Psychopathology and eating behaviour in people with type 2 diabetes referred for bariatric surgery.

PURPOSE: Psychopathology and disordered eating behaviours are putative pre-operative risk factors for suboptimal outcomes post-bariatric surgery. Documented psychopathology prevalence rates vary in bariatric candidate samples. Further, less attention has been paid to vulnerable subgroups such as people with diabetes who might be at an elevated risk. For these reasons, this study aimed to investigate the rates of psychopathology and disordered eating in pre-surgical candidates with type 2 diabetes mellitus (T2DM). METHODS: Participants were 401 consecutive patients from a state-wide bariatric surgery service for people with T2DM. Psychopathology was measured using multi-modal assessment including diagnostic interview and battery of validated questionnaires. The mean age of the sample was 51 years with a mean BMI of 46 kg/m2. The majority of the sample was female (60.6%), born in Australia (87%) and 18.2% identified as Aboriginal and/or Torres Strait Islander. RESULTS: Rates of current psychopathology in this sample included: major depressive disorder (MDD; 16.75%), generalised anxiety disorder (GAD; 20.25%), insomnia (17.75%) and binge eating disorder (BED; 10.75%). There were no significant differences on measures between people who endorsed Aboriginal and/or Torres Strait Islander status compared to those who did not endorse. The mean total score on the BES was 21.82 ± 10.40 (range 0-39), with 8.2% of participants meeting criteria for severe binge eating. Presence of an eating disorder was not significantly associated with degree of glycemic compensation. Average emotional eating scores were significantly higher in this study, compared to reference samples. Significantly increased binge eating severity and emotional eating severity was revealed for people with T2DM and comorbid MDD, social anxiety and eating disorders. Binge eating severity was associated with GAD, food addiction, substance use disorders, and history of suicide attempt but not emotional eating severity. CONCLUSION: Amongst people with T2DM seeking bariatric surgery, MDD, GAD and emotional eating were common. Psychopathology in a sample of people with T2DM seeking bariatric surgery was significantly associated with severity of disordered eating. These findings suggest people with T2DM seeking bariatric surgery may be vulnerable to psychopathology and disordered eating with implications for early identification and intervention. LEVEL OF EVIDENCE: Evidence obtained from cohort or case-control analytic studies.

Prescribing of psychotropic drugs and indicators for use in residential aged care and residents with dementia.

ABSTRACTIntroduction:It is well established that there is a high prescribing rate of psychotropic agents in residential aged care (RAC). The appropriateness of these medications has become controversial, given the limited data on efficacy and growing evidence of associated adverse outcomes. OBJECTIVE: To assess psychotropic prescribing in RAC including identification of potentially inappropriate prescriptions (PIPs) and common psychological and behavioral symptoms indicated for prescribing. These were viewed in context of dementia and different RAC facilities. METHODS: Electronic care plans of 779 RAC residents across 12 facilities were examined to elucidate psychotropic prescribing rates, PIPs, and indications for use. RESULTS: One in two residents (48.1%) were prescribed a psychotropic drug. The primary reasons for prescribing were depression (61.5%), anxiety (26.7%), sleep problems (25.4%), agitation (13.7%), psychosis (11.0%), and other behaviors (7.2%). Residents with dementia (56.6%) were more likely to be prescribed a drug for agitation and psychosis, and had a significantly increased prescription rate for antidepressants (OR = 1.50, 95% CI = 1.08-2.08, p = 0.01) and antipsychotics (OR = 1.88, 95% CI = 1.23-2.88, p < 0.01). Conversely, residents with dementia were less likely to receive medication to combat sleeping difficulties, with significantly lower benzodiazepine prescribing (OR = 0.63, 95% CI = 0.44-0.91, p = 0.01). Over half of all psychotropic prescriptions (54.0%) were potentially inappropriate based on the Beers Criteria. There was high variability of prescribing rates between homes. CONCLUSION: There is a high prescribing rate of potentially inappropriate medications. Residents with dementia are more likely to receive medication for agitation and psychosis, and are less likely to receive medication to combat sleeping difficulties.

Silver nanoparticles induce pro-inflammatory gene expression and inflammasome activation in human monocytes.

A complete cytotoxic profile of exposure to silver (AgNP) nanoparticles investigating their biological effects on the innate immune response of circulating white blood cells is required to form a complete understanding of the risk posed. This was explored by measuring AgNP-stimulated gene expression of the pro-inflammatory cytokines interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in THP-1 monocytes. A further study, on human monocytes extracted from a cohort of blood samples, was carried out to compare with the AgNP immune response in THP-1 cells along with the detection of pro-IL-1ß which is a key mediator of the inflammasome complex. The aims of the study were to clearly demonstrate that AgNP can significantly up-regulate pro-inflammatory cytokine gene expression of IL-1, IL-6 and TNF-α in both THP-1 cells and primary blood monocytes thus indicating a rapid response to AgNP in circulation. Furthermore, a role for the inflammasome in AgNP response was indicated by pro-IL-1ß cleavage and release. These results highlight the potential inflammatory effects of AgNP exposure and the responses evoked should be considered with respect to the potential harm that exposure may cause. Copyright © 2016 John Wiley & Sons, Ltd.

Immunological indicators of coeliac disease activity are not altered by long-term oats challenge.

Coeliac disease is a gluten-sensitive enteropathy that develops in genetically susceptible individuals. The disease exhibits many features of an autoimmune disorder. These include the production of highly specific anti-endomysial autoantibodies directed against the enzyme tissue transglutaminase. It is well accepted that wheat-, barley- and rye-based foods should be excluded in the gluten-free diet. Although several studies report that oats ingestion is safe in this diet, the potential toxicity of oats remains controversial. In the current study, 46 coeliac patients ingested oats for 1 year and were investigated for a potential immunogenic or toxic effect. Stringent clinical monitoring of these patients was performed and none experienced adverse effects, despite ingestion of a mean of 286 g of oats each week. Routine histological analysis of intestinal biopsies showed improvement or no change in 95% of the samples examined. Furthermore, tissue transglutaminase expression in biopsy samples, determined quantitatively using the IN Cell Analyzer, was unchanged. Employing immunohistochemistry, oats ingestion was not associated with changes in intraepithelial lymphocyte numbers or with enterocyte proliferation as assessed by Ki-67 staining. Finally, despite the potential for tissue transglutaminase to interact with oats, neither endomysial nor tissue transglutaminase antibodies were generated in any of the patients throughout the study. To conclude, this study reaffirms the lack of oats immunogenicity and toxicity to coeliac patients. It also suggests that the antigenic stimulus caused by wheat exposure differs fundamentally from that caused by oats.

Prospective observational study of dementia and delirium in the acute hospital setting.

BACKGROUND: Dementia and delirium appear to be common among older patients admitted to acute hospitals, although there are few Australian data regarding these important conditions. AIM: The aim of this study was to determine the prevalence and incidence of dementia and delirium among older patients admitted to acute hospitals in Queensland and to profile these patients. METHOD: Prospective observational cohort study (n = 493) of patients aged 70 years and older admitted to general medical, general surgical and orthopaedic wards of four acute hospitals in Queensland between 2008 and 2010. Trained research nurses completed comprehensive geriatric assessments and obtained detailed information about each patient's physical, cognitive and psychosocial functioning using the interRAI Acute Care and other standardised instruments. Nurses also visited patients daily to identify incident delirium. Two physicians independently reviewed patients' medical records and assessments to establish the diagnosis of dementia and/or delirium. RESULTS: Overall, 29.4% of patients (n = 145) were considered to have cognitive impairment, including 102 (20.7% of the total) who were considered to have dementia. This rate increased to 47.4% in the oldest patients (aged ≥ 90 years). The overall prevalence of delirium at admission was 9.7% (23.5% in patients with dementia), and the rate of incident delirium was 7.6% (14.7% in patients with dementia). CONCLUSION: The prevalence of dementia and delirium among older patients admitted to acute hospitals is high and is likely to increase with population aging. It is suggested that hospital design, staffing and processes should be attuned better to meet these patients' needs.

X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.

To determine whether human X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome (IPEX; MIM 304930) is the genetic equivalent of the scurfy (sf) mouse, we sequenced the human ortholog (FOXP3) of the gene mutated in scurfy mice (Foxp3), in IPEX patients. We found four non-polymorphic mutations. Each mutation affects the forkhead/winged-helix domain of the scurfin protein, indicating that the mutations may disrupt critical DNA interactions.

Lymphokine enhances oxygen-independent activity against intracellular pathogens.

To determine if mechanisms other than the generation of toxic oxygen intermediates are active against intracellular pathogens, oxidatively deficient mouse L cells and monocyte-derived macrophages from patients with chronic granulomatous disease were stimulated with soluble lymphocyte products. Despite no enhancement in oxidative activity, these cells displayed effective microbistatic activity against both T. gondii and C. psittaci. These results suggest a potential role for nonoxidative mechanisms in the mononuclear phagocyte's activity against intracellular pathogens, and indicate that lymphokines can regulate both oxygen-dependent and oxygen-independent antimicrobial responses.

Postmenopausal hormone therapy and cognition: effects of timing and treatment type.

SETTING: Hormone therapy used for the management of postmenopausal symptoms in older women appears to result in variable effects on cognitive function, depending on study design, subjects, tests used, and types of therapy. OBJECTIVE: To determine the effects of estrogen-only and estrogen plus progestogen preparations on cognitive performance (cognitive status, general and working memory) when taken 'early' and 'late' from the onset of menopause. METHOD: The study consisted of 410 women who were participants in a longitudinal study, first recruited at age 40-80 years. They were tested for change over 5 years as an observational cohort by the Mini-Mental State Examination, National Adult Reading Test and the Wechsler Memory Scale Version 3. Cognitive decline, measured by age-adjusted scores, was defined as >or=10% negative change in each individual woman. RESULTS: Controlling for age and lifestyle factors, and using the criterion of decrease in score >or=10% over 5 years for 'cognitive decline', 'early start' of hormone therapy (<3 years from menopause) was strongly associated with reduction in risk by the Mini-Mental State Examination (estrogen-only preparation, p = 0.005) but with increase in risk for general memory (with estrogen plus progestogen preparation, p = 0.02). Overall, there were no major effects on subgroups with type/timing of hormone therapy in relation to testing for a negative change in cognitive function. CONCLUSION: 'Early start' of estrogen-only hormone therapy was associated with reduced risk of global cognitive decline, and 'early start' estrogen-only and estrogen/progestogen hormone therapies showed increased risks of general memory decline. Even though this study did not have the power to discriminate between minor and mixed effects, it suggests that cognitive effects of hormone therapies may be mixed, depending on cognitive domain and timing of use/type of preparation.

Dielectrically heated sensor of water-vapor pressure.

Existing psychrometers of small dimensions cannot provide accurate long-term measurements of water-vapor pressure without frequent maintenance and recalibration. A small, simply constructed instrument employing dielectric heating and avoiding many of the problems of available sensors is described. The calibration curve depends only on the pressure-temperature curve for saturated lithium chloride.

In vivo transfer of GPI-linked complement restriction factors from erythrocytes to the endothelium.

Many proteins are associated with the outer layer of the cell membrane through a posttranslationally added glycosyl phosphatidylinositol (GPI) anchor. The functional significance of this type of protein linkage is unclear, although it results in increased lateral mobility, sorting to the apical surface of the cell, reinsertion into cell membranes, and possibly cell signaling. Here evidence is presented that GPI-linked proteins can undergo intermembrane transfer in vivo. GPI-linked proteins expressed on the surface of transgenic mouse red blood cells were transferred in a functional form to endothelial cells in vivo. This feature of GPI linkage may be potentially useful for the delivery of therapeutic proteins to vascular endothelium.

Early changes in the haemostatic and procoagulant systems after chemotherapy for breast cancer.

Venous thromboembolism (VTE) following breast cancer chemotherapy is common. Chemotherapy-induced alterations in markers of haemostasis occur during chemotherapy. It is unclear how rapidly this occurs, whether this is upregulated in patients developing VTE and whether changes predict for VTE. Markers of haemostasis, functional clotting assays and vascular endothelial growth factor were measured before chemotherapy and at 24 h, 4 days, 8 days and 3 months following commencement of chemotherapy in early and advanced breast cancer patients and in age- and sex-matched controls. Duplex ultrasound imaging was performed after 1 month or if symptomatic. Of 123 patients, 9.8% developed VTE within 3 months. Activated partial thromboplastin time (APTT), prothrombin time (PT), D-dimer, fibrinogen, platelet count, VEGF and fibrinogen were increased in cancer. Fibrinogen, D-dimer, VEGF and tissue factor were increased, at baseline, in patients subsequently developing VTE. D-dimer of less than 500 ng ml(-1) has a negative predictive value of 97%. Activated partial thromboplastin time, PT and thrombin-antithrombin showed significantly different trends, as early as within 24 h, in response to chemotherapy in patients subsequently developing VTE. Markers of coagulation and procoagulants are increased, before chemotherapy, in patients who subsequently develop VTE. A group of patients at minimal risk of VTE can be identified, allowing targeted thrombopropylaxis to the higher risk group.

Expression of complement regulatory proteins in accommodated xenografts induced by anti-alpha-Gal IgG1 in a rat-to-mouse model.

Anti-graft antibodies are often associated with graft rejection. Under special conditions, grafts continue to function normally even in the presence of anti-graft antibodies and complement. This condition is termed accommodation. We developed a xenograft accommodation model in which baby Lewis rat hearts are transplanted into Rag/GT-deficient mice, and accommodation is induced by repeated i.v. injections of low-dose anti-alpha-Gal IgG(1). The accommodated grafts survived a bolus dose of anti-alpha-Gal IgG(1), while freshly transplanted second grafts were rejected. To study the mechanism of anti-alpha-Gal IgG(1)-mediated accommodation, both real-time PCR and immunohistochemical staining revealed elevated expression of DAF, Crry and CD59 in the accommodated grafts. In vitro exposure of rat endothelial cells to anti-alpha-Gal IgG(1) also induced the up-regulation of DAF, Crry and CD59, as revealed by Western blot analyses, and was associated with an acquired resistance to antibody and complement-mediated lysis in vitro. Collectively, these studies suggest that the up-regulation of complement regulatory proteins may abrogate complement-mediated rejection and permit the development of xenograft accommodation.

Total internal reflection microscopy for live imaging of cellular uptake of sub-micron non-fluorescent particles.

This paper presents a simple, high-resolution, non-fluorescent imaging technique called total internal reflection microscopy (TIRM) and demonstrates its potential application to real-time imaging of live cellular events. In addition, a novel instrument is introduced that combines the simplicity of TIRM with the specificity afforded by dual-colour total internal reflection fluorescence (TIRF) microscopy and allows sequential imaging with the two modalities. The key design considerations necessary to apply these imaging modes in a single instrument are discussed. The application of TIRM alone yielded high-resolution live images of cell adherence to a poly-L-lysine modified substrate, whereby fine cellular structures are imaged. Non-fluorescent imaging of the uptake of sub-micron-sized polymeric particles by live cells is also demonstrated. Finally, images of fluorescently labelled cells were obtained in TIRF mode, sequentially to images obtained of the same cell in TIRM mode. Visual information gained using TIRF is compared with TIRM to demonstrate that the level of cell structure information obtainable with our total internal reflection microscope is comparable with the TIRF technique.

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

Long-term success in xenotransplantation is currently hampered by acute vascular rejection. The inciting cause of acute vascular rejection is not yet known; however, a variety of observations suggest that the humoral immune response of the recipient against the donor may be involved in the pathogenesis of this process. Using a pig-to-baboon heterotopic cardiac transplant model, we examined the role of antibodies in the development of acute vascular rejection. After transplantation into baboons, hearts from transgenic pigs expressing human decay-accelerating factor and CD59 underwent acute vascular rejection leading to graft failure within 5 d; the histology was characterized by endothelial injury and fibrin thrombi. Hearts from the transgenic pigs transplanted into baboons whose circulating antibodies were depleted using antiimmunoglobulin columns (Therasorb, Unterschleisshein, Germany) did not undergo acute vascular rejection in five of six cases. Biopsies from the xenotransplants in Ig-depleted baboons revealed little or no IgM or IgG, and no histologic evidence of acute vascular rejection in the five cases. Complement activity in the baboons was within the normal range during the period of xenograft survival. In one case, acute vascular rejection of a xenotransplant occurred in a baboon in which the level of antidonor antibody rose after Ig depletion was discontinued. This study provides evidence that antibodies play a significant role in the pathogenesis of acute vascular rejection, and suggests that acute vascular rejection might be prevented or treated by therapies aimed at the humoral immune response to porcine antigens.

Angiogenic characteristics of circulating and tumoural thrombospondin-1 in breast cancer.

In cancer models, thrombospondin-1 (TSP-1) has been shown to inhibit angiogenesis or promote metastasis by increasing adhesion of malignant cells to endothelium. To determine the role of TSP-1 in breast cancer and breast cancer angiogenesis, we have measured TSP-1 in plasma and tumour cytosols and compared levels to established clinicopathological prognostic parameters and intratumoural microvessel density. TSP-1 was measured, by radioimmunoassay, in plasma (pTSP-1) and tumour cytosols (cTSP-1) of women with early breast cancer (EBC) (n=71). pTSP-1 in EBC was compared to pTSP-1 levels in women with advanced breast cancer (ABC) (n=66), normal controls (n=77) and was correlated with prognostic features and microvessel density (MVD) (measured by CD31 immunostaining). cTSP-1 levels were compared to prognostic features and microvessel density. pTSP-1 in women with EBC (median 484, IQR 344-877 ng/ml) and ABC (median 588, IQR 430-952 ng/ml) were elevated when compared to normal controls (median 21, IQR 175-247) (p<0.001). Women with lymph node metastases (n=35) had higher levels of TSP-1 (median 799 ng/ml, IQR 455-943) than women who were node negative (median 343 ng/ml, IQR 267-514) (n=36) (p<0.05). Levels of pTSP-1 in EBC correlated with MVD (R=0.39, p<0.05). Levels of TSP-1 in tumour cytosols of women with EBC (median 1714, IQR 893-5283 ng/ml) correlated with microvessel density (R=0.46, p<0.01). Circulating levels of TSP-1 appear to be a marker of breast cancer aggressiveness and in breast cancer may have a pro-angiogenic rather than anti-angiogenic role.

Serum vascular endothelial growth factor in breast cancer.

Many studies have reported elevated serum concentrations of vascular endothelial growth factor (VEGF) in patients with cancer and claimed that the measurement of circulating VEGF is a surrogate marker of angiogenesis and/or metastasis. To determine the value of VEGF measurement in the diagnosis and prognosis of breast cancer, we measured levels in women with and without breast cancer. Platelet-depleted plasma VEGF levels were measured in premenopausal women at four-day intervals across the menstrual cycle, postmenopausal women and postmenopausal women who had undergone hysterectomy. Platelet-depleted plasma VEGF was also measured in pre- and postmenopausal women with early breast cancer (EBC) and levels compared with intratumoral levels, clinicopathological prognostic parameters and microvessel density. Levels of VEGF were determined using ELISA and immuno-histochemistry. Microvessel density was determined by immunohistochemical CD34 staining. Plasma VEGF in premenopausal women remained stable across the menstrual cycle except for a peak between days 8 and 12. VEGF levels in postmenopausal women were higher than in premenopausal women unless postmenopausal women had undergone hysterectomy. Amongst premenopausal women, levels of VEGF were high in 22 EBC patients when compared to normal premenopausal controls. No correlation was found between plasma and intratumoral VEGF, clinicopathological prognostic parameters or tumour microvessel density. The origin of circulating VEGF differs between pre- and postmenopausal women. Its measurement is unlikely to provide clinically useful diagnostic and prognostic information in women with early and advanced breast cancer.

Screening younger women with a family history of breast cancer--does early detection improve outcome?

Women with a family history are often offered mammographic surveillance at an earlier age and with greater frequency than those in the National Breast Screening Programme. In this study, we compared the survival of 62 breast cancer patients diagnosed in the context of a family history clinic offering 12-18 monthly mammographic screening with that of 1108 patients of the same age range but having no exposure to screening. We subtracted the expected additional observation time due to lead time from the survival of the screen-detected cases. Survival was significantly better in the family history group with relative hazards of 0.19 (95% CI 0.07-0.52, P<0.001) for breast cancer death and 0.19 (95% CI 0.08-0.43, P<0.001) for disease-free survival. After correcting for lead-time, the relative hazards were 0.24 (95% CI 0.09-0.66, P=0.005) for breast cancer death and 0.25 (95% CI 0.11-0.57, P<0.001) for disease-free survival. These results strongly suggest that screening younger women with a family history of breast cancer leads to improved survival. More precise estimates of the benefit will accrue from further follow-up and other such studies.