Recommendations for the Nomenclature of Cognitive Change Associated with Anaesthesia and Surgery-2018.

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines (Diagnostic and Statistical Manual for Mental Disorders, fifth edition [DSM-5] and National Institute for Aging and the Alzheimer Association [NIA-AA]) are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018.

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Recommendations for the Nomenclature of Cognitive Change Associated With Anaesthesia and Surgery-2018.

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018.

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Effects of clarithromycin on the pharmacokinetics of evogliptin in healthy volunteers.

WHAT IS KNOWN AND OBJECTIVE: Evogliptin (DA-1229), a novel dipeptidyl peptidase (DPP)-4 inhibitor with high potency and selectivity, was approved in Korea for the treatment of type 2 diabetes. Preclinical studies suggest that it is metabolized by cytochrome (CYP) P450 isozymes. Based on these findings, a clinical study was designed to investigate the pharmacokinetic (PK) interaction of evogliptin with a CYP inhibitor, clarithromycin. METHODS: An open-label, two-phase, crossover study was conducted with 12 healthy subjects. On day 1, a single dose of evogliptin 5 mg was administered alone to assess the reference PK profile of evogliptin. On day 10, after a 2-day pretreatment with clarithromycin, evogliptin 5 mg was administered again to evaluate the effect of CYP inhibition on the PK profile of evogliptin. Administration of clarithromycin continued until day 14. Blood sampling in the reference and test phases was performed until 96 and 168 hours after dosing, respectively for PK assays. RESULTS: Eleven of the 12 subjects completed the study, and their data were analysed. In the presence of clarithromycin, exposure to evogliptin increased without any serious adverse events and the geometric mean peak plasma concentration (Cmax ) and area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-∞ ) of evogliptin increased by 116.5% and 89.6%, respectively. WHAT IS NEW AND CONCLUSION: Administration of clarithromycin significantly increased exposure to evogliptin in healthy subjects.

A combination of excimer laser treatment and topical tacrolimus is more effective in treating vitiligo than either therapy alone for the initial 6 months, but not thereafter.

BACKGROUND: There are insufficient data on the long-term outcome of a combination therapy that comprises phototherapy and topical administration of tacrolimus. AIM: To evaluate the clinical efficacy according to the duration of treatment and in vitro results of a combination therapy involving topical tacrolimus and an excimer laser in the treatment of vitiligo. METHODS: In total, 276 patients with nonsegmental vitiligo were treated with an excimer laser twice weekly, or with tacrolimus ointment twice daily, or both. The melanin contents and levels of melanogenic enzymes were measured in cultured human melanocytes treated with tacrolimus and/or excimer laser. RESULTS: After adjusting for potential confounders, the combination of tacrolimus plus excimer laser was significantly more effective than either tacrolimus or excimer laser alone (P < 0.001 and P < 0.01, respectively) for the first 6 months. However, this superiority was not observed after the initial 6 months of treatment. In vitro, the combination of tacrolimus plus excimer laser led to a higher level of melanogenesis than with either treatment alone. CONCLUSIONS: A combination treatment with topical tacrolimus and an excimer laser may be useful as an induction therapy for up to 6 months, but continuation of this therapy for > 6 months might not provide a better final outcome than monotherapy.

Recommendations for the Nomenclature of Cognitive Change Associated with Anaesthesia and Surgery-20181.

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Regulation of early events in integrin signaling by protein tyrosine phosphatase SHP-2.

The nontransmembrane protein tyrosine phosphatase SHP-2 plays a critical role in growth factor and cytokine signaling pathways. Previous studies revealed that a fraction of SHP-2 moves to focal contacts upon integrin engagement and that SHP-2 binds to SHP substrate 1 (SHPS-1)/SIRP-1alpha, a transmembrane glycoprotein with adhesion molecule characteristics (Y. Fujioka et al., Mol. Cell. Biol. 16:6887-6899, 1996; M. Tsuda et al., J. Biol. Chem. 273:13223-13229). Therefore, we asked whether SHP2-SHPS-1 complexes participate in integrin signaling. SHPS-1 tyrosyl phosphorylation increased upon plating of murine fibroblasts onto specific extracellular matrices. Both in vitro and in vivo studies indicate that SHPS-1 tyrosyl phosphorylation is catalyzed by Src family protein tyrosine kinases (PTKs). Overexpression of SHPS-1 in 293 cells potentiated integrin-induced mitogen-activated protein kinase (MAPK) activation, and potentiation required functional SHP-2. To further explore the role of SHP-2 in integrin signaling, we analyzed the responses of SHP-2 exon 3(-/-) and wild-type cell lines to being plated on fibronectin. Integrin-induced activation of Src family PTKs, tyrosyl phosphorylation of several focal adhesion proteins, MAPK activation, and the ability to spread on fibronectin were defective in SHP-2 mutant fibroblasts but were restored upon SHP-2 expression. Our data suggest a positive-feedback model in which, upon integrin engagement, basal levels of c-Src activity catalyze the tyrosyl phosphorylation of SHPS-1, thereby recruiting SHP-2 to the plasma membrane, where, perhaps by further activating Src PTKs, SHP-2 transduces positive signals for downstream events such as MAPK activation and cell shape changes.

The utility of in-phase/opposed-phase imaging in differentiating malignancy from acute benign compression fractures of the spine.

BACKGROUND AND PURPOSE: Benign and malignant fractures of the spine may have similar signal intensity characteristics on conventional MR imaging sequences. This study assesses whether in-phase/opposed-phase imaging of the spine can differentiate these 2 entities. METHODS: Twenty-five consecutive patients who were evaluated for suspected malignancy (lymphoma [4 patients], breast cancer [3], multiple myeloma [2], melanoma [2], prostate [2], and renal cell carcinoma [1]) or for trauma to the thoracic or lumbar spine were entered into this study. An 18-month clinical follow-up was performed. Patients underwent standard MR imaging with an additional sagittal in-phase (repetition time [TR], 90-185; echo time [TE], 2.4 or 6.5; flip angle, 90 degrees ) and opposed-phase gradient recalled-echo sequence (TR, 90-185, TE, 4.6-4.7, flip angle, 90 degrees ). Areas that were of abnormal signal intensity on the T1 and T2 sequences were identified on the in-phase/opposed-phase sequences. An elliptical region of interest measurement of the signal intensity was made on the abnormal region on the in-phase as well as on the opposed-phase images. A computation of the signal intensity ratio (SIR) in the abnormal marrow on the opposed-phase to signal intensity measured on the in-phase images was made. RESULTS: Twenty-one patients had 49 vertebral lesions, consisting of 20 malignant and 29 benign fractures. There was a significant difference (P < .001, Student t test) in the mean SIR for the benign lesions (mean, 0.58; SD, 0.02) compared with the malignant lesions (mean, 0.98; SD, 0.095). If a SIR of 0.80 as a cutoff is chosen, with >0.8 defined as malignant and <0.8 defined as a benign result, in-phase/opposed-phase imaging correctly identified 19 of 20 malignant lesions and 26 of 29 benign lesions (sensitivity, 0.95; specificity, 0.89). CONCLUSION: There is significant difference in signal intensity between benign compression fractures and malignancy on in-phase/opposed-phase MR imaging.

Broad-scale impacts of salmon farms on temperate macroalgal assemblages on rocky reefs.

Intensive fish culture in open sea pens delivers large amounts of nutrients to coastal environments. Relative to particulate waste impacts, the ecological impacts of dissolved wastes are poorly known despite their potential to substantially affect nutrient-assimilating components of surrounding ecosystems. Broad-scale enrichment effects of salmonid farms on Tasmanian reef communities were assessed by comparing macroalgal cover at four fixed distances from active fish farm leases across 44 sites. Macroalgal assemblages differed significantly between sites immediately adjacent (100m) to fish farms and reference sites at 5km distance, while sites at 400m and 1km exhibited intermediate characteristics. Epiphyte cover varied consistently with fish farm impacts in both sheltered and exposed locations. The green algae Chaetomorpha spp. predominated near fish farms at swell-exposed sites, whereas filamentous green algae showed elevated densities near sheltered farms. Cover of canopy-forming perennial algae appeared unaffected by fish farm impacts.

Syndecan proteoglycans and cell adhesion.

It is now becoming clear that a family of transmembrane proteoglycans, the syndecans, have important roles in cell adhesion. They participate through binding of matrix ligand to their glycosaminoglycan chains, clustering, and the induction of signaling cascades to modify the internal microfilament organization. Syndecans can modulate the type of adhesive responses induced by other matrix ligand-receptor interactions, such as those involving the integrins, and so contribute to the control of cell morphology, adhesion and migration.

Relationship between circulating cytokine levels and thyroid function following bone marrow transplantation.

The relation between thyroid hormone changes and cytokines in bone marrow transplantation (BMT) patients has not been studied. This prospective study was designed to determine the relation between thyroid hormones and cytokine levels after BMT and their effects on the mortality. We studied 80 patients undergoing allogeneic BMT. Serum thyroid hormone parameters and cytokine levels were measured before and serially during 6 months after BMT. Serum T(3) decreased to a nadir 3 weeks post-BMT and serum T(4) was lowest at 3 months post-BMT. Serum thyroid stimulating hormone (TSH) sharply decreased to a nadir at 1 week and recovered. Serum interleukin-6 increased for 2 weeks after BMT and declined thereafter. Serum tumor necrosis factor-alpha increased for 3 weeks after BMT and declined thereafter. After 3 weeks post-BMT, both cytokine levels were negatively correlated with serum T(3) and T(4) levels. A total of 29 patients died before 1 year post-BMT and 51 patients survived longer than 1 year. Those patients who died before 1 year post-BMT had significantly lower levels of T(4) at 3 weeks, 3 and 6 months than surviving patients. In conclusion, increased levels of serum IL-6 and TNF-alpha were negatively correlated with thyroid hormone concentrations in BMT recipients suggesting the role of these cytokines in euthyroid sick syndrome.

Impact of circulating bone-resorbing cytokines on the subsequent bone loss following bone marrow transplantation.

Cytokines including IL-6 and TNF-alpha play an important role in the pathogenesis of postmenopausal osteoporosis. However, the relationship between changes in the cytokine levels and subsequent bone loss in patients undergoing a bone marrow transplantation (BMT) is unclear. A total of 46 patients undergoing an allogeneic BMT were prospectively investigated. The bone turnover markers and the serum cytokines were measured before BMT and serially after BMT. Bone mineral density (BMD) was measured before and 1 year after BMT. At 1 year after BMT, the lumbar spine BMD had decreased by 4.8%, and the total proximal femoral BMD had decreased by 12.3%. The serum IL-6 and TNF-alpha levels increased until 2 and 3 weeks after BMT, respectively. The lumbar BMD was significantly decreased as the serum IL-6 and TNF-alpha levels increased by post-BMT 3 weeks. The lumbar BMD decreased significantly as the cumulative prednisolone and cyclosporine dose increased. Patients with GVHD > or =grade II had higher lumbar bone loss than patients with GVHD

Changes in autoimmune thyroid disease following allogeneic bone marrow transplantation.

Autoimmune diseases can be transmitted and eliminated by bone marrow transplantation (BMT). There have been several cases of autoimmune thyroid disease (AITD) occurring after BMT, but AITD remission has been rarely reported. We present four cases in which the remission or transfer of AITD occurred after an allogeneic BMT. Two patients with severe aplastic anemia (SAA) showed evidence of remission of Hashimoto's thyroiditis which they had before allogeneic BMT. One patient with SAA, which developed during treatment with propylthiouracil for Graves' disease, underwent allogeneic BMT and showed evidence of Graves' disease remission following BMT. In one patient, new AITD occurred after an allogeneic BMT from an HLA-matched sibling who already had AITD. These cases support the evidence that the immune system is newly reconstituted after BMT, and severe autoimmune disease can be an indication for BMT. To fully understand the real changes in autoimmune status after BMT, long-term prospective studies are necessary.

Syndecan signaling: when, where and why?

Syndecans are the only family of transmembrane heparan sulphate proteoglycans. Invertebrates all appear to have one Syndecan core protein, but in mammals there are four. Examination of the core protein sequences shows that the cytoplasmic domains are the most conserved. This suggests that Syndecans make important interactions and/or signalling contributions. It has been established that all syndecans can interact with proteins of the actin-associated cytoskeleton, but details of signalling have been harder to ascertain. However, it appears that Syndecans can signal, primarily to the cytoskeleton, and the details are reviewed here. Only for vertebrate syndecan-4 is there substantial detail, and it remains a challenge to dissect the functions and signalling of other vertebrate and invertebrate syndecans.

Responsiveness of the state of O-linked N-acetylglucosamine modification of nuclear pore protein p62 to the extracellular glucose concentration.

O-linked N-acetylglucosamine (O-GlcNAc) modification has been described in many proteins, including nuclear pore glycoproteins. In the present study we investigated the effect of extracellular glucose on the level of modification of nuclear pore protein p62 by O-GlcNAc. We found that exposure of cells to a high concentration of glucose caused an increased level of modification of p62 with O-GlcNAc, whereas the modification of other proteins did not change detectably. The increased O-GlcNAc modification of p62 in response to glucose required the metabolism of glucose to glucosamine. The exposure of the cells to glucosamine itself also caused increased O-GlcNAc modification, whereas mannosamine and galactosamine did not. Furthermore, changes in glucose concentrations within the physiological range induced the O-GlcNAc modification in p62 in rat aortic smooth-muscle cells, indicating that this modification of p62 might occur in an intact animal. These results imply that the ambient glucose concentration has an impact on the level of O-GlcNAc modification of proteins such as p62, and that functional changes in some of these proteins might ensue.

Plasma and urinary concentrations of methamphetamine after oral administration of famprofazone to man.

1. To obtain further evidence for the metabolic formation of methamphetamine from famprofazone in man, concentrations of methamphetamine in plasma, as well as in urine, were measured by g.l.c. In addition, intact famprofazone and famprofazone N-oxide were analysed in the urine. 2. Methamphetamine appeared in plasma 1 h after a single 100 mg dose of the drug to two male subjects, and the concentration maintained between 24 and 44 ng/ml over 2-12 h, declining to 10 ng/ml and an undetectable level respectively after 24 h. 3. Total urinary excretion of methamphetamine over 72 h was 1.9 mg for a 25 mg dose and 2.2 mg for a 50 mg dose. After a 100 mg dose, 4.6 mg of methamphetamine was excreted over 36 h. Neither intact famprofazone nor famprofazone N-oxide were detected when the urine samples after the 100 mg dose were examined. 4. The results provide further evidence that methamphetamine is a bona fide human metabolite of famprofazone and suggest that at least 20% dose may be broken down via the pathways leading to the formation of methamphetamine. This could have significant clinical implications as the result of pharmacological activity of this metabolite.

Serine phosphorylation of syndecan-2 proteoglycan cytoplasmic domain.

Protein kinase C (PKC) is involved in cell-matrix and cell-cell adhesion, and the cytoplasmic domain of syndecan-2 contains two serines (residues 197 and 198) which lie in a consensus sequence for phosphorylation by PKC. Other serine and threonine residues are present but not in a consensus sequence. We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC, using purified GST-syndecan-2 fusion proteins and synthetic peptides corresponding to regions of the cytoplasmic domain. A synthetic peptide encompassing the entire cytoplasmic domain of syndecan-2 was phosphorylated by PKC with high affinity. Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. The efficiency of phosphorylation was concentration-dependent. At low concentrations, the cytoplasmic domain peptides were monomeric, with 2 mol/mol serine phosphorylation. At higher concentrations, however, the peptides formed dimers, with only 0.5 mol/mol phosphorylation. Concentration-dependent dimerization was not altered by phosphorylation. Phosphorylation is, therefore, dependent on the conformation of syndecan-2 cytoplasmic domain, but does not affect its oligomeric status.