Subjective, neuropsychological, and neural markers of memory in older adults.

OBJECTIVES: To investigate the relationship between the P300 event-related potential, neuropsychological measures of memory, subjective memory complaints (SMCs), and indicators of psychosocial functioning. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study of 79 community-based older adults, aged 60-75 years, participants completed online surveys and in-person neuropsychological and electroencephalogram (EEG) assessments. MEASUREMENTS: Measures included: the Change subscale of the Metamemory in Adulthood Questionnaire, NIH Toolbox Emotions battery (Perceived Stress and Psychological Well-Being), Geriatric Depression Scale, Geriatric Anxiety Scale, electrocortical measures (EEG), California Verbal Learning Test, 3rd Edition, and diagnostic ratings for mild and major neurocognitive disorders based on full neuropsychological battery, clinical interview, and two-clinician consensus. RESULTS: P300 amplitude was associated with long-delay verbal memory recall and diagnostic rating. SMCs were not associated with objective memory or diagnostic rating. SMCs were associated with higher perceived stress, anxiety, and depression symptoms and lower psychological well-being. CONCLUSIONS: Neural indicators such as the P300 may be useful for early detection of cognitive impairment. SMCs were not a reliable indicator of early memory impairment in relation to neuropsychological or neural indicators, but may be a useful indicator of unreported stress and mood symptoms in clinical settings.

Lessons learnt from delayed diagnosis of FGF-23-producing tumour-induced osteomalacia and post-operative hungry bone syndrome.

Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by a fibroblast growth-factor-23 (FGF-23)-secreting phosphaturic mesenchymal tumour (PMT) and is characterised by hypophosphataemic osteomalacia. We present a 36-year-old man initially presenting with diffuse bone and joint pain who was inappropriately treated for presumed ankylosing spondylitis for 2 years. Whole-body bone scan suggested metabolic bone disease, prompting referral to our endocrine institution. He was subsequently diagnosed with persistent hypophosphataemia, inappropriately high renal tubular phosphate excretion, 1,25-dihydroxyvitamin D3 suppression, severe osteoporosis and severe osteomalacia. FGF-23 concentrations (140 ng/L) were raised 3-fold above the upper limit of normal. Initial Gallium-68 (68Ga) DOTATATE positron emission tomography (PET)/CT scan missed an active lesion in the left fibular head as the field only included the mid-brain to the proximal femora. Histopathology results from tumour resection confirmed a PMT over-expressing FGF-23. Serum phosphate and FGF-23 normalised immediately post-operatively. He developed severe hypocalcaemia 3-weeks post-operatively (1.77 mmol/L) which normalised after 1 month of high-dose caltrate and calcitriol therapy. Osteomalacia, osteoporosis and associated symptoms resolved during medium-term follow-up with >100% improvement in his bone mineral density. This case report and discussion highlights the pitfalls contributing to delayed diagnosis of TIO and alerts clinicians to the potential complication of hungry bone syndrome post-tumour resection.

Paraneoplastic syndrome - a rare but treatable cause of non-thyroid-related extraocular muscle enlargement.

Paraneoplastic syndrome is a rare but reversible cause of non-thyroid-related extraocular muscle enlargement. We present a 71-year-old lady with diplopia, restricted eye movements, suppressed thyroid-stimulating hormone and enlargement of all extraocular muscles while on thyroxine replacement for hypothyroidism. She had distant history of metastatic breast cancer treated with chemotherapy, surgical resection and tamoxifen. She had negative anti-thyroid autoantibodies and thyroid ultrasound was not consistent with autoimmune thyroid disease. Carcinoembryonic antigen and cancer antigens 15-3, 125 and 72-4 were elevated, and whole-body positron emission tomography-computed tomography showed avid liver, left adrenal and skeletal lesions, with liver biopsy confirming breast cancer recurrence. She received prednisone and chemotherapy (letrozole, palbociclib) and achieved normalisation of eye movements and reduction in her EOME at 9-month follow-up. Our case highlights the importance of exploring paraneoplastic syndrome as a treatable cause of EOME in a patient lacking features of thyroid orbitopathy and autoimmune thyroid disease.

First-Principles and Thermodynamics Study of Compositionally Tuned Complex Metal Oxides: Cation Release from the (001) Surface of Mn-Rich Lithium Nickel Manganese Cobalt Oxide.

Compositional tuning of nanoscale complex metal oxides (CMOs) can lead to enhanced performance and favorable properties for a variety of energy-related applications. However, investigations of the nanoscale CMOs used in energy storage technologies demonstrate that these nanomaterials may have an adverse biological impact, highlighting a fundamental knowledge gap between nanomaterial design and the structure and properties at the end of life. CMO nanomaterials can enter the environment due to improper disposal, where they undergo subsequent (as of yet poorly understood) nanoscale transformations that may affect biological response and, ultimately, environmental fate. This points to the need for studies at the nano-bio interface that can be used to shape rules for the redesign of CMOs: materials that are are potentially more benign by design and serve as examples of sustainable nanotechnology. The example given here is to enrich lithium nickel manganese cobalt oxide, Li x(Ni yMn zCo1- y- z)O2 (NMC), with Mn to create a family of materials that are less expensive and potentially less toxic to a wide range of organisms. In this paper, we investigate the structure and electronic states of Mn-rich NMC at the density functional theory (DFT) level to elucidate the interplay of redox properties, oxidation state, and coordination environment of a compositionally tuned CMO. We find that the oxidation states of Ni and Co remain mostly unaffected while Mn exists as both Mn2+ and Mn4+. Our models show that the ratio of Mn2+ and Mn4+ varies with changes in the coordination environment, such as the identity of neighboring atoms and surface OH group coverage. The surface metal release properties of Mn-rich NMC compositions are predicted using a DFT + solvent ion model and show that Mn-rich NMC compositions are inherently more prone to dissolution than NMC and that this is attributed to the changes in oxidation state of the transition metals in Mn-rich NMC.

Anomalous biliary and vascular anatomy-Potential pitfalls during cholecystectomy.

Laparoscopic cholecystectomy is usually a low-risk procedure associated with a short stay and a low rate of conversion to open surgery. Complications are sometimes associated with anomalous vascular or biliary anatomy. Outlined below are the variations in vascular and biliary anatomy which may result in complications either due to involvement in the inflammatory process or inadvertent division during dissection. Clin. Anat. 30:1103-1106, 2017. © 2017 Wiley Periodicals, Inc.

Role of carcinoembryonic antigen as a marker for colorectal liver metastases.

Carcinoembryonic antigen (CEA), a marker for colorectal adenocarcinoma, can monitor disease progression and treatment response. This study aims to determine the accuracy of CEA in the detection and resectability of colorectal liver metastases. Patients with primary colorectal cancer were divided into three groups: resectable hepatic metastases (group 1), unresectable metastases (group 2), and disease-free cases (group 3). The CEA concentration was recorded pre- and post-hepatectomy in group 1 and on radiological confirmation of disease state in the other groups. It was expressed as median (95% confidence interval [CI]), with predictors of concentration determined. Group 1 (n=141) had pre-operative CEA of 8.9 (4.6-13.1), with 38.1% of patients being normal. Maximum tumour diameter correlated with CEA level (r=0.41, P<0.0001). Post-hepatectomy CEA was 2.3 (1.9-2.7; P<0.0001), with 81.1% of patients being normal. Group 2 (n=158) had CEA of 20.6 (9.4-31.9). Group 3 (n=361) had CEA of 2.0 (1.8-2.2). Sensitivity of CEA pre- and post-hepatectomy was 61.2% and 69.3%, respectively, while specificity was 79.8% for both groups. Concentration was elevated in hepatic colorectal metastases but is not a marker of resectability. A CEA reduction post-resection indicates that it may be used as an indicator of treatment response, while CEA is increased by tumour burden and lesion size.

Hepatic cytokine response can be modulated using the Kupffer cell blocker gadolinium chloride in obstructive jaundice.

INTRODUCTION: Depletion of Kupffer cells by gadolinium chloride (GdCl(3)) reduces the systemic response during sepsis. The study aim was to investigate the effect of this depletion on hepatic proinflammatory cytokine response to portal endotoxaemia. METHODS: Sixteen Wistar rats were randomised to receive either saline IV (n = 8) or GdCl(3) (10 mg/kg IV, n = 8) six days after bile duct ligation (BDL). 24 h later the animals were perfused for 2 h, using isolated hepatic perfusion. Aliquots of effluent perfusate were collected at 20-min intervals for cytokine analysis. Sections of liver were sampled and the hepatic Kupffer cell number of each group was measured using ED1 immunohistochemistry. RESULTS: Pre-treatment with GdCl(3) resulted in significantly reduced serum bilirubin concentrations but significantly elevated serum ALP and AST levels compared to the control group. It was also associated with a significant reduction in Kupffer cell numbers and a corresponding significant reduction in hepatic TNFα and IL-6 production in response to portal endotoxaemia. CONCLUSIONS: Pre-treatment with GdCl(3) in jaundiced animals reduced Kupffer cell numbers, attenuated liver enzyme abnormalities and reduced TNFα and IL-6 in response to portal endotoxaemia. Hepatic Kupffer cells, therefore, play a significant role in the development of an exaggerated inflammatory response in obstructive jaundice.

Effect of oral cholecalciferol 2,000 versus 5,000 IU on serum vitamin D, PTH, bone and muscle strength in patients with vitamin D deficiency.

UNLABELLED: Treatment of vitamin D deficiency for 3 months with oral cholecalciferol 5,000 IU daily was more effective than 2,000 IU daily in achieving optimal serum 25-hydroxyvitamin D (25OHD) concentrations. Optimal 25OHD serum level calculated to be 63.8 nmol/L. All parameters of muscle strength improved following administration of cholecalciferol for 3 months. INTRODUCTION: The aim of this study was to determine the optimal dose of cholecalciferol required to achieve target serum 25OHD level ≥ 75 nmol/L and its relationship to both bone turnover and muscle strength. METHODS: Thirty deficient patients (serum 25OHD ≤ 50 nmol/L) were randomly assigned into two groups-i.e. 2,000 and 5,000 IU/day. Data were collected at baseline, at 2 and 3 months post-therapy: (a) clinical demographics, (b) dietary calcium recall, (c) physical tests of muscle function and (d) biochemistry. Statistical analysis used paired student t test and analysis of variance. Regression analysis was used to determine relationship between serum 25OHD and parathyroid hormone (PTH). RESULTS: Twenty-six (87%) patients completed 3 months of therapy. The percent increase in serum 25OHD (compared to baseline) was 82.7% in 2,000-IU group and 219.5% in 5,000-IU group. All participants (100%) achieved a serum 25OHD concentration >50 nmol/L; only 5 subjects (45.4%) in 2,000-IU group compared to 14 subjects (93.3%) in 5,000-IU group achieved final 25OHD concentration ≥ 75 nmol/L (p < 0.01). In the regression analysis, the reflexion point at which the PTH level increased above the normal range was calculated to be 63.8 nmol/L 25OHD. All parameters of muscle strength showed trends in improvements following the administration of both the 2,000 and 5,000 IU doses. No patient reported untoward side effects and no patient developed hypercalcaemia. CONCLUSION: Treatment for 3 months with oral cholecalciferol 5,000 IU daily may be more effective than 2,000 IU daily in achieving optimal serum 25OHD concentrations in vitamin D-deficient patients.

PET-CT accurately predicts the pre-operative characteristics of colorectal hepatic metastases.

BACKGROUND: Since 2002, Positron Emission Tomography (PET-CT) has been considered to be an essential pre-operative investigation in the management of colorectal liver metastases (CRLM) in our institution. This study aimed to compare characteristics of hepatic metastases on PET-CT with post-operative histological findings and pathology of the primary tumour. METHODS: All patients with CRLM, who underwent surgical intervention from 2002 to 2008, were reviewed. PET-CT and pathology reports of hepatic resections and original colorectal resections were retrieved. Patient demographics, colorectal staging, number of metastases and their maximum diameter from both PET-CT and pathology reports were recorded. Values were expressed as mean (±SD). RESULTS: 141 patients were identified. The maximum diameter on PET-CT (4.2 ± 2.6) was similar to pathology (4.8 ± 3.6; p = 0.39), with significant correlation (r = 0.72, p < 0.0001). The number of lesions on PET-CT (1.6 ± 1.0) was similar to pathology (1.7 ± 1.3; p = 0.43) with significant correlation (r = 0.80, p < 0.0001). Mean SUV max was 9.22 (±4.39), with no correlation to lesion diameter (r = 0.25, p = 0.045), but significantly increased with decreasing differentiation (p = 0.01). CONCLUSIONS: PET-CT scanning accurately detected the number of lesions and their maximum diameter, with radiological evidence of poorer differentiation. Further studies of non-surgical patients are required to assess its overall accuracy.

Estimation of lean body weight in older women with hip fracture.

OBJECTIVE: Lean body weight (LBW) decreases with age while total body fat increases, resulting in altered drug pharmacokinetics. A semi-mechanistic equation estimating LBW using height, weight and sex has been developed for potential use across a wide range of body compositions. The aim of this study was to determine the ability of the LBW equation to estimate dual energy x-ray absorptiometry-derived fat free mass (FFM(DXA)) in a population of older women with recent hip fracture. METHODS: Baseline, four and 12 month data obtained from 23 women enrolled in the Sarcopenia and Hip Fracture study were pooled to give 58 measurements. LBW was estimated using the equation: LBW (kg) = (9270 x Wt) / (8780 + (244 x BMI)). Body composition was classified as: 'normal' (BMI <25kg/m(2) and not sarcopenic), 'overweight-obese' (BMI >25kg/m(2) and not sarcopenic), 'sarcopenic' (sarcopenic and BMI <25kg/m(2)), or 'sarcopenic-obese' (sarcopenic and BMI >25kg/m(2)). The ability of the LBW equation to predict FFMDXA was determined graphically using Bland-Altman plots and quantitatively using the method of Sheiner and Beal. RESULTS: The mean ± SD age of female participants women was 83±7 years (n=23). Sarcopenia was frequently observed (65.2%). Bland-Altman plots demonstrated an underestimation by the LBW equation compared to FFMDXA. The bias (95% CI) and precision (95% CI) calculated using the method of Sheiner and Beal was 0.5kg (-0.7, 1.66kg) and 4.4kg (-3.7, 12.4kg) respectively for pooled data. CONCLUSION: This equation can be used to easily calculate LBW. When compared to FFMDXA, the LBW equation resulted in a small underestimation on average in this population of women with recent hip fracture. The degree of bias may not be clinically important although further studies of larger heterogeneous cohorts are needed to investigate and potentially improve the accuracy of this predictive equation in larger clinical cohorts.

Expression of osteopontin coregulators in primary colorectal cancer and associated liver metastases.

BACKGROUND: A transcription regulatory complex (TRC) that includes Ets1, Ets2, PEA3 and ß-catenin/T-cell factors regulates osteopontin (OPN) that is implicated in colorectal cancer (CRC) dissemination. The consistency of OPN transcriptional control between primary CRC and metastases is unclear. This study investigates expression and prognostic significance of the OPN-TRC in primary human CRC and associated colorectal liver metastases (CRLM). METHODS: Osteopontin-TRC factors were assayed by digital microscopy in 38 primary CRCs and matched CRLM specimens and assessed against clinical prognosis. RESULTS: In primary CRC, OPN expression intensity correlated with that of its co-activators, PEA3 (r=0.600; P<0.01), Ets1 (r=0.552; P<0.01), Ets2 (r=0.521; P<0.01) and had prognostic significance. Osteopontin intensity in primary CRC inversely correlated with the interval between diagnosis and resection of CRLM. Overall OPN intensity was lower in CRLM than primary CRC and correlations with co-activators were weaker, for example, Ets1 (P=0.047), PEA3 (P=0.022) or nonsignificant (Ets2). The ratio of OPN expression in CRLM vs primary CRC had prognostic significance. CONCLUSION: This study supports transcriptional control of OPN by known coregulators in both primary and secondary CRC. Weaker associations in CRLM suggest involvement of other unknown factors possibly from the liver microenvironment or resulting from additional genetic or epigenetic changes that drive tumour metastatic capability in OPN transcriptional control.

The role of surgery for pancreatic cancer: a 12-year review of patient outcome.

INTRODUCTION: Pancreatic cancer has a poor prognosis with <5% alive at 5 years, despite active surgical treatment. The study aim was to review patients undergoing pancreatic resection and assess the effect of clinical and pathological parameters on survival. PATIENTS AND METHODS: All patients who had undergone radical pancreatic surgery, January 1996 to December 2008, were identified from the unit database. Additional information was retrieved from the patient records. The demographic, clinical, and pathological records were recorded using Microsoft Excel. Survival was assessed using Kaplan-Meier and predictors of survival determined by multinominal logistic regression and log rank test. RESULTS: 126 patients were identified from the database. The majority (106) had a Whipple's procedure, 14 had a distal pancreatectomy and 6 had local periampullary excision. The average age of the Whipple's group of patients was 61.7 years (± 11.7) with most procedures performed for malignancy (n=100). Survival was worse with adenocarcinoma compared to all other pathologies (p=0.013), while periampullary tumours had a better prognosis compared to other locations (p=0.019). Survival decreased with poorer differentiation (p=0.001), increasing pT (p<0.001) and pN stage (p<0.001). Survival was worse with perineural (p=0.04) or lymphovascular invasion (p=0.05). A microscopic postive resection margin (R1) was associated with a worse survival (p=0.007). Tumour differentiation (p=0.001) and positive nodal status (p<0.001) were found to be independent predictors of mortality. CONCLUSION: Tumour differentiation and nodal status are important predictors of outcome. A positive resection margin is associated with a poorer survival.

Management of liver trauma.

BACKGROUND: Blunt and penetrating liver trauma is common and often presents major diagnostic and management problems. METHODS: A literature review was undertaken to determine the current consensus on investigation and management strategies. RESULTS: The liver is the most frequently injured organ following abdominal trauma. Immediate assessment with ultrasound has replaced diagnostic peritoneal lavage in the resuscitation room, but computerised tomography remains the gold standard investigation. Nonoperative management is preferred in stable patients but laparotomy is indicated in unstable patients. Damage control techniques such as perihepatic packing, hepatotomy plus direct suture, and resectional debridement are recommended. Major complex surgical procedures such as anatomical resection or atriocaval shunting are now thought to be redundant in the emergency setting. Packing is also recommended for the inexperienced surgeon to allow control and stabilisation prior to transfer to a tertiary centre. Interventional radiological techniques are becoming more widely used, particularly in patients who are being managed nonoperatively or have been stabilised by perihepatic packing. CONCLUSIONS: Management of liver injuries has evolved significantly throughout the last two decades. In the absence of other abdominal injuries, operative management can usually be avoided. Patients with more complex injuries or subsequent complications should be transferred to a specialist centre to optimise final outcome.

Tryptophan catabolites in mesenteric lymph may contribute to pancreatitis-associated organ failure.

BACKGROUND: Multiple organ failure (MOF) is the key determinant of mortality in acute pancreatitis (AP). Mesenteric lymph cytotoxicity contributes to organ failure in experimental models of systemic inflammation. The aim of this study was to evaluate the mesenteric lymph pathway and the lymph injury proteome in experimental AP-associated MOF, and to test the hypothesis that immunoregulatory tryptophan catabolites contribute to mesenteric lymph cytotoxicity. METHODS: Using an experimental model of AP in rats, the humoral component of mesenteric lymph in AP was compared with that from sham-operated control animals, using in vitro and in vivo cytotoxicity assays, high-throughput proteomics and high-performance liquid chromatography. The experimental findings were corroborated in a cohort of 34 patients with AP. RESULTS: Compared with biologically inactive lymph from sham-operated rats, mesenteric lymph in AP became cytotoxic 3 h after induction. Hierarchical clustering of lymph proteomic mass spectra predicted the biological behaviour of lymph. Levels of the immunoregulatory tryptophan catabolite, 3-hydroxykynurenine, were increased in cytotoxic lymph and re-created cytotoxicity in vitro. In humans with AP, plasma kynurenine concentrations correlated in real time with MOF scores and preceded a requirement for mechanical ventilation and haemodialysis. CONCLUSION: These results support the concept that mesenteric lymph-borne kynurenines may contribute to pancreatitis-associated MOF.

A sensitive stain for aluminum in undecalcified cancellous bone.

Aluminum is known to accumulate with age in bone and other tissues of humans, even in the absence of renal disease. Our study aimed to develop a histological staining method sufficiently sensitive to detect aluminum in plastic sections of undecalcified bone biopsies from healthy volunteers as well as from patients with renal and non-renal bone diseases. We used quantitative histomorphometry to measure the percentage of trabecular surface stained by aluminum and found that our new method was approximately 50% more sensitive for detecting aluminum than the Acid Solochrome Azurine (ASA) method which in turn was significantly more sensitive than the Aluminon method. Aluminon is widely used in pathology laboratories for diagnostic purposes despite concerns in the literature about Aluminon's limited sensitivity for aluminum. Our histomorphometric results showed that the newly developed method stained approximately 10% of the trabecular surface in bone sections from healthy controls, 38% from renal patients, 26% from patients with vitamin D deficiency, and 29% from patients with osteoporosis. Histomorphometric measurements of aluminum-stained trabecular surfaces in sections stained with ASA were consistent with those obtained in Walton-stained sections but proportionately lower. Moreover, the Walton and ASA methods stained aluminum at similar locations in adjacent bone sections. As the ASA and Walton methods are considerably more sensitive for bone aluminum than the Aluminon method, we recommend that either of them should be used in place of the Aluminon method for routine diagnostic purposes.

The probiotic bacterium Lactobacillus plantarum species 299 reduces intestinal permeability in experimental biliary obstruction.

AIMS: Extrahepatic biliary obstruction is associated with the failure of intestinal barrier function, allowing bacteria and other substances from the intestine to enter the circulation and initiate a systemic inflammatory response, causing impairment of organ function. Probiotic bacteria have been shown to have beneficial effects on intestinal barrier function in other conditions, but their effects have never been studied in biliary obstruction. METHODS AND RESULTS: This study examined the effects of enteral administration of Lactobacillus plantarum species 299 (LP299) in oatmeal fibre compared with sterile oatmeal fibre in water or water alone in an animal model of biliary obstruction. Administration of LP299 was associated with reduced intestinal permeability compared with sterile oatmeal alone (0.262 +/- 0.105%vs 0.537 +/- 0.037%, P=0.019, percentage excretion of (14)Carbon), but there was no evidence of reduced endotoxin exposure or blunting of the systemic inflammatory response. Animals receiving sterile oatmeal fibre alone also failed to develop the hyperpermeability after biliary obstruction seen in animals receiving water only (0.512+/- 0.05%vs 0.788 +/- 0.18%), suggesting that oatmeal itself may have some beneficial effects on intestinal barrier function. CONCLUSION: Enteral administration of the probiotic bacterium LP299 reduces intestinal hyperpermeability associated with experimental biliary obstruction. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides insight to direct further work into the modulation of intestinal barrier function by probiotic bacteria.

Patterns of bacterial translocation in experimental biliary obstruction.

INTRODUCTION: Biliary obstruction is associated with impaired intestinal barrier function and translocation of enteric bacteria to the systemic circulation. Traditional live culture techniques may overlook translocation of dead bacterial fragments that stimulate the inflammatory response. The aim of this study was to estimate the extent and pattern of bacterial translocation in experimental biliary obstruction. MATERIALS AND METHODS: Thirty 9-week-old male Wistar rats were randomized to undergo bile duct ligation (BDL, n = 20) or sham operation (n = 10). Seven days after operation, each animal received 1 ml of (111)indium-oxyquinolone-labeled Escherichia coli p.o. Samples of liver, spleen, mesenteric lymph nodes, and lung were harvested 4 h later and analyzed for live bacteria and (111)indium activity. RESULTS: There was significantly more live bacterial translocation detected in BDL animals than in sham-operated animals (P = 0.00008, chi(2)). Labeled bacterial fragments were detected in all locations sampled in all animals. Sham-operated animals had significantly more labeled bacterial fragments detected in the liver (P = 0.0001) and the spleen (P = 0.03) than the BDL animals. The mean total bacterial survival in the BDL group was 30 +/- 13% and 0% in the sham operated group. CONCLUSION: These results demonstrate that non-viable bacterial fragments are present in sterile extra-intestinal sites in normal animals and that translocation of live bacteria is markedly increased in experimental biliary obstruction. These results also suggest that failure of bacterial killing is an important factor facilitating bacterial translocation in the presence of established biliary obstruction.