Dura Management Strategies in the Surgical Treatment of Adult Chiari Type I Malformation: A Retrospective, Multicenter, Population-Based Parallel Cohort Case Series.

BACKGROUND: Symptomatic Chiari I malformation is treated with suboccipital decompression and C1 laminectomy. However, whether the dura should be opened (durotomy) or enlarged with a graft (duraplasty) remains unclear. OBJECTIVE: To compare outcomes in adult Chiari I malformation patients treated with duraplasty, durotomy, or without dural opening ("mini-decompression"). METHODS: A retrospective, multicenter, population-based cohort study was performed of all adult patients surgically treated for a Chiari I malformation at 3 regional neurosurgical centers between 2005 and 2017. Three different dura management strategies were favored by the participating hospitals, with data stratified accordingly. The primary outcome was measured using the Chicago Chiari Outcome Scale (CCOS), dichotomized into favorable (CCOS ≥13) or unfavorable (CCOS ≤12). Propensity score matching was used to adjust for potential confounders in outcome comparisons. RESULTS: In total, 318 patients were included, of whom 52% were treated with duraplasty, 37% with durotomy, and 11% with mini-decompression. In total, 285 (90%) showed a favorable surgical outcome (CCOS ≥13). Duraplasty was associated with more favorable CCOS and shorter hospital stay compared with durotomy, both in unadjusted (93% vs 84%. P = .018 and 6.0 vs 8.0 days, P < .001) and adjusted analyses (92% vs 84%, P = .044 and 6.0 vs 8.0 days, P < .001). Mini-decompression was excluded from the adjusted analyses because of its small sample size. CONCLUSION: In this study of adult Chiari I malformation, posterior fossa decompression with duraplasty was associated with more favorable postoperative outcome, as determined by the CCOS, compared with posterior fossa decompression with durotomy alone.

Ultrasensitive circulating tumor DNA analysis enables precision medicine: experimental workflow considerations.

Introduction: Circulating tumor DNA (ctDNA) has become a relevant biomarker in cancer management, allowing tumor assessment through analysis of minimally invasive liquid biopsies. Applications include screening, diagnostics, monitoring of treatment efficacy and detection of minimal residual disease as well as relapse. The potential of ctDNA analysis is significant, but several biological and technical challenges need to be addressed before widespread clinical implementation.Areas covered: Several clinical applications where ctDNA analysis may be beneficial require detection of individual DNA molecules. Consequently, to acquire accurate and informative data the entire workflow from sampling to final data interpretation needs to be optimized. In this review, we discuss the biological and technical challenges of ctDNA analysis and how preanalytical and analytical approaches affect different cancer applications.Expert opinion: While numerous studies have demonstrated the potential of using ctDNA in cancer applications, yet few reports about true clinical utility exist. Despite encouraging data, the sensitivity of ctDNA analyses, i.e. the probability to detect presence of cancer in liquid biopsies, is still an issue. Analysis of multiple mutations in combination with simultaneous assessment of other analytes is one solution. Improved standardization and guidelines will also facilitate the introduction of ctDNA analysis into clinical routine.

Clinical Course in Chronic Subdural Hematoma Patients Aged 18-49 Compared to Patients 50 Years and Above: A Multicenter Study and Meta-Analysis.

Objective: Chronic Subdural Hematoma (cSDH) is primarily a disease of elderly, and is rare in patients <50 years, and this may in part be related to the increased brain atrophy from 50 years of age. This fact may also influence clinical presentation and outcome. The aim of this study was to study the clinical course with emphasis on clinical presentation of cSDH patients in the young (<50 years). Methods: A retrospective review of a population-based cohort of 1,252 patients operated for cSDH from three Scandinavian neurosurgical centers was conducted. The primary end-point was difference in clinical presentation between the patients <50 y/o and the remaining patients (≥50 y/o group). The secondary end-points were differences in perioperative morbidity, recurrence and mortality between the two groups. In addition, a meta-analysis was performed comparing clinical patterns of cSDH in the two age groups. Results: Fifty-two patients (4.2%) were younger than 50 years. Younger patients were more likely to present with headache (86.5% vs. 37.9%, p < 0.001) and vomiting (25% vs. 5.2%, p < 0.001) than the patients ≥50 y/o, while the ≥50 y/o group more often presented with limb weakness (17.3% vs. 44.8%, p < 0.001), speech impairment (5.8% vs. 26.2%, p = 0.001) and gait disturbance or falls (23.1% vs. 50.7%, p < 0.001). There was no difference between the two groups in recurrence, overall complication rate and mortality within 90 days. Our meta-analysis confirmed that younger patients are more likely to present with headache (p = 0.015) while the hemispheric symptoms are more likely in patients ≥50 y/o (p < 0.001). Conclusion: Younger patients with cSDH present more often with signs of increased intracranial pressure, while those ≥50 y/o more often present with hemispheric symptoms. No difference exists between the two groups in terms of recurrence, morbidity, and short-term mortality. Knowledge of variations in clinical presentation is important for correct and timely diagnosis in younger cSDH patients.

Role of antithrombotic therapy in the risk of hematoma recurrence and thromboembolism after chronic subdural hematoma evacuation: a population-based consecutive cohort study.

OBJECTIVE: To establish the risk of recurrence in patients with chronic subdural hematoma (cSDH) on antithrombotic treatment (AT, i.e., antiplatelets and anticoagulants). Secondary end points were perioperative morbidity and mortality between groups (AT vs. no-AT group) and exploration if timing of resumption of AT treatment (i.e., prophylactic early vs. late resumption) influenced the occurrence of thromboembolism and hematoma recurrence. MATERIALS: In a population-based consecutive cohort, we conducted a retrospective review of 763 patients undergoing primary burr hole procedures for cSDH between January 1, 2005, and December 31, 2010, at the Karolinska University Hospital, Stockholm, Sweden. Early AT resumption was ≤30 days and late >30 days after the procedure. RESULTS: A total of 308/763 (40.4%) cSDH patients were on AT treatment at the time of diagnosis. There was no difference in cSDH recurrence within 3 months (11.0% vs. 12.0%, p = 0.69) nor was there any difference in perioperative mortality (4.0% vs. 2.0%, p = 0.16) between those using AT compared to those who were not. However, perioperative morbidity was more common in the AT group compared to no-AT group (10.7% vs. 5.1%, p = 0.003). Comparing early vs. late AT resumption, there was no difference with respect to recurrence (7.0% vs. 13.9%, p = 0.08), but more thromboembolism in the late AT resumption group (2.0% vs. 7.0%, p < 0.01). CONCLUSION: In clinical practice, cSDH patients on AT therapy at the time of diagnosis have similar recurrence rates and mortality compared to those without AT therapy, but with higher morbidity. Early resumption was not associated with more recurrence, but with lower thromboembolic frequency. Early AT resumption seems favorable, and a prospective RCT is needed.

Predictors of Recurrence and Complications After Chronic Subdural Hematoma Surgery: A Population-Based Study.

OBJECTIVE: To investigate predictors of recurrence and moderate to severe complications after burr-hole surgery for chronic subdural hematoma (cSDH). METHODS: A retrospective review was conducted in a Scandinavian single-center population-based cohort of 759 adult patients with cSDH operated with burr-hole surgery between January 1, 2005 and December 31, 2010. Possible predictors of recurrence and complications, assessed using a standardized reporting system of adverse events, were identified and analyzed in univariable analyses. Variables with a P value < 0.10 were included in a multivariable regression model. RESULTS: Recurrence was observed in 85 patients (11.2%), whereas moderate to severe complications were observed in 35 patients (4.6%). Bilateral hematoma (odds ratio [OR], 2.05; 95% confidence interval [CI], 1.25-3.35; P < 0.01) and largest hematoma diameter in millimeters (OR, 1.05; 95% CI, 1.01-1.09; P < 0.01) were independent predictors of recurrence in the multivariable model analysis. Glasgow Coma Scale (GCS) score of <13 (OR, 6.06; 95% CI, 2.72-13.51; P < 0.01) and Charlson Comorbidity Index (CCI) >1 (OR, 2.28; 95% CI, 1.10-4.75; P = 0.03) were independent predictors of moderate to severe complications. CONCLUSIONS: Recurrence after cSDH surgery is more often encountered in patients with radiologically more extensive disease reflected by bilateral hematoma and large hematoma diameter. On the other hand, moderate to severe complications are more often seen in patients in a worse clinical condition, reflected by decreased level of consciousness and more comorbidities.

Assessment of drainage techniques for evacuation of chronic subdural hematoma: a consecutive population-based comparative cohort study.

OBJECTIVE Surgery for chronic subdural hematoma (CSDH) is one of the most common neurosurgical procedures. The benefit of postoperative passive subdural drainage compared with no drains has been established, but other drainage techniques are common, and their effectiveness compared with passive subdural drains remains unknown. METHODS In Scandinavian population-based cohorts the authors conducted a consecutive, parallel cohort study to compare different drainage techniques. The techniques used were continuous irrigation and drainage (CID cohort, n = 166), passive subdural drainage (PD cohort, n = 330), and active subgaleal drainage (AD cohort, n = 764). The primary end point was recurrence in need of reoperation within 6 months of index surgery. Secondary end points were complications, perioperative mortality, and overall survival. The analyses were based on direct regional comparison (i.e., surgical strategy). RESULTS Recurrence in need of surgery was observed in 18 patients (10.8%) in the CID cohort, in 66 patients (20.0%) in the PD cohort, and in 85 patients (11.1%) in the AD cohort (p < 0.001). Complications were more common in the CID cohort (14.5%) compared with the PD (7.3%) and AD (8.1%) cohorts (p = 0.019). Perioperative mortality rates were similar between cohorts (p = 0.621). There were some differences in baseline and treatment characteristics possibly interfering with the above-mentioned results. However, after adjusting for differences in baseline and treatment characteristics in a regression model, the drainage techniques were still significantly associated with clinical outcome (p < 0.001 for recurrence, p = 0.017 for complications). CONCLUSIONS Compared with the AD cohort, more recurrences were observed in the PD cohort and more complications in the CID cohort, also after adjustment for differences at baseline. Although the authors cannot exclude unmeasured confounding factors when comparing centers, AD appears superior to the more common PD. Clinical trial registration no.: NCT01930617 (clinicaltrials.gov).

Galactokinase promiscuity: a question of flexibility?

Galactokinase catalyses the first committed step of the Leloir pathway, i.e. the ATP-dependent phosphorylation of α-D-galactose at C1-OH. Reduced galactokinase activity results in the inherited metabolic disease type II galactosaemia. However, inhibition of galactokinase is considered a viable approach to treating more severe forms of galactosaemia (types I and III). Considerable progress has been made in the identification of high affinity, selective inhibitors. Although the structure of galactokinase from a variety of species is known, its catalytic mechanism remains uncertain. Although the bulk of evidence suggests that the reaction proceeds via an active site base mechanism, some experimental and theoretical studies contradict this. The enzyme has potential as a biocatalyst in the production of sugar 1-phosphates. This potential is limited by its high specificity. A variety of approaches have been taken to identify galactokinase variants which are more promiscuous. These have broadened galactokinase's specificity to include a wide range of D- and L-sugars. Initial studies suggest that some of these alterations result in increased flexibility at the active site. It is suggested that modulation of protein flexibility is at least as important as structural modifications in determining the success or failure of enzyme engineering.

mRNA-binding protein TIA-1 reduces cytokine expression in human endometrial stromal cells and is down-regulated in ectopic endometrium.

BACKGROUND: Cytokines and growth factors play important roles in endometrial function and the pathogenesis of endometriosis. mRNAs encoding cytokines and growth factors undergo rapid turnover; primarily mediated by adenosine- and uridine-rich elements (AREs) located in their 3'-untranslated regions. T-cell intracellular antigen (TIA-1), an mRNA-binding protein, binds to AREs in target transcripts, leading to decreased gene expression. OBJECTIVE: The purpose of this article was to determine whether TIA-1 plays a role in the regulation of endometrial cytokine and growth factor expression during the normal menstrual cycle and whether TIA-1 expression is altered in women with endometriosis. METHODS: Eutopic endometrial tissue obtained from women without endometriosis (n = 30) and eutopic and ectopic endometrial tissues from women with endometriosis (n = 17) were immunostained for TIA-1. Staining intensities were evaluated by histological scores (HSCOREs). The regulation of endometrial TIA-1 expression by immune factors and steroid hormones was studied by treating primary cultured human endometrial stromal cells (HESCs) with vehicle, lipopolysaccharide, TNF-α, IL-6, estradiol, or progesterone, followed by protein blot analyses. HESCs were engineered to over- or underexpress TIA-1 to test whether TIA-1 regulates IL-6 or TNF-α expression in these cells. RESULTS: We found that TIA-1 is expressed in endometrial stromal and glandular cells throughout the menstrual cycle and that this expression is significantly higher in the perimenstrual phase. In women with endometriosis, TIA-1 expression in eutopic and ectopic endometrium was reduced compared with TIA-1 expression in eutopic endometrium of unaffected control women. Lipopolysaccharide and TNF-α increased TIA-1 expression in HESCs in vitro, whereas IL-6 or steroid hormones had no effect. In HESCs, down-regulation of TIA-1 resulted in elevated IL-6 and TNF-α expression, whereas TIA-1 overexpression resulted in decreased IL-6 and TNF-α expression. CONCLUSIONS: Endometrial TIA-1 is regulated throughout the menstrual cycle, TIA-1 modulates the expression of immune factors in endometrial cells, and downregulation of TIA-1 may contribute to the pathogenesis of endometriosis.

Measuring elevated intracranial pressure through noninvasive methods: a review of the literature.

Elevated intracranial pressure (ICP) is an important cause of secondary brain injury, and a measurement of ICP is often of crucial value in neurosurgical and neurological patients. The gold standard for ICP monitoring is through an intraventricular catheter, but this invasive technique is associated with certain risks. Intraparenchymal ICP monitoring methods are considered to be a safer alternative but can, in certain conditions, be imprecise due to zero drift and still require an invasive procedure. An accurate noninvasive method to measure elevated ICP would therefore be desirable. This article is a review of the current literature on noninvasive methods for measuring and evaluating elevated ICP. The main focus is on studies that compare noninvasively measured ICP with invasively measured ICP. The aim is to provide an overview of the current state of the most common noninvasive techniques available. Several methods for noninvasive measuring of elevated ICP have been proposed: radiologic methods including computed tomography and magnetic resonance imaging, transcranial Doppler, electroencephalography power spectrum analysis, and the audiological and ophthalmological techniques. The noninvasive methods have many advantages, but remain less accurate compared with the invasive techniques. None of the noninvasive techniques available today are suitable for continuous monitoring, and they cannot be used as a substitute for invasive monitoring. They can, however, provide a reliable measurement of the ICP and be useful as screening methods in select patients, especially when invasive monitoring is contraindicated or unavailable.

N-acetylgalactosamine kinase: a naturally promiscuous small molecule kinase.

N-acetylgalactosamine kinase is a member of the GHMP family of small molecule kinases which catalyses the ATP-dependent phosphorylation of N-acetylgalactosamine. It is highly similar in structure and sequence to galactokinase. Alteration of galactokinase at a key tyrosine residue (Tyr-379 in the human enzyme) has been shown to dramatically enhance the substrate range of this enzyme. Here, we investigated the substrate specificity of the wild type N-acetylgalactosamine kinase and demonstrated that it can also catalyse the phosphorylation of N-acetylglucosamine and N-acetylmannosamine. In human N-acetylgalactosamine kinase, the equivalent residue to Tyr-379 in galactokinase is Phe-444. Alteration of this residue did not result in dramatic changes to the specificity of the enzyme. The more relaxed substrate specificity of N-acetylgalactosamine kinase, compared to galactokinase, can be explained by the greater flexibility of a glycine rich loop in the active site of the enzyme. These results suggest that N-acetylgalactosamine kinase is a potential biocatalyst for the phosphorylation of N-acetyl sugars. However, it is unlikely that it will be possible to further broaden the substrate range by alteration of Phe-444.

Increased promiscuity of human galactokinase following alteration of a single amino acid residue distant from the active site.

Galactokinase catalyses the site- and stereospecific phosphorylation of galactose at the expense of ATP. The specificity of bacterial galactokinase enzymes can be broadened by alteration of a tyrosine residue to a histidine. The effects of altering the equivalent residue in human galactokinase (Tyr379) were investigated by testing all 19 possible variants. All of these alterations, except Y379P, resulted in soluble protein on expression in Escherichia coli and all the soluble variants could catalyse the phosphorylation of galactose, except Y379A and Y379E. The variants Y379C, Y379K, Y379R, Y379S and Y379W were all able to catalyse the phosphorylation of a variety of monosaccharides, including ones that are not acted on by the wild-type enzyme. Novel substrates for these variant galactokinases included D-mannose and D-fructose. The latter monosaccharide is presumed to react in the pyranose configuration. Molecular modelling suggested that the alterations do not cause changes to the overall structure of the enzyme. However, alteration of Tyr379 increases the flexibility of the peptide backbone in regions surrounding the active site. Therefore, it is proposed that alteration of Tyr379 affects the substrate specificity by the propagation of changes in flexibility to the active site, permitting a broader range of compounds to be accommodated.

Comprehensive repertoire and phylogenetic analysis of the G protein-coupled receptors in human and mouse.

Understanding differences in the repertoire of orthologous gene pairs is vital for interpretation of pharmacological and physiological experiments if conclusions are conveyed between species. Here we present a comprehensive dataset for G protein-coupled receptors (GPCRs) in both human and mouse with a phylogenetic road map. We performed systematic searches applying several search tools such as BLAST, BLAT, and Hidden Markov models and searches in literature data. We aimed to gather a full-length version of each human or mouse GPCR in only one copy referring to a single chromosomal position. Moreover, we performed detailed phylogenetic analysis of the transmembrane regions of the receptors to establish accurate orthologous pairs. The results show the identity of 495 mouse and 400 human functional nonolfactory GPCRs. Overall, 329 of the receptors are found in one-to-one orthologous pairs, while 119 mouse and 31 human receptors originate from species-specific expansions or deletions. The average percentage similarity of the orthologue pairs is 85%, while it varies between the main GRAFS families from an average of 59 to 94%. The orthologous pairs for the lipid-binding GPCRs had the lowest levels of conservation, while the biogenic amines had highest levels of conservation. Moreover, we searched for expressed sequence tags (ESTs) and identified more than 17,000 ESTs matching GPCRs in mouse and human, providing information about their expression patterns. On the whole, this is the most comprehensive study of the gene repertoire that codes for human and mouse GPCRs. The datasets are available for downloading.