptomatic CHMP2B mutation carriers compared to presymptomatic carriers and in both groups compared to healthy family controls. Serum-NfL levels appear to increase progressively with age in presymptomatic carriers, and this is perhaps followed by a change in trajectory when patients become symptomatic. Measurements of NfL in serum and CSF were highly correlated and fold-changes in serum and CSF between clinical groups were similar. Increase in serum-NFL levels was correlated with reduced ACE-score. Higher CSF/serum-albumin ratios were demonstrated in FTD-3 patients, but this did not affect the significant associations between serum-NfL and clinical groups. CONCLUSION: Serum-NfL could be utilized as an accurate surrogate marker of CSF levels to segregate symptomatic CHMP2B carriers, presymptomatic carriers, and non-carriers. The observed indication of BBB dysfunction in FTD-3 patients did not confound this use of serum-NfL. The results support the occurrence of mutation-related differences in NfL dynamics in familial FTD.

A Prospective Observational Feasibility Study of Jugular Bulb Microdialysis in Subarachnoid Hemorrhage.

BACKGROUND: Cerebral metabolic perturbations are common in aneurysmal subarachnoid hemorrhage (aSAH). Monitoring cerebral metabolism with intracerebral microdialysis (CMD) allows early detection of secondary injury and may guide decisions on neurocritical care interventions, affecting outcome. However, CMD is a regional measuring technique that is influenced by proximity to focal lesions. Continuous microdialysis of the cerebral venous drainage may provide information on global cerebral metabolism relevant for the care of aSAH patients. This observational study aimed to explore the feasibility of jugular bulb microdialysis (JBMD) in aSAH and describe the output characteristics in relation to conventional multimodal monitoring. METHODS: Patients with severe aSAH were included at admission or after in-house deterioration when local clinical guidelines prompted extended multimodal monitoring. Non-dominant frontal CMD, intracranial pressure (ICP), partial brain tissue oxygenation pressure (PbtO2), and cerebral perfusion pressure (CPP) were recorded every hour. The dominant jugular vein was accessed by retrograde insertion of a microdialysis catheter with the tip placed in the jugular bulb under ultrasound guidance. Glucose, lactate, pyruvate, lactate/pyruvate ratio, glycerol, and glutamate were studied for correlation to intracranial measurements. Modified Rankin scale was assessed at 6 months. RESULTS: Twelve adult aSAH patients were monitored during a mean 4.2 ± 2.6 days yielding 22,041 data points for analysis. No complications related to JBMD were observed. Moderate or strong significant monotonic CMD-to-JBMD correlations were observed most often for glucose (7 patients), followed by lactate (5 patients), and pyruvate, glycerol, and glutamate (3 patients). Moderate correlation for lactate/pyruvate ratio was only seen in one patient. Analysis of critical periods defined by ICP > 20, CPP < 65, or PbtO2 < 15 revealed a tendency toward stronger CMD-to-JBMD associations in patients with many or long critical periods. Possible time lags between CMD and JBMD measurements were only identified in 6 out of 60 patient variables. With the exception of pyruvate, a dichotomized outcome was associated with similar metabolite patterns in JBMD and CMD. A nonsignificant tendency toward greater differences between outcome groups was seen in JBMD. CONCLUSIONS: Continuous microdialysis monitoring of the cerebral drainage in the jugular bulb is feasible and safe. JBMD-to-CMD correlation is influenced by the type of metabolite measured, with glucose and lactate displaying the strongest associations. JBMD lactate correlated more often than CMD lactate to CPP, implying utility for detection of global cerebral metabolic perturbations. Studies comparing JBMD to other global measures of cerebral metabolism, e.g., PET CT or Xenon CT, are warranted.

Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation.

Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD. Therefore, we investigated neuroinflammation in our CHMP2B mutant mice. We observed very early microglial proliferation that develops into a clear pro-inflammatory phenotype at late stages. Importantly, we also observed a similar inflammatory profile in CHMP2B patient frontal cortex. Aberrant microglial function has also been implicated in FTD caused by GRN, MAPT and C9orf72 mutations. The presence of early microglial changes in our CHMP2B mutant mice indicates neuroinflammation may be a contributing factor to the neurodegeneration observed in FTD.

FGF2 and dual agonist of NCAM and FGF receptor 1, Enreptin, rescue neurite outgrowth loss in hippocampal neurons expressing mutated huntingtin proteins.

In the present study, we developed an in vitro model of Huntington disease (HD) by transfecting primary rat hippocampal neurons with plasmids coding for m-htt exon 1 with different number of CAG repeats (18, 50 and 115) and demonstrated the influence of the length of polyQ sequence on neurite elongation. We found that exogenously applied FGF2 significantly rescued the m-htt-induced loss of neurite outgrowth. Moreover, the Enreptin peptide, an FGFR1 and NCAM dual agonist, had a similar neuritogenic effect to FGF2 in clinically relevant m-htt 50Q-expressing neurons. This study has developed an in vitro model of primary hippocampal neurons transfected with m-htt-coding vectors that is a powerful tool to study m-htt-related effects on neuronal placticity.

Patterns of cerebral tissue oxygen tension and cytoplasmic redox state in bacterial meningitis.

BACKGROUND: Compromised cerebral energy metabolism is common in patients with bacterial meningitis. In this study, simultaneous measurements of cerebral oxygen tension and lactate/pyruvate ratio were compared to explore whether disturbed energy metabolism was usually caused by insufficient tissue oxygenation or compromised oxidative metabolism of pyruvate indicating mitochondrial dysfunction. SUBJECT AND METHODS: Ten consecutive patients with severe streptococcus meningitis were included in this prospective cohort study. Intracranial pressure, brain tissue oxygen tension (PbtO2 ), and energy metabolism (intracerebral microdialysis) were continuously monitored in nine patients. A cerebral lactate/pyruvate (LP) ratio <30 was considered indicating normal oxidative metabolism, LP ratio >30 simultaneously with pyruvate below lower normal level (70 µmol/L) was interpreted as biochemical indication of ischemia, and LP ratio >30 simultaneously with a normal or increased level of pyruvate was interpreted as mitochondrial dysfunction. The biochemical variables were compared with PbtO2 simultaneously monitored within the same cerebral region. RESULTS: In two cases, the LP ratio was normal during the whole study period and the simultaneously monitored PbtO2 was 18 ± 6 mm Hg. In six cases, interpreted as mitochondrial dysfunction, the simultaneously monitored PbtO2 was 20 ± 6 mm Hg and without correlation with the LP ratio. In one patient, exhibiting a pattern interpreted as ischemia, PbtO2 decreased below 10 mm Hg and a correlation between LP and PbtO2 was observed. CONCLUSION: This study demonstrated that compromised cerebral energy metabolism, evidenced by increased LP ratio, was common in patients with severe bacterial meningitis while not related to insufficient tissue oxygenation.

Systematic in vitro and in vivo characterization of Leukemia-inhibiting factor- and Fibroblast growth factor-derived porcine induced pluripotent stem cells.

Derivation and stable maintenance of porcine induced pluripotent stem cells (piPSCs) is challenging. We herein systematically analyzed two piPSC lines, derived by lentiviral transduction and cultured under either leukemia inhibitory factor (LIF) or fibroblast growth factor (FGF) conditions, to shed more light on the underlying biological mechanisms of porcine pluripotency. LIF-derived piPSCs were more successful than their FGF-derived counterparts in the generation of in vitro chimeras and in teratoma formation. When LIF piPSCs chimeras were transferred into surrogate sows and allowed to develop, only their prescence within the embryonic membranes could be detected. Whole-transcriptome analysis of the piPSCs and porcine neonatal fibroblasts showed that they clustered together, but apart from the two pluripotent cell populations of early porcine embryos, indicating incomplete reprogramming. Indeed, bioinformatic analysis of the pluripotency-related gene network of the LIF- versus FGF-derived piPSCs revealed that ZFP42 (REX1) expression was absent in both piPSC-like cells, whereas it was expressed in the porcine inner cell mass at Day 7/8. A second striking difference was the expression of ATOH1 in piPSC-like cells, which was absent in the inner cell mass. Moreover, our gene expression analyses plus correlation analyses of known pluripotency genes identified unique relationships between pluripotency genes in the inner cell mass, which are to some extent, in the piPSC-like cells. This deficiency in downstream gene activation and divergent gene expression may be underlie the inability to derive germ line-transmitting piPSCs, and provides unique insight into which genes are necessary to achieve fully reprogrammed piPSCs. 84: 229-245, 2017. © 2016 Wiley Periodicals, Inc.

SCA28: Novel Mutation in the AFG3L2 Proteolytic Domain Causes a Mild Cerebellar Syndrome with Selective Type-1 Muscle Fiber Atrophy.

The spinocerebellar ataxias (SCA) are a group of rare inherited neurodegenerative diseases characterized by slowly progressive cerebellar ataxia, resulting in unsteady gait, clumsiness, and dysarthria. The disorders are predominantly inherited in an autosomal dominant manner. Mutations in the gene AFG3L2 that encodes a subunit of the mitochondrial m-AAA protease have previously been shown to cause spinocerebellar ataxia type 28 (SCA28). Here, we present the clinical phenotypes of three patients from a family with autosomal dominant cerebellar ataxia and show by molecular genetics and in silico modelling that this is caused by a novel missense mutation in the AFG3L2 gene. Furthermore, we show, for the first time, fluorodeoxyglucose-positron emission tomography (FDG-PET) scans of the brain and selective type I fiber atrophy of skeletal muscle of SCA28 patients indicating non-nervous-system involvement in SCA28 as well.

Bedside Monitoring of Cerebral Energy State During Cardiac Surgery-A Novel Approach Utilizing Intravenous Microdialysis.

OBJECTIVES: This study investigated whether the lactate-to-pyruvate (LP) ratio obtained by microdialysis (MD) of the cerebral venous outflow reflected a derangement of global cerebral energy state during cardiopulmonary bypass (CPB). DESIGN: Interventional, prospective, randomized study. SETTING: Single-center, university teaching hospital. PARTICIPANTS: The study included 10 patients undergoing primary, elective coronary artery bypass grafting. INTERVENTIONS: Patients were randomized blindly to low mean arterial pressure (MAP) (40-60 mmHg; n = 5) or high MAP (60-80 mmHg; n = 5) during CPB. The MD catheters were positioned in a retrograde direction into the jugular bulb, and a reference catheter was inserted into the brachial artery. The correlations among LP ratio, MAP, data obtained from bifrontal near-infrared spectroscopy (NIRS), and postoperative neurologic outcome measures were assessed. MEASUREMENTS AND MAIN RESULTS: The correlated difference between pooled LP ratio (low and high MAP) of the jugular venous and the arterial blood was significant (LParterial 17 [15-20] v LPvenous 26 [23-27]; p = 0.0001). No cerebral desaturations (decrease in rSO2>20% from baseline) were observed in either group during CPB. In each group, 50% of the patients showed significant cognitive decline (mini-mental state examination, 3 points) 2 days after surgery. CONCLUSION: The LP ratio of cerebral venous blood increased significantly during CPB, indicating compromised cerebral oxidative metabolism. Conventional monitoring of rSO2 by NIRS did not show a corresponding decrease in cerebral oxygenation. As the patients exhibited decreased cognitive functions after CPB, increases in jugular venous LP ratio may be a sensitive indicator of impending cerebral damage.

Biochemical indications of cerebral ischaemia and mitochondrial dysfunction in severe brain trauma analysed with regard to type of lesion.

BACKGROUND: The study focuses on three questions related to the clinical usefulness of microdialysis in severe brain trauma: (1) How frequently is disturbed cerebral energy metabolism observed in various types of lesions? (2) How often does the biochemical pattern indicate cerebral ischaemia and mitochondrial dysfunction? (3) How do these patterns relate to mortality? METHOD: The study includes 213 consecutive patients with severe brain trauma (342 intracerebral microdialysis catheters). The patients were classified into four groups according to the type of lesion: extradural haematoma (EDH), acute subdural haematoma (SDH), cerebral haemorrhagic contusion (CHC) and no mass lesion (NML). Altogether about 150,000 biochemical analyses were performed during the initial 96 h after trauma. RESULTS: Compromised aerobic metabolism occurred during 38 % of the study period. The biochemical pattern indicating mitochondrial dysfunction was more common than that of ischaemia. In EDH and NML aerobic metabolism was generally close to normal. In SDH or CHC it was often severely compromised. Mortality was increased in SDH with impaired aerobic metabolism, while CHC did not exhibit a similar relation. CONCLUSIONS: Compromised energy metabolism is most frequent in patients with SDH and CHC (32 % and 49 % of the study period, respectively). The biochemical pattern of mitochondrial dysfunction is more common than that of ischaemia (32 % and 6 % of the study period, respectively). A correlation between mortality and biochemical data is obtained provided the microdialysis catheter is placed in an area where energy metabolism reflects tissue outcome in a large part of the brain.

The introduction of sialendoscopy has significantly contributed to a decreased number of excised salivary glands in Denmark.

Excision has been the treatment of choice in benign non-tumorous obstructive disorders of the major salivary glands, when symptoms persisted in spite of conservative measures. Unfortunately surgical resection has been associated with a relatively high rate of adverse effects. To meet the need for a less invasive treatment modality for benign obstructive non-tumorous disorders (i.e., salivary stones or stenosis), sialendoscopy has been developed and implemented in several countries here among Denmark. This study is a 13-year retrospective registry-based study using The Danish National Patient Register. ICD-10 codes used for non-tumorous obstructive disease of the salivary glands were identified and used to extract patients potentially eligible for sialendoscopy in order to compare sialendoscopic surgery and extirpations of salivary glands. In 2012 sialendoscopy accounted for almost 20 % of all surgical interventions on the major salivary glands due to benign non-tumorous disease. Nationally and regionally the total number of resected major salivary glands due to benign obstructive disease also decreased significantly during the study period. A positive outcome, like the ones described here, will inspire further development and dissemination of gland preserving techniques, to great benefit for the patients.