The number of comorbidities as an important cofactor to ASA class in predicting postoperative outcome: An international multicentre cohort study.

BACKGROUND: Multimorbidity is a growing burden in our ageing society and is associated with perioperative morbidity and mortality. Despite several modifications to the ASA physical status classification, multimorbidity as such is still not considered. Thus, the aim of this study was to quantify the burden of comorbidities in perioperative patients and to assess, independent of ASA class, its potential influence on perioperative outcome. METHODS: In a subpopulation of the prospective ClassIntra® validation study from eight international centres, type and severity of anaesthesia-relevant comorbidities were additionally extracted from electronic medical records for the current study. Patients from the validation study were of all ages, undergoing any type of in-hospital surgery and were followed up until 30 days postoperatively to assess perioperative outcomes. Primary endpoint was the number of comorbidities across ASA classes. The associated postoperative length of hospital stay (pLOS) and Comprehensive Complication Index (CCI®) were secondary endpoints. On a scale from 0 (no complication) to 100 (death) the CCI® measures the severity of postoperative morbidity as a weighted sum of all postoperative complications. RESULTS: Of 1421 enrolled patients, the mean number of comorbidities significantly increased from 1.5 in ASA I (95% CI, 1.1-1.9) to 10.5 in ASA IV (95% CI, 8.3-12.7) patients. Furthermore, independent of ASA class, postoperative complications measured by the CCI® increased per each comorbidity by 0.81 (95% CI, 0.40-1.23) and so did pLOS (geometric mean ratio, 1.03; 95% CI, 1.01-1.06). CONCLUSIONS: These data quantify the high prevalence of multimorbidity in the surgical population and show that the number of comorbidities is predictive of negative postoperative outcomes, independent of ASA class.

A cross-species spatiotemporal proteomic analysis identifies UBE3A-dependent signaling pathways and targets.

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of neuronal E3 ligase UBE3A. Restoring UBE3A levels is a potential disease-modifying therapy for AS and has recently entered clinical trials. There is paucity of data regarding the molecular changes downstream of UBE3A hampering elucidation of disease therapeutics and biomarkers. Notably, UBE3A plays an important role in the nucleus but its targets have yet to be elucidated. Using proteomics, we assessed changes during postnatal cortical development in an AS mouse model. Pathway analysis revealed dysregulation of proteasomal and tRNA synthetase pathways at all postnatal brain developmental stages, while synaptic proteins were altered in adults. We confirmed pathway alterations in an adult AS rat model across multiple brain regions and highlighted region-specific differences. UBE3A reinstatement in AS model mice resulted in near complete and partial rescue of the proteome alterations in adolescence and adults, respectively, supporting the notion that restoration of UBE3A expression provides a promising therapeutic option. We show that the nuclear enriched transketolase (TKT), one of the most abundantly altered proteins, is a novel direct UBE3A substrate and is elevated in the neuronal nucleus of rat brains and human iPSC-derived neurons. Taken together, our study provides a comprehensive map of UBE3A-driven proteome remodeling in AS across development and species, and corroborates an early UBE3A reinstatement as a viable therapeutic option. To support future disease and biomarker research, we present an accessible large-scale multi-species proteomic resource for the AS community ( https://www.angelman-proteome-project.org/ ).

The p75 neurotrophin receptor is required for the survival of neuronal progenitors and normal formation of the basal forebrain, striatum, thalamus and neocortex.

During development, the p75 neurotrophin receptor (p75NTR) is widely expressed in the nervous system where it regulates neuronal differentiation, migration and axonal outgrowth. p75NTR also mediates the survival and death of newly born neurons, with functional outcomes being dependent on both timing and cellular context. Here, we show that knockout of p75NTR from embryonic day 10 (E10) in neural progenitors using a conditional Nestin-Cre p75NTR floxed mouse causes increased apoptosis of progenitor cells. By E14.5, the number of Tbr2-positive progenitor cells was significantly reduced and the rate of neurogenesis was halved. Furthermore, in adult knockout mice, there were fewer cortical pyramidal neurons, interneurons, cholinergic basal forebrain neurons and striatal neurons, corresponding to a relative reduction in volume of these structures. Thalamic midline fusion during early postnatal development was also impaired in Nestin-Cre p75NTR floxed mice, indicating a novel role for p75NTR in the formation of this structure. The phenotype of this strain demonstrates that p75NTR regulates multiple aspects of brain development, including cortical progenitor cell survival, and that expression during early neurogenesis is required for appropriate formation of telencephalic structures.

Construction and reconstruction of brain circuits: normal and pathological axon guidance.

Perception of our environment entirely depends on the close interaction between the central and peripheral nervous system. In order to communicate each other, both systems must develop in parallel and in coordination. During development, axonal projections from the CNS as well as the PNS must extend over large distances to reach their appropriate target cells. To do so, they read and follow a series of axon guidance molecules. Interestingly, while these molecules play critical roles in guiding developing axons, they have also been shown to be critical in other major neurodevelopmental processes, such as the migration of cortical progenitors. Currently, a major hurdle for brain repair after injury or neurodegeneration is the absence of axonal regeneration in the mammalian CNS. By contrasts, PNS axons can regenerate. Many hypotheses have been put forward to explain this paradox but recent studies suggest that hacking neurodevelopmental mechanisms may be the key to promote CNS regeneration. Here we provide a seminar report written by trainees attending the second Flagship school held in Alpbach, Austria in September 2018 organized by the International Society for Neurochemistry (ISN) together with the Journal of Neurochemistry (JCN). This advanced school has brought together leaders in the fields of neurodevelopment and regeneration in order to discuss major keystones and future challenges in these respective fields.

Mortality and longevity after a spinal cord injury: systematic review and meta-analysis.

BACKGROUND/AIMS: Mortality and longevity studies of spinal cord injury (SCI) are essential for informing healthcare systems and policies. This review evaluates the current evidence among people with SCIs worldwide in relation to the WHO region and country income level; demographic and lesion characteristics; and in comparison with the general population. METHODS: A systematic review of relevant databases for original studies. Pooled estimates were derived using random effects meta-analysis, restricted to traumatic SCI. RESULTS: Seventy-four studies were included. In-hospital mortality varied, with pooled estimates of 24.1% (95% confidence interval (CI) 14.1-38.0), 7.6% (95% CI 6.3-9.0), 7.0% (95% CI 1.5-27.4), and 2.1% (95% CI 0.9-5.0) in the WHO regions of Africa, the Americas, Europe and Western Pacific. The combined estimate for low- and middle-income countries was nearly three times higher than for high-income countries. Pooled estimates of first-year survival were 86.5% (95% CI 75.3-93.1), 95.6% (95% CI 81.0-99.1), and 94.0% (95% CI 93.3-94.6) in the Americas, Europe and Western Pacific. Pooled estimates of standardized mortality ratios in tetraplegics were 2.53 (2.00-3.21) and 2.07 (1.47-2.92) in paraplegics. CONCLUSION: This study found substantial variation in mortality and longevity within the SCI population, compared to the general population, and between WHO regions and country income level. Improved standardization and quality of reporting is needed to improve inferences regarding the extent to which mortality outcomes following an SCI are related to healthcare systems, services and policies.

PEGylation of lysine residues reduces the pro-migratory activity of IGF-I.

BACKGROUND: The insulin-like growth factor (IGF) system is composed of ligands and receptors which regulate cell proliferation, survival, differentiation and migration. Some of these functions involve regulation by the extracellular milieu, including binding proteins and other extracellular matrix proteins. However, the functions and exact nature of these interactions remain incomplete. METHODS: IGF-I variants PEGylated at lysines K27, K65 and K68, were assessed for binding to IGFBPs using BIAcore, and for phosphorylation of the IGF-IR. Furthermore, functional consequences of PEGylation were investigated using cell viability and migration assays. In addition, downstream signaling pathways were analyzed using phospho-AKT and phospho-ERK1/2 assays. RESULTS: IGF-I PEGylated at lysines 27 (PEG-K27), 65 (PEG-K65) or 68 (PEG-K68) was employed. Receptor phosphorylation was similarly reduced 2-fold with PEG-K65 and PEG-K68 in 3T3 fibroblasts and MCF-7 breast cancer cells, whereas PEG-K27 showed a more than 10- and 3-fold lower activation for 3T3 and MCF-7 cells, respectively. In addition, all PEG-IGF-I variants had a 10-fold reduced association rate to IGF binding proteins (IGFBPs). Functionally, all PEG variants lost their ability to induce cell migration in the presence of IGFBP-3/vitronectin (VN) complexes, whereas cell viability was fully preserved. Analysis of downstream signaling revealed that AKT was preferentially affected upon treatment with PEG-IGF-I variants whereas MAPK signaling was unaffected by PEGylation. CONCLUSION: PEGylation of IGF-I has an impact on cell migration but not on cell viability. GENERAL SIGNIFICANCE: PEG-IGF-I may differentially modulate IGF-I mediated functions that are dependent on receptor interaction as well as key extracellular proteins such as VN and IGFBPs.

Manual compression versus MANTA device for access management after impella removal on the ICU.

To compare the safety and efficacy of manual compression versus use of the MANTA closure device for access management after Impella removal on the intensive care unit (ICU). The number of patients treated with percutaneous left ventricular assist devices (pLVAD), namely Impella and ECMO, for complex cardiac procedures or shock, is growing. However, removal of pLVAD and large bore arteriotomy closure among such patients on the ICU remains challenging, since it is associated with a high risk for bleeding and vascular complications. Patients included in a prospective registry between 2017 and 2020 were analyzed. Bleeding and vascular access site complications were assessed and adjudicated according to VARC-2 criteria. We analyzed a cohort of 87 consecutive patients, who underwent access closure after Impella removal on ICU by using either the MANTA device or manual compression. The cohort´s mean age was 66.1 ± 10.7 years and 76 patients (87%) were recovering from CS. Mean support time was 40 h (interquartile range 24-69 h). MANTA was used in 31 patients (35.6%) and manual compression was applied in 56 patients (64.4%). Overall access related bleedings were significantly lower in the MANTA group (6.5% versus 39.3% (odds ratio (OR) 0.10, 95% CI 0.01-0.50; p = 0.001), and there was no significant difference in vascular complications between the two groups (p = 0.55). Our data suggests that the application of the MANTA device directly on the ICU is safe. In addition, it seems to reduce access related bleeding without increasing the risk of vascular complications.

Secreted retrovirus-like GAG-domain-containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of maternal UBE3A, a ubiquitin protein ligase E3A. Here, we study neurons derived from patients with AS and neurotypical individuals, and reciprocally modulate UBE3A using antisense oligonucleotides. Unbiased proteomics reveal proteins that are regulated by UBE3A in a disease-specific manner, including PEG10, a retrotransposon-derived GAG protein. PEG10 protein increase, but not RNA, is dependent on UBE3A and proteasome function. PEG10 binds to both RNA and ataxia-associated proteins (ATXN2 and ATXN10), localizes to stress granules, and is secreted in extracellular vesicles, modulating vesicle content. Rescue of AS patient-derived neurons by UBE3A reinstatement or PEG10 reduction reveals similarity in transcriptome changes. Overexpression of PEG10 during mouse brain development alters neuronal migration, suggesting that it can affect brain development. These findings imply that PEG10 is a secreted human UBE3A target involved in AS pathophysiology.

Epitope switching as a novel escape mechanism of HIV to CCR5 monoclonal antibodies.

In passaging experiments, we isolated HIV strains resistant to MAb3952, a chemokine (C-C motif) receptor 5 (CCR5) monoclonal antibody (MAb) that binds to the second extracellular domain (extracellular loop 2 [ECL-2]) of CCR5. MAb3952-resistant viruses remain CCR5-tropic and are cross-resistant to a second ECL-2-specific antibody. Surprisingly, MAb3952-resistant viruses were more susceptible to RoAb13, a CCR5 antibody binding to the N terminus of CCR5. Using CCR5 receptor mutants, we show that MAb3952-resistant virus strains preferentially use the N terminus of CCR5, while the wild-type viruses preferentially use ECL-2. We propose this switch in the CCR5 binding site as a novel mechanism of HIV resistance.

Prospective validation of classification of intraoperative adverse events (ClassIntra): international, multicentre cohort study.

OBJECTIVE: To prospectively assess the construct and criterion validity of ClassIntra version 1.0, a newly developed classification for assessing intraoperative adverse events. DESIGN: International, multicentre cohort study. SETTING: 18 secondary and tertiary centres from 12 countries in Europe, Oceania, and North America. PARTICIPANTS: The cohort study included a representative sample of 2520 patients in hospital having any type of surgery, followed up until discharge. A follow-up to assess mortality at 30 days was performed in 2372 patients (94%). A survey was sent to a representative sample of 163 surgeons and anaesthetists from participating centres. MAIN OUTCOME MEASURES: Intraoperative complications were assessed according to ClassIntra. Postoperative complications were assessed daily until discharge from hospital with the Clavien-Dindo classification. The primary endpoint was construct validity by investigating the risk adjusted association between the most severe intraoperative and postoperative complications, measured in a multivariable hierarchical proportional odds model. For criterion validity, inter-rater reliability was evaluated in a survey of 10 fictitious case scenarios describing intraoperative complications. RESULTS: Of 2520 patients enrolled, 610 (24%) experienced at least one intraoperative adverse event and 838 (33%) at least one postoperative complication. Multivariable analysis showed a gradual increase in risk for a more severe postoperative complication with increasing grade of ClassIntra: ClassIntra grade I versus grade 0, odds ratio 0.99 (95% confidence interval 0.69 to 1.42); grade II versus grade 0, 1.39 (0.97 to 2.00); grade III versus grade 0, 2.62 (1.31 to 5.26); and grade IV versus grade 0, 3.81 (1.19 to 12.2). ClassIntra showed high criterion validity with an intraclass correlation coefficient of 0.76 (95% confidence interval 0.59 to 0.91) in the survey (response rate 83%). CONCLUSIONS: ClassIntra is the first prospectively validated classification for assessing intraoperative adverse events in a standardised way, linking them to postoperative complications with the well established Clavien-Dindo classification. ClassIntra can be incorporated into routine practice in perioperative surgical safety checklists, or used as a monitoring and outcome reporting tool for different surgical disciplines. Future studies should investigate whether the tool is useful to stratify patients to the appropriate postoperative care, to enhance the quality of surgical interventions, and to improve long term outcomes of surgical patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03009929.

Socio-behavioural characteristics and HIV: findings from a graphical modelling analysis of 29 sub-Saharan African countries.

INTRODUCTION: Socio-behavioural factors may contribute to the wide variance in HIV prevalence between and within sub-Saharan African (SSA) countries. We studied the associations between socio-behavioural variables potentially related to the risk of acquiring HIV. METHODS: We used Bayesian network models to study associations between socio-behavioural variables that may be related to HIV. A Bayesian network consists of nodes representing variables, and edges representing the conditional dependencies between variables. We analysed data from Demographic and Health Surveys conducted in 29 SSA countries between 2010 and 2016. We predefined and dichotomized 12 variables, including factors related to age, literacy, HIV knowledge, HIV testing, domestic violence, sexual activity and women's empowerment. We analysed data on men and women for each country separately and then summarized the results across the countries. We conducted a second analysis including also the individual HIV status in a subset of 23 countries where this information was available. We presented summary graphs showing associations that were present in at least six countries (five in the analysis with HIV status). RESULTS: We analysed data from 190,273 men (range across countries 2295 to 17,359) and 420,198 women (6621 to 38,948). The two variables with the highest total number of edges in the summary graphs were literacy and rural/urban location. Literacy was negatively associated with false beliefs about AIDS and, for women, early sexual initiation, in most countries. Literacy was also positively associated with ever being tested for HIV and the belief that women have the right to ask their husband to use condoms if he has a sexually transmitted infection. Rural location was positively associated with false beliefs about HIV and the belief that beating one's wife is justified, and negatively associated with having been tested for HIV. In the analysis including HIV status, being HIV positive was associated with female-headed household, older age and rural location among women, and with no variables among men. CONCLUSIONS: Literacy and urbanity were strongly associated with several factors that are important for HIV acquisition. Since literacy is one of the few variables that can be improved by interventions, this makes it a promising intervention target.

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors.

Cholinergic basal forebrain (cBF) neurons are defined by their expression of the p75 neurotrophin receptor (p75NTR) and tropomyosin-related kinase (Trk) neurotrophin receptors in addition to cholinergic markers. It is known that the neurotrophins, particularly nerve growth factor (NGF), mediate cholinergic neuronal development and maintenance. However, the role of neurotrophin signalling in regulating adult cBF function is less clear, although in dementia, trophic signalling is reduced and p75NTR mediates neurodegeneration of cBF neurons. Here we review the current understanding of how cBF neurons are regulated by neurotrophins which activate p75NTR and TrkA, B or C to influence the critical role that these neurons play in normal cortical function, particularly higher order cognition. Specifically, we describe the current evidence that neurotrophins regulate the development of basal forebrain neurons and their role in maintaining and modifying mature basal forebrain synaptic and cortical microcircuit connectivity. Understanding the role neurotrophin signalling plays in regulating the precision of cholinergic connectivity will contribute to the understanding of normal cognitive processes and will likely provide additional ideas for designing improved therapies for the treatment of neurological disease in which cholinergic dysfunction has been demonstrated.

Age-induced changes in the lower limb muscle activities during uphill walking at steep grades.

BACKGROUND: Uphill walking is particularly challenging for elderly persons. However, there is a lack of age-differentiated studies investigating the underlying differences in muscle activation when walking on sloped surfaces. These studies are needed, e.g., for planning of evacuations of large modern cruise ships with long walking distances on often inclined surfaces. METHODS: An age-differentiated, gender-balanced study with 26 young (20-30 years) and 26 elderly people (60-77 years) was therefore conducted, investigating uphill walking at 7° and at 14° contrasted to level walking on a treadmill. EMG signals of musculus gluteus maximus (GMAX), m. biceps femoris (BF), m. rectus femoris (RF), m. vastus medialis (VM), m. gastrocnemius medialis (GAS) and m. soleus (SOL) were analysed with regard to mean and maximum muscle activities and timing during the gait cycle. RESULTS: The results showed that walking uphill at 14° was highly strainful for elderly people. In line with previous research, young people mostly "pushed" themselves uphill with the GAS and SOL. In contrast, elderly people not only used the known compensatory ability of hip muscles to propel the trailing leg, but also showed a high level of BF activation prolonged until the mid-stance phase at the steepest uphill gradient of 14°. SIGNIFICANCE: The strikingly long activation of the BF until the mid-stance phase in elderly people at steep gradients is an unexpected, new finding. It suggests that, instead of pushing, elderly people "pull" themselves uphill. In cases of evacuations, the lower physical fitness levels of elderly passengers and their increased need for assistance on inclined surfaces have to be planned for in advance. Considering the findings in (home) training programmes might help elderly people to strengthen lower limb muscles and to enhance the efficiency of muscle activation patterns enabling them to manage steep inclinations more easily.

Age-related differences in decision-making for digital escape route signage under strenuous emergency conditions of tilted passenger ships.

This age-differentiated study investigated preferences for new digital, situation-adaptive escape route signage with informative and flashing elements under simulated emergency conditions of tilted passenger ships. The decision-making behaviour of 26 young (20-30 years) and 26 elderly (60-77 years) participants was observed in four conditions varying in applied stressors and in level versus uphill walking at 7° and 14°. In line with previous studies, decisions of young participants were significantly influenced by flashing elements on signs. In contrast, elderly participants based their decisions significantly stronger on integrated information about the sign's updatedness and reported irritation by flashing elements. These preferences were also persistent under increased mental, emotional and physical strain, evaluated by ratings and (psycho-)physiological measures. The findings demonstrate the importance to carefully design digital, situation-adaptive signage for passenger ships in a way that it not only attracts attention but also inspires trust especially for the elderly population.

Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers.

Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the splicing deficit of the SMN2 (survival of motor neuron 2) gene have been identified and these molecules are moving towards a potential therapy for spinal muscular atrophy (SMA). Here by using a combination of RNA splicing, transcription, and protein chemistry techniques, we show that these molecules directly bind to two distinct sites of the SMN2 pre-mRNA, thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes. In addition to the therapeutic potential of these molecules for treatment of SMA, our work has wide-ranging implications in understanding how small molecules can interact with specific quaternary RNA structures.

Health conditions in people with spinal cord injury: Contemporary evidence from a population-based community survey in Switzerland.

BACKGROUND: Health conditions in people with spinal cord injury are major determinants for disability, reduced well-being, and mortality. However, population-based evidence on the prevalence and treatment of health conditions in people with spinal cord injury is scarce. OBJECTIVE: To investigate health conditions in Swiss residents with spinal cord injury, specifically to analyse their prevalence, severity, co-occurrence, and treatment. METHODS: Cross-sectional data (n = 1,549) from the community survey of the Swiss Spinal Cord Injury (SwiSCI) cohort study, including Swiss residents with spinal cord injury aged over 16 years, were analysed. Nineteen health conditions and their self-reported treatment were assessed with the spinal cord injury Secondary Conditions Scale and the Self-Administered Comorbidity Questionnaire. Prevalence and severity were compared across demographics and spinal cord injury characteristics. Co-occurrence of health conditions was examined using a binary non-metric dissimilarity measure and multi-dimensional scaling. Treatment rates were also examined. RESULTS: Number of concurrent health conditions was high (median 7; interquartile range 4-9; most frequent: spasticity, chronic pain, sexual dysfunction). Prevalence of health conditions increased with age and was higher in non-traumatic compared with traumatic spinal cord injury. Spinal cord injury specific conditions co-occurred. Relative frequencies of treatment were low (median 44%, interquartile range 25-64%), even for significant or chronic problems. DISCUSSION: A high prevalence of multimorbidity was found in community-dwelling persons with spinal cord injury. Treatment for some highly prevalent health conditions was infrequent.

Epidemiology and contemporary risk profile of traumatic spinal cord injury in Switzerland.

BACKGROUND: Traumatic spinal cord injury (TSCI) has a high personal and socio-economic impact. Effective public health prevention policies that aim to reduce this burden are reliant on contemporary information of the risk and underlying causes of TSCI. This study contextualizes Swiss annual incidence rates within the European context, and provides detailed estimates by age, gender and etiology towards informing targeted intervention strategies. METHODS: TSCI cases that occurred in the years 2005 to 2012 were identified as part of the Swiss Spinal Cord Injury (SwiSCI) cohort study through a rehabilitation-based study of local medical files. RESULTS: The crude annual incidence rate (IR) estimate of TSCI for the study period was 18.0 (95 % confidence interval 16.9-19.2) per one million population; standardized to the WHO world population IR was 21.7 (20.3-23.1) population. The injury rate of TSCI in Switzerland was intermediate in comparison to estimates for other European countries, which ranged from around 8.3 in Denmark to 33.6 per million in Greece. Males exhibited consistently higher IRs than females, with a highest IR ratio (IRR) of 3.9 (2.8-5.5) in young adults (aged 16 to 30). Sports and leisure and transport-related injuries were the predominant causes of TSCI in the youngest age group (aged 16 to 30); falls were the predominant cause among the oldest age group (76 years or over). With increasing age, a greater proportion of fall-related TSCIs were due to low-level falls, with more than 80 % of fall-related TSCIs due to low-level falls in the oldest age group. CONCLUSIONS: Evidence suggests sports/leisure- and transport-related injuries in young men and falls among the elderly as prime targets for prevention policies and programs.

Mitotic redistribution of the mitochondrial network by Miro and Cenp-F.

Although chromosome partitioning during mitosis is well studied, the molecular mechanisms that allow proper segregation of cytoplasmic organelles in human cells are poorly understood. Here we show that mitochondria interact with growing microtubule tips and are transported towards the daughter cell periphery at the end of mitosis. This phenomenon is promoted by the direct and cell cycle-dependent interaction of the mitochondrial protein Miro and the cytoskeletal-associated protein Cenp-F. Cenp-F is recruited to mitochondria by Miro at the time of cytokinesis and associates with microtubule growing tips. Cells devoid of Cenp-F or Miro show decreased spreading of the mitochondrial network as well as cytokinesis-specific defects in mitochondrial transport towards the cell periphery. Thus, Miro and Cenp-F promote anterograde mitochondrial movement and proper mitochondrial distribution in daughter cells.

Histological yield, complications, and technological considerations in 114 consecutive frameless stereotactic biopsy procedures aided by open intraoperative magnetic resonance imaging.

OBJECT: The authors undertook a prospective study of frameless, magnetic resonance (MR)-guided stereotactic brain biopsy procedures performed with the aid of an open MR system. Morbidity and mortality rates, frequency of postoperative hemorrhage, and histological yield were evaluated, as well as the size and location of the lesions under investigation. METHODS: During a period of 51 months (July 1996-November 2000), 114 consecutive frameless stereotactic biopsy procedures were performed with the aid of an open intraoperative MR system to investigate supratentorial lesions in 113 patients. The median volume of the lesions was 33.5 cm3, and 31.9% were deep seated. All biopsy samples comprised pathological tissue and in 111 (97.4%) of 114 a specific neuropathological diagnosis was made. A follow-up computerized tomography (CT) scan was obtained on the 1st postoperative day in all patients to evaluate postoperative complications. In two cases (1.8%), a hemorrhage was found on postoperative CT scans, with no neurological worsening of the patients. Morbidity with neurological worsening was seen in three patients; it was transient in two of them (1.8%), and in one (0.9%) subsequent emergency craniotomy was necessary because of increased edema. There were no infections, but there was one death (0.9%) CONCLUSIONS: Open intraoperative MR imaging transforms a blind conventional stereotactic procedure into a visually controlled procedure that is adaptable to dynamic anatomical changes. Routine postprocedural MR imaging makes follow-up CT scanning obsolete. This largest reported series of intraoperative MR-guided biopsy procedures shows results that are at least comparable with those in reports of larger series of conventional stereotactic biopsy sampling. The mean procedure time was 60 minutes including planning, and this method produced low morbidity and complication rates and a high histological yield.

Low plasma lactate concentration as a biomarker of an incompetent brain-pull: a risk factor for weight gain in type 2 diabetes patients.

OBJECTIVE: Body weight development is closely regulated by central nervous mechanisms. As has been demonstrated recently, the capability of the brain to actively demand energy from the body (brain-pull) is indispensable for the maintenance of systemic homeostasis. A deficit in this brain-pull may result in compensatory ingestive behavior followed by weight gain in the medium or long term. The aim of this study was to establish a biomarker of such an incompetent brain-pull. Since lactate is an alternative cerebral energy substrate to glucose, we investigated whether low fasting plasma lactate concentrations are associated with weight gain and increased feelings of hunger in patients with type 2 diabetes over a 3-year period. METHODS: In a population based cohort study 134 type 2 diabetes patients were examined at baseline and 3-year follow-up. Plasma lactate concentrations and additional hormones associated with food intake such as e.g. insulin, or leptin, as well as psychological variables like hunger feelings before and after a standardized breakfast were measured. The relation between fasting plasma lactate concentrations and postprandial hunger as well as follow-up weight was analyzed. RESULTS: Low fasting plasma lactate concentrations predicted a higher 3-year follow-up weight (B=-1.268, SE=0.625, p=0.04). Moreover, low fasting plasma lactate concentrations were associated with more pronounced feelings of postprandial hunger (B=-0.406, SE=0.137, p<0.01). CONCLUSIONS: We conclude that low plasma lactate concentrations may represent a biomarker of an incompetent brain-pull, which is associated with weight gain and increased postprandial hunger in patients with type 2 diabetes mellitus. These results are in line with the view that plasma lactate can be used by the brain as an alternative energy substrate and thereby to some extent prevent overeating and obesity.