Prevalence of neurocognitive disorders 5 years after elective orthopaedic surgery.

BACKGROUND: Peri-operative neurocognitive disorders are one of the most common complications affecting older adults after anaesthesia and surgery. It is not clear how exposure to surgery and anaesthesia contributes to the prevalence of long-term neurocognitive disorders. This study aimed to report the prevalence of neurocognitive disorders, and explore pre-operative factors associated with neurocognitive disorders 5 years after elective orthopaedic surgery. METHODS: A prospective, 5-year longitudinal, cohort study was performed recruiting patients (aged ≥ 60 y) undergoing elective orthopaedic surgery and a contemporaneous non-surgical control group. Neurocognitive disorder was evaluated and classified at baseline and 5-year review incorporating: self- and informant-reported cognition; functional participation; and performance on neuropsychological tests. RESULTS: Recruitment at 5-year follow-up included 195 patients and 21 control participants. In the patient cohort the prevalence of neurocognitive disorder was 38.1% (n = 75), with 61 (30.1%) meeting the criteria for mild neurocognitive disorder and 14 (7.1%) for major neurocognitive disorder. At 5-year follow-up, 121 (61.4%) patients were classified with a neurocognitive disorder, with 88 (44.7%) characterised with mild neurocognitive disorder and 33 (16.8%) with major neurocognitive disorder. Age (odds ratio (95%CI) 1.07 (1.02-1.13); p = 0.01) and baseline cognitive impairment (odds ratio (95%CI) 2.1 (1.06-4.15); p = 0.03) were significant predictors of neurocognitive disorder 5 years after surgery. CONCLUSION: More than half of older adult patients had some form of neurocognitive disorder 5 years after elective orthopaedic surgery. Surgery and anaesthesia may be associated with the trajectory of cognitive decline in at-risk older adults, including those with pre-operative cognitive impairment. Cognitive screening should be factored into pre-operative assessments of older adults to inform subsequent care.

Advancing specificity in delirium: The delirium subtyping initiative.

BACKGROUND: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long-term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology. METHODS: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts. RESULTS: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium-spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations. DISCUSSION: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes. HIGHLIGHTS: Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning.

Inflammatory Biomarker Levels After Propofol or Sevoflurane Anesthesia: A Meta-analysis.

BACKGROUND: The perioperative inflammatory response may be implicated in adverse outcomes including neurocognitive dysfunction and cancer recurrence after oncological surgery. The immunomodulatory role of anesthetic agents has been demonstrated in vitro; however, its clinical relevance is unclear. The purpose of this meta-analysis was to compare propofol and sevoflurane with respect to biomarkers of perioperative inflammation. The secondary aim was to correlate markers of inflammation with clinical measures of perioperative cognition. METHODS: Databases were searched for randomized controlled trials examining perioperative inflammation after general anesthesia using propofol compared to sevoflurane. Inflammatory biomarkers investigated were interleukin (IL)-6, IL-10, tissue necrosis factor alpha (TNF-α), and C-reactive protein (CRP). The secondary outcome was incidence of perioperative neurocognitive disorders. Meta-analysis with metaregression was performed to determine the difference between propofol and sevoflurane. RESULTS: Twenty-three studies were included with 1611 participants. Studies varied by surgery type, duration, and participant age. There was an increase in the mean inflammatory biomarker levels following surgery, with meta-analysis revealing no difference in effect between propofol and sevoflurane. Heterogeneity between studies was high, with surgery type, duration, and patient age contributing to the variance across studies. Only 5 studies examined postoperative cognitive outcomes; thus, a meta-analysis could not be performed. Nonetheless, of these 5 studies, 4 reported a reduced incidence of cognitive decline associated with propofol use. CONCLUSIONS: Surgery induces an inflammatory response; however, the inflammatory response did not differ as a function of anesthetic technique. This absence of an effect suggests that patient and surgical variables may have a far more significant impact on the postoperative inflammatory responses than anesthetic technique. The majority of studies assessing perioperative cognition in older patients reported a benefit associated with the use of propofol; however, larger trials using homogenous outcomes are needed to demonstrate such an effect.

Preoperative Frailty Predicts Postoperative Neurocognitive Disorders After Total Hip Joint Replacement Surgery.

BACKGROUND: Frailty is a reduced capacity to recover from a physiologically stressful event. It is well established that preoperative frailty is associated with poor postoperative outcomes, but it is unclear if this includes cognitive decline following anesthesia and surgery. This retrospective observational study was a secondary analysis of data from a previous study (the Anaesthesia, Cognition, Evaluation [ACE] study). We aimed to identify if preoperative frailty or prefrailty is associated with preoperative and postoperative neurocognitive disorders or postoperative cognitive dysfunction. METHODS: The ACE study enrolled 300 participants aged ≥60 scheduled for elective total hip joint replacement and who underwent a full neuropsychological assessment at baseline and 3 and 12 months postoperatively. We applied patient data to 2 frailty models; both were based on an accumulation of deficits score: the reported Edmonton frail scale (REFS) and the comprehensive geriatric assessment-frailty index (CGA-FI) based on the comprehensive geriatric assessment. We calculated these 2 scores using baseline data collected from the medical history, demographic and clinical data as well as self-reported questionnaires. Some items on the REFS (3 of 18 or 17%) and the CGA-FI (37 of 51 or 27%) did not have an equivalent item in the ACE data. RESULTS: The mean age (standard deviation [SD]) was 70.1 years (6.6) with more women (197 [66%]). Using the REFS model, 40 of 300 (13.3%) patients were classified as vulnerable, mild, or moderately frail. Using the CGA-FI model, 69 of 300 (23%) were classified as intermediate or high frailty. The REFS and the CGA-FI were strongly correlated (r = 0.75; P < .01) with 34 of 300 (11%) meeting criteria for frailty by both the REFS and the CGA-FI.Frailty or prefrailty was associated with cognitive decline at 3 and 12 months using the REFS (odds ratio [OR], 1.51, 95% confidence interval [CI], 1.02-2.23 and OR, 2.00, 95% CI, 1.26-3.17, respectively) after adjusting for baseline mini-mental state examination (MMSE), smoking, hypertension, diabetes, history of acute myocardial infarction (AMI), and estimated intelligence quotient (IQ). Age did not modify this association. After adjusting for multiple comparisons, 3-month cognitive decline was no longer significantly associated with baseline frailty. CONCLUSIONS: This retrospective analysis demonstrates an association between baseline frailty and postoperative neurocognitive disorders, particularly using the more extensive REFS scoring method. This supports preoperative screening for frailty to risk-stratify patients, and identify and implement preventive strategies and to improve postoperative outcomes for older individuals.

Subsyndromal delirium is associated with poor functional outcome after ischaemic stroke.

BACKGROUND AND PURPOSE: Subsyndromal delirium (SSD) refers to patients with delirious symptoms who do not meet the criteria for delirium. The aim was to determine the prognostic significance of SSD in stroke patients. METHODS: In all, 564 patients with ischaemic stroke (median age 71 years, 50.5% female) were included. The Confusion Assessment Method was used to assess symptoms of delirium and the Diagnostic and Statistical Manual of Mental Disorders, 5th edn, criteria were used to diagnose delirium. SSD was defined as one or more core features of delirium without fulfilling diagnostic criteria. Functional outcome was assessed using the modified Rankin Scale at 3 and 12 months after stroke. RESULTS: Delirium was diagnosed in 23.4% of patients and SSD in 10.3% of patients. SSD was associated with increased risk of poor functional outcome. The adjusted odds ratios (ORs) for unfavourable outcome at 3 and 12 months were 2.88 [95% confidence interval (CI) 1.43-5.79, P < 0.01] and 2.93 (95% CI 1.39-6.22, P < 0.01), respectively. In multivariate analysis, delirium was an independent predictor of poor functional outcome at 3 months (OR 6.41, 95% CI 3.36-12.21, P < 0.01) and 12 months (OR 6.11, 95% CI 3.05-12.27, P < 0.01) after stroke. Delirium was also independently associated with increased risk of death within 3 months (hazard ratio 3.68, 95% CI 1.69-8.02, P < 0.01) and 12 months (hazard ratio 3.76, 95% CI 2.05-6.90, P < 0.01). SSD was not associated with increased risk of death. CONCLUSIONS: In SSD patients the risk of poor functional outcome after stroke is increased and intermediate between patients with and patients without delirium.

Analysis of corpus callosum size depending on age and sex.

BACKGROUND: The aim of the study was to analyse changes in the size of the corpus callosum (CC) depending on age and sex and to establish the reference values of the morphometric indices of the CC in the Polish population. MATERIALS AND METHODS: The results of magnetic resonance studies of 1108 patients performed in the years 2010-2014 were analysed. Two independent radiologists evaluated cerebral images to exclude deviations from normal state. In patients divided according to sex and to 10 age groups, measurements of CC and brain dimensions were made and morphometric indices were calculated. RESULTS: The results of measurements related to the following parameters: lengths of longitudinal cross-section of CC (CD), CC thickness in the narrowest place - isthmus (EF), the largest linear dimension of the brain from the frontal pole to the occipital pole (AB), the longitudinal cross-section area of the CC (A1) and cerebral cross-section area (A2) as well as CD/AB and A1/A2 ratios are summarised in 7 figures and 3 tables. CONCLUSIONS: It was demonstrated, that in all age groups there are statistically significant differences in the values of the analysed parameters and ratios of CC size. It was indicated, that there are no statistically significant differences between men and women in the CD, EF, and A1 parameters related to CC size, and the profiles of variations of these parameters are very similar. It was proved that the- re are statistical differences between women and men in parameters/indicators concerning of the brain size.

Neurotoxicity of anesthetic drugs: an update.

PURPOSE OF REVIEW: This article reviews the most recently published evidence that investigated anesthesia-induced neurotoxicity in both animals and humans, especially as it pertains to the perinatal period. RECENT FINDINGS: Several recent studies have focused on better understanding the complex mechanisms that underlie intravenous and volatile anesthesia-induced neurotoxicity in animals. Adjuvant agents that target these pathways have been investigated for their effectiveness in attenuating the neuroapoptosis and neurocognitive deficits that result from anesthesia exposure, including dexmedetomidine, rutin, vitamin C, tumor necrosis factor α, lithium, apocynin, carreic acid phenethyl ester. Five clinical studies, including one randomized control trial, provided inconsistent evidence on anesthesia-induced neurotoxicity in humans. SUMMARY: Despite a growing body of preclinical studies that have demonstrated anesthesia-induced neurotoxic effects in the developing and aging brain, their effects on the human brain remains to be determined. The performance of large-scale human studies is limited by several important factors, and noninvasive biomarkers and neuroimaging modalities should be employed to define the injury phenotypes that reflect anesthesia-induced neurotoxicity. Ultimately, the use of these modalities may provide new insights into whether the concerns of anesthetics are justified in humans.

Selective sweep of Wolbachia and parthenogenetic host genomes - the example of the weevil Eusomus ovulum.

Most parthenogenetic weevil species are postulated to have originated via hybridization, but Wolbachia has also been speculated to play a role via the induction of parthenogenesis. Here, we examine the molecular diversity of Wolbachia and parthenogenetic host genomes. The host species studied here, Eusomus ovulum, is known to be exclusively parthenogenetic and triploid. The E. ovulum populations that we examined had a low genetic diversity of mitochondrial (cytochrome oxidase I gene) and nuclear markers (internal transcribed spacer 2 and elongation factor 1-α gene), and they all were infected by only single bacteria strains (genotyped for five genes according to the multilocus sequence typing system). We found significant signs of linkage disequilibrium and a lack of recombination amongst all of the examined genomes (bacteria and host), which strongly indicates a selective sweep. The lack of heterozygosity in host nuclear genes, missing bisexual populations and selective sweep between the parthenogenetic host and bacteria genomes suggest that parthenogenesis in this species could have originated as a result of infection rather than hybridization. However, the finding that highly similar Wolbachia strains are also present in other parthenogenetic weevils from the same habitat suggests the opposite scenario: bacteria may have infected the already parthenogenetic lineage and taken advantage of the host's unisexual reproduction.

Hospital for joint diseases participates in international spine registry Spine Tango after successful pilot study.

Spine Tango is currently the only international spine registry in existence. It was developed under the auspices of Eurospine, the Spine Society of Europe, and is hosted at the University of Bern, Switzerland. The HJD Spine Center successfully tested Spine Tango during a 3-month pilot study and has since expanded documentation activities to more surgeons. Workflow integration and dedicated research staff are key factors for such an endeavor. Participation enables benchmarking against national and international peers and outcome research and quality assurance of surgical and non-surgical treatments.

Microstructure of electrodeposited NiFe/Cu multilayers.

NiFe/Cu multilayer films have been electrodeposited potentiostatically on (001)-oriented Si and polycrystalline Cu substrates by a single bath technique. Standard error of mean and energy dispersive X-ray studies of single NiFe(Cu) layers allow us to establish the right deposition parameters for NiFe and Cu sublayer. Standard error of mean results reveal the layered structure of deposits for relatively thick bilayer thickness (ca. approximately 200 nm). The modulated structure of NiFe/Cu multilayers with extremely thin bilayer thickness (nominal period Lambda= 8 nm) was investigated by transmission electron microscope techniques. A columnar structure of the deposit with column diameter in the range from 10 to 30 nm was observed. These results are comparable with X-ray diffraction measurements of crystallites size obtained by Scherer equation. The line scans acquired using EDS confirmed the layered structure of the deposit, but pointed towards possibility of intermixing of species from alternating sublayers especially in case of those with finer period.

The influence of different error estimates in the detection of postoperative cognitive dysfunction using reliable change indices with correction for practice effects.

The reliable change index (RCI) expresses change relative to its associated error, and is useful in the identification of postoperative cognitive dysfunction (POCD). This paper examines four common RCIs that each account for error in different ways. Three rules incorporate a constant correction for practice effects and are contrasted with the standard RCI that had no correction for practice. These rules are applied to 160 patients undergoing coronary artery bypass graft (CABG) surgery who completed neuropsychological assessments preoperatively and 1 week postoperatively using error and reliability data from a comparable healthy nonsurgical control group. The rules all identify POCD in a similar proportion of patients, but the use of the within-subject standard deviation (WSD), expressing the effects of random error, as an error estimate is a theoretically appropriate denominator when a constant error correction, removing the effects of systematic error, is deducted from the numerator in a RCI.

Anomalies of tooth formation in hypohidrotic ectodermal dysplasia.

OBJECTIVE: The X-linked hypohidrotic ectodermal dysplasia (HED) is the most common type of ectodermal dysplasia. The clinical identification of possible heterozygous females can be difficult because of the varying degrees of clinical signs caused by X-chromosome inactivation. This study is the first to elaborate on anomalies of tooth formation found in a group of hemizygous males and heterozygous females with known ED1 mutations. These tooth anomalies may be used as dental biomarkers for heterozygous females, enabling an earlier diagnosis, and therefore, better treatment and genetic counselling. METHODS: Anomalies of tooth formation were examined using panoramic radiographs, dental casts and oral photographs in hemizygous males and heterozygous females who were identified by molecular genetic analysis. The results were compared to existing controls and normative data. RESULTS: All affected males had multiple missing permanent teeth and tooth malformations. The heterozygous females had a significantly higher frequency of agenesis of permanent teeth compared to normative data. The heterozygous females had an increased prevalence of tooth malformations and reduced tooth size, especially in the mesiodistal dimension. CONCLUSIONS: We conclude that observed anomalies of tooth formation may be used as dental biomarkers in the clinical identification of potentially heterozygous females.

The influence of different error estimates in the detection of post-operative cognitive dysfunction using reliable change indices with correction for practice effects.

The reliable change index (RCI) expresses change relative to its associated error, and is useful in the identification of post-operative cognitive dysfunction (POCD). This paper examines four common RCIs that each account for error in different ways. Three rules incorporate a constant correction for practice effects and are contrasted with the standard RCI that had no correction for practice. These rules are applied to 160 patients undergoing coronary artery bypass graft (CABG) surgery who completed neuropsychological assessments preoperatively and 1 week post-operatively using error and reliability data from a comparable healthy non-surgical control group. The rules all identify POCD in a similar proportion of patients, but the use of the within subject standard deviation, expressing the effects of random error, as an error estimate is a theoretically appropriate denominator when a constant error correction, removing the effects of systematic error, is deducted from the numerator in a RCI.

Detection of postoperative cognitive decline after coronary artery bypass graft surgery is affected by the number of neuropsychological tests in the assessment battery.

BACKGROUND: The assessment of postoperative cognitive dysfunction after coronary artery bypass graft surgery is made with the repeated administration of cognitive tests. This classification is vulnerable to error, and it has been suggested that increasing the number of tests in a battery while maintaining constant inclusion criteria for postoperative cognitive dysfunction increases the rate of false positive classification of deterioration. The current study tested this by applying a constant rule for cognitive dysfunction using combinations of two to seven cognitive tests. METHODS: Two hundred and four coronary artery bypass graft patients (surgical) and 90 healthy nonsurgical controls aged 55 years or older completed a battery of cognitive tests at baseline (preoperative) and 1 week later (postoperative). In both groups, postoperative cognitive dysfunction was classified using all unique combinations of two to seven cognitive tests when performance deteriorated on two or more tests by at least the value of the baseline standard deviation. RESULTS: The average incidence of cognitive dysfunction progressively increased in both groups as the number of cognitive tests increased from two (surgical: 13.3%; control: 3.1%) to seven tests (surgical: 49.4%; control: 41.1%). CONCLUSIONS: Increasing the number of tests used to classify postoperative cognitive dysfunction appears to increase the sensitivity to change in the coronary artery bypass graft group. However, accompanying false positive classifications suggest that this improved sensitivity reflected increased error. Future rules for postoperative cognitive dysfunction need to account for this error and include a control group.

Computer-identified nuclear localization signal in exon 1A of the transporter DMT1 is essentially ineffective in nuclear targeting.

Divalent metal transporter 1 (DMT1; also called DCT1, Nramp2, or SLC11A2) has multiple isoforms that localize differently in many cell types. DMT1 +IRE species (encoded by mRNA with an iron-responsive element) are limited to the plasma membrane and cytosolic vesicles. In neural cells, -IRE isoforms of DMT1 (encoded by mRNA lacking an IRE) localize to the nucleus, plasma membrane, and cytosolic vesicles. In considering nuclear compartmentalization of -IRE isoforms, we hypothesized that the newly identified exon 1A in the N-terminus of this transporter might contain a nuclear localization signal. DNA constructs starting with exon 1A and ending with exons encoding alternative isoforms were made and transiently transfected into HEK293T and PC12 cells as well as rat sympathetic neurons. None of the constructs appeared in the nucleus despite the presence of exon 1A. Antibody specific for exon 1A was also used in both immunostaining and Western blots to investigate localization of exon 1A expressed both endogenously and ectopically in cells. Again, nuclear localization of DMT1 containing exon 1A was not observed. Our data suggest that exon 1A is neither sufficient nor necessary for DMT1 to appear in the nucleus.

Syngeneic central nervous system transplantation of genetically transduced mature, adult astrocytes.

Advances in the development of highly infectious, replication-deficient recombinant retroviruses provide an efficient means of stable transfer of gene expression. Coupled with ex vivo transduction, surrogate cell populations can be readily implanted into the brain, thus serving as vehicles for delivering selected gene products into the central nervous system (CNS). Here we report that rat astrocytes can be routinely and safely isolated from brain tissue of a living donor by use of short-term gelatin sponge implants. The mature, nontransformed astrocytes were easily expanded, maintained in long-term tissue cultures and were efficiently transduced with an amphotropic retrovirus harboring a heterologous, fused transgene. In vitro retroviral infection rendered the nontransformed cells essentially 100% viable after exposure. The level of efficiency of infection (30-50% effective genome integration of provirus and expression of transgene in target cell populations) and minimal cell toxicity obviated the need to harvest large numbers of target cells. Cultured transduced astrocytes were resilient and exhibited select peptide expression for up to 1 year. Subsequently, transduced astrocytes were used in a series of experiments in which cells were transplanted intracerebrally in syngeneic animals. Post-implantation, astrocytes seeded locally and either insinuated into the surrounding parenchyma in situ or exhibited a variable degree of migration, depending on the anatomic source of astrocytes and the targeted brain implantation site. Transduced astrocytes remained viable in excess of 8 months post-transplantation and exhibited sustained transgenic peptide expression of green fluorescent protein/neomycin phosphotransferase in vivo. The sequential isolation and culture of nontransformed, mature, adult astrocytes and recombinant retrovirus-mediated transduction in vitro followed by brain reimplantation represents a safe and effective means for transferring genetic expression to the CNS. This study lays the foundation for exploring the utility of using a human autologous transplantation system as a potential gene delivery approach to treat neurological disorders. Prepared and utilized in this manner, autologous astrocytes may serve as a vehicle to deliver gene therapy to the CNS.

Melatonin-induced suppression of PC12 cell growth is mediated by its Gi coupled transmembrane receptors.

The effects of pertussis toxin, an uncoupler of Gi protein from adenylate cyclase, and luzindole, a competitive inhibitor of melatonin receptor binding, were examined for their ability to inhibit melatonin-induced suppression of PC12 cell growth. Both agents inhibited the melatonin response suggesting that melatonin may be acting through one of its Gi coupled cell surface receptors. This is confirmed by Western blots demonstrating the presence of MT1 receptors in PC12 cells. Coupling of the Gi protein to these receptors is demonstrated by failure of melatonin to suppress cell growth in PKA deficient A126-1B2-1 mutant PC12 cells. Similarly, melatonin failed to prevent cell proliferation when cells were incubated in the presence of the PKA inhibitor, Rp-cAMP. Retinoic acid and dexamethasone, agents known to effect PC12 cell growth and/or differentiation, displayed differential effects on the actions of melatonin. In the presence of melatonin and low concentrations of retinoic acid (100 nM), PC12 cell proliferation was stimulated compared to that seen with either agent alone, whereas no increase in cell proliferation was observed when higher concentrations of retinoic acid (100 microM) were used. The effects of dexamethasone on suppression of PC12 cell growth were additive with that of melatonin whereas, 1,25-dihydroxyvitamin D(3) (IC(50)=10 nM), which by itself had no effect on PC12 cell growth, was found to inhibit the melatonin response. This study demonstrates that inhibition of PC12 cell growth, at physiological concentrations of melatonin, is mediated by cAMP-dependent cell surface receptors and this response is altered by other growth factors known to effect PC12 cell proliferation and differentiation.

[The role of cell-mediated immune response in pathogenesis of alopecia areata]. / Rola odpowiedzi immunologicznej typu komórkowego w patogenezie lysienia plackowatego.

Recent studies have suggested that cell-mediated immune response play a critical role in the pathogenesis of alopecia areata (AA). Eighteen patients with AA were included in the study. Fifteen healthy subjects served as controls. Serum levels of sTNF alpha RI and sIL-2R were measured using enzyme-linked immunosorbent assay technique. The serum levels of sTNF alpha RI were significantly elevated in patients with AA in comparison with control group. The serum levels of sIL-2R were higher in AA patients than in healthy subjects but not significantly. These results indicate, that immune mechanisms in AA are characterized by activation of T cells and other cells, possibly keratinocytes.