Interaction between geriatric syndromes in predicting three months mortality risk.

OBJECTIVES: Capturing frailty using a quick tool has proven to be challenging. We hypothesise that this is due to the complex interactions between frailty domains. We aimed to identify these interactions and assess whether adding interactions between domains improves mortality predictability. METHODS: In this retrospective cohort study, we selected all patients aged 70 or older who were admitted to one Dutch hospital between April 2015 and April 2016. Patient characteristics, frailty screening (using VMS (Safety Management System), a screening tool used in Dutch hospital care), length of stay, and mortality within three months were retrospectively collected from electronic medical records. To identify predictive interactions between the frailty domains, we constructed a classification tree with mortality as the outcome using five variables: the four VMS-domains (delirium risk, fall risk, malnutrition, physical impairment) and their sum. To determine if any domain interactions were predictive for three-month mortality, we performed a multivariable logistic regression analysis. RESULTS: We included 4,478 patients. (median age: 79 years; maximum age: 101 years; 44.8% male) The highest risk for three-month mortality included patients that were physically impaired and malnourished (23% (95%-CI 19.0-27.4%)). Subgroups had comparable three-month mortality risks based on different domains: malnutrition without physical impairment (15.2% (96%-CI 12.4-18.6%)) and physical impairment and delirium risk without malnutrition (16.3% (95%-CI 13.7-19.2%)). DISCUSSION: We showed that taking interactions between domains into account improves the predictability of three-month mortality risk. Therefore, when screening for frailty, simply adding up domains with a cut-off score results in loss of valuable information.

Recognition of cognitive impairment and depressive symptoms in older patients with heart failure.

INTRODUCTION: Cognitive impairment and depression in patients with heart failure (HF) are common comorbidities and are associated with increased morbidity, readmissions and mortality. Timely recognition of cognitive impairment and depression is important for providing optimal care. The aim of our study was to determine if these disorders were recognised by clinicians and, secondly, if they were associated with hospital admissions and mortality within 6 months' follow-up. METHODS: Patients (aged ≥65 years) diagnosed with HF were included from the cardiology outpatient clinic of Gelre Hospitals. Cognitive status was evaluated with the Montreal Cognitive Assessment test (score ≤22). Depressive symptoms were assessed with the Geriatric Depression Scale (score >5). Patient characteristics were collected from electronic patient files. The clinician was blinded to the tests and asked to assess cognitive status and mood. RESULTS: We included 157 patients. Their median age was 79 years (65-92); 98 (62%) were male. The majority had New York Heart Association functional class II. Cognitive impairment was present in 56 (36%) patients. Depressive symptoms were present in 21 (13%) patients. In 27 of 56 patients (48%) cognitive impairment was not recognised by clinicians. Depressive symptoms were not recognised in 11 of 21 patients (52%). During 6 months' follow-up 24 (15%) patients were readmitted for HF-related reasons and 18 (11%) patients died. There was no difference in readmission and mortality rate between patients with or without cognitive impairment and patients with or without depressive symptoms. CONCLUSION: Cognitive impairment and depressive symptoms were infrequently recognised during outpatient clinic visits.

Does the Dutch Safety Management Program predict adverse outcomes for older patients in the emergency department?

PURPOSE: Frailty screening in the emergency department may identify frail patients at risk for adverse outcomes. This study investigated if the Dutch Safety Management Program (VMS) screener predicts outcomes in older patients in the emergency department. METHODS: In this prospective cohort study, patients aged 70 years or older presenting to the emergency department were recruited on workdays between 10:00 AM and 7:00 PM from May 2017 until August 2017. Patients were screened in four domains: activities of daily living, malnutrition, risk of delirium, and risk of falling. After 90 days of follow up, mortality, functional decline, living situation, falls, readmission to the emergency department, and readmission to the hospital were recorded. VMS was studied using the total VMS score as a predictor with ROC curve analysis, and using a cut-off point to divide patients into frail and non-frail groups to calculate positive predictive value (PPV) and negative predictive value (NPV). RESULTS: A total of 249 patients were included. Higher VMS score was associated with 90-day mortality (AUC 0.65, 95% CI 0.54-0.76) and falling (AUC 0.67, 95% CI 0.56-0.78). VMS frailty predicted mortality (PPV 0.15, NPV 0.94, p = 0.05) and falling (PPV 0.22, NPV 0.92, p = 0.02), but none of the other outcomes. CONCLUSION: In this selected group of patients, higher VMS score was associated with 90-day mortality and falls. The low positive predictive value shows that the VMS screener is unsuitable for identifying high-risk patients in the ED. The high negative predictive value indicates that the screener can identify patients not at risk for adverse medical outcomes. This could be useful to determine which patients should undergo additional screening.

Experiences with cerebrospinal fluid analysis in Dutch memory clinics.

BACKGROUND: Evidence on cerebrospinal fluid (CSF) analysis to demonstrate Alzheimer's disease has not yet been implemented in diagnostic guidelines. METHODS: We investigated the use of CSF analysis in a survey amongst all known memory clinics in the Netherlands, of which 85 of 113 (75.2%) responded. RESULTS: Sixty per cent of respondents used CSF analysis in 5% (median) of patients. The analysis almost always confirmed the working diagnosis in 68.4% and sometimes changed it in 28.2%. Complications occurred very infrequently (0%, median) and were mild. Reasons not to perform CSF analysis included the lack of clear recommendations in diagnostic guidelines. CONCLUSIONS: These results ask for a guideline update to clarify the use of CSF analysis as an add-on diagnostic method.

The cerebrospinal fluid amyloid beta42/40 ratio in the differentiation of Alzheimer's disease from non-Alzheimer's dementia.

BACKGROUND: Amyloid beta(40) (Abeta(40)) is the most abundant Abeta peptide in the brain. The cerebrospinal fluid (CSF) level of Abeta(40) might therefore be considered to most closely reflect the total Abeta load in the brain. Both in Alzheimer's disease (AD) and in normal aging the Abeta load in the brain has a large inter-individual variability. Relating Abeta(42) to Abeta(40) levels might consequently provide a more valid measure for reflecting the change in Abeta metabolism in dementia patients than the CSF Abeta(42) concentrations alone. This measure may also improve differential diagnosis between AD and other dementia syndromes, such as vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). OBJECTIVE: To investigate the diagnostic value of the CSF Abeta(42)/Abeta(40) ratio in differentiating AD from controls, VaD, DLB and FTD. METHODS: We analysed the CSF Abeta(42)/Abeta(40) ratio, phosphorylated tau(181) and total tau in 69 patients with AD, 26 patients with VaD, 16 patients with DLB, 27 patients with FTD, and 47 controls. RESULTS: Mean Abeta(40) levels were 2850 pg/ml in VaD and 2830 pg/ml in DLB patients, both significantly lower than in AD patients (3698 pg/ml; p<0.01). Abeta(40) levels in AD patients were not significantly different from those in controls (4035 pg/ml; p=0.384). The Abeta(42)/Abeta(40) ratio was significantly lower in AD patients than in all other groups (p <0.001, ANCOVA). Differentiating AD from VaD, DLB and non-AD dementia improved when the Abeta(42)/Abeta(40) ratio was used instead of Abeta(42) concentrations alone (p<0.01) The Abeta(42)/Abeta(40) ratio performed equally well as the combination of Abeta(42), phosphorylated tau(181) and total tau in differentiating AD from FTD and non-AD dementia. The diagnostic performance of the latter combination was not improved when the Abeta(42)/Abeta(40) ratio was used instead of Abeta(42) alone. CONCLUSION: The CSF Abeta42/Abeta40 ratio improves differentiation of AD patients from VaD, DLB and non-AD dementia patients, when compared to Abeta42 alone, and is a more easily interpretable alternative to the combination of Abeta42, p-tau and t-tau when differentiating AD from either FTD or non-AD dementia.

Aberrant monocyte prostaglandin synthase 2 (PGS2) expression in type 1 diabetes before and after disease onset.

METHODS: We examined monocyte prostaglandin synthase 2 (PGS2/COX2) expression in individuals at risk for or with type 1 diabetes including: (i) 58 established type 1 and 2 diabetic patients; (ii) 34 autoantibody positive (AA+) children and adults; (iii) 164 infants and young children with insulin-dependent diabetes mellitus (IDDM) susceptibility human leukocyte antigen (HLA) alleles; and (iv) 37 healthy control individuals, over a 5-yr period. RESULTS: Established type 1 diabetic patients (1 month to 30+ yr post-disease onset) had significantly higher PGS2 expression than healthy controls; by contrast, insulin-treated type 2 diabetic patients had significantly lower PGS2 expression than healthy controls. Longitudinal studies of AA+ subjects at risk for type 1 diabetes indicated that 73% (11/15) of individuals who developed this disease during the study period expressed high levels of PGS2 prior to or after onset. We also found high level PGS2 expression in genetically at-risk infants and young children that correlated with having a first-degree relative with type 1 diabetes, but not with age, gender, or HLA genotype. In this population, high level PGS2 expression coincided with or preceded autoantibody detection in 30% (3/10) of subjects. CONCLUSIONS: These findings suggest that high level monocyte PGS2 expression, although subject to fluctuation, is present in at-risk subjects at an early age and is maintained during progression to and after type 1 diabetes onset.

The value of immunohistochemistry and in situ hybridization in detecting cytomegalovirus in bone marrow transplant recipients.

Autopsy tissues of 19 patients with complications after bone marrow transplantation (BMT) were analysed for the presence of cytomegalovirus (CMV) using histochemical methods. CMV antigens were detected by antibodies to CMV Immediate Early Antigen (IEA) or CMV Late Antigen (LA). CMV-DNA was detected by DNA in situ hybridization (DISH). IEA was detected in one or more tissues in 79% of 14 patients from whom frozen tissue was available. CMV-DNA was detected on paraffin sections in 84% of all 19 patients. CMV components were present in all organs studied; the highest incidence was found in lung, gastrointestinal tract and kidney. In histology, only 37% of patients showed signs of CMV infection by the presence of cytomegalic cells with nuclear inclusions (or so called "owl eye cells"). In tissue culture, only 33% of 15 patients were CMV positive. Serologically, 68% of all patients had active CMV infection, as indicated by a rise in antibody titres. We conclude that the quick detection of CMV IEA and CMV-DNA has a high sensitivity and predictive value, which is comparable to or exceeds the serological detection of CMV.

Detection of calcitonin-encoding mRNA by radioactive and non-radioactive in situ hybridization: improved colorimetric detection and cellular localization of mRNA in thyroid sections.

The localization of mRNA encoding calcitonin was studied by in situ hybridization using 35S-labeled RNA probes and biotin-labeled DNA probes. Radiolabeled probes were detected by autoradiography and biotin-labeled probes by streptavidin-biotin-peroxidase. To intensify the colorimetric signal, the indirect avidin-biotin complex (ABC) method was performed. However, the results were often variable. To improve the sensitivity, the peroxidase reaction signal was enhanced with a gold-silver deposit intensification reaction. To shorten the incubation times and to enhance the colorimetric reaction, several reaction steps were performed in a microwave oven. The localization of calcitonin mRNA in thyroid tissue, as detected with in situ hybridization, was confirmed by immunohistochemical localization of the calcitonin polypeptide. The results of in situ hybridization using biotinylated probes were compared to in situ hybridization using radioactive probes. Our data show that the results of in situ hybridization applied on frozen and paraffin-embedded sections using biotinylated DNA probes, detected with an indirect streptavidin-biotin-peroxidase reaction and intensified by silver-gold enhancement, were comparable to those obtained with radioactive probes. The localization of calcitonin encoding mRNA was in agreement with the localization of the calcitonin polypeptide.

Ultrastructural cytochemistry of non-specific esterase in murine peritoneal macrophages.

Non-specific esterase (NSE) activity was demonstrated in glutaraldehyde-fixed monolayers of murine peritoneal macrophages. Using 2-naphthylthiol acetate (NTA) as substrate and Fast Blue BB as coupling agent a strong osmiophilic reaction product was obtained. The reaction product was observed as electron-dense dots covering cisterns of the rough endoplasmic reticulum, Golgi saccules and vesicles, or as large aggregates in lysosomes. Using alpha-naphthyl butyrate (ANB) as substrate and hexazotized pararosaniline as coupling agent the osmiophilic reaction product was observed extracellularly on the plasma membrane as an electron-dense continuous layer, whereas intracytoplasmic staining of lysosomes was rare. Substitution of the coupling agents in the respective media resulted in a slight reaction with the ANB medium whereas with the NTA medium reaction product was observed only in lysosomal structures. The substrate specificity of the different types of esterases was confirmed after isoelectric focusing on thin-layer polyacrylamide gels. The results indicate that in murine peritoneal macrophages different types on NSE are detected with NTA and ANB, having distinct ultrastructural localizations.

Tumor growth stimulatory macrophages induced by a subclinical bacterial infection in vivo.

Nonelicited peritoneal macrophages obtained from normal mice from our animal house unexpectedly expressed a strong tumor growth stimulatory effect in vitro. Macrophages expressing this stimulatory effect had an aberrant morphology compared to the morphology of normal macrophages as observed by electron microscopy. The results of immunization of these affected mice with tumour cells led to the usual lymphocyte sensitization. No external symptoms were observed, and the mice looked healthy. Treatment of the affected macrophage donors with antibiotics resulted in the abolishment of the tumor growth stimulatory effect by the macrophages. Thus, this tumor cell growth stimulation by macrophages was probably due to a subclinical infection of the mice.

Characterization of two cell lines, derived from two malignant fibrous histiocytomas.

We have investigated the phenotype and ultrastructure of tumour cells from two cell lines each derived from a malignant fibrous histiocytoma (MFH) as a means of studying the histogenesis of this group of tumours. The first MFH (MFH-I) was of the pleomorphic subtype, with a predominantly histiocytic appearance, the second was of the pleomorphic subtype associated with myxoid and storiform areas (MFH-II). In vitro tumour cells from both neoplasms showed aberrant growth properties. Xenografts in nude mice from both neoplasms showed a similar histology to that of the original tumour. Both tumours showed hyaluronidase sensitive alcian blue staining. Phenotypic studies of the two cell lines and of the tumour tissues demonstrated that the cells differed in the presence of collagen types I and III. They did not show evidence of histiocytic, endothelial, leiomyoblastic, rhabdomyoblastic, lipoblastic of schwannian origin. Ultrastructurally, the two cell lines were found to be different. In vitro and in xenografts the cell type of MFH-I resembled a primitive mesenchymal cell. Whereas that of MFH-II resembled a fibroblast-like cell. We concluded that the group of MFH is heterogeneous and is probably derived from more than one progenitor cell.

Surface immunoglobulin restriction in B-non Hodgkin's lymphomas in cell suspension and on frozen tissue sections.

The diagnostic relevance of different tests for detection of surface immunoglobulin on tumour cells of B-type non-Hodgkin's lymphomas (B-NHL) was investigated by comparison of the direct antiglobulin rosetting reaction (DARR) in suspension with two-colour direct immunofluorescence (DIF) on frozen tissue sections. In benign lymph nodes (n = 27) the kappa/lambda ratio by DARR test ranged from 0.9 to 2.8. Tested by suspension and frozen tissue analysis, light chain restriction was found in 24 and 27 of 31 cases of B-NHL, respectively. Heavy chain restriction was found in half of the cases (14 of 26) studied in suspension and in almost all (28 of 31) tested on sections. In 9 cases DARR tests showed restriction of more than one Ig class on tumour cells, which was infrequent (2 of 28) in frozen section analysis. Although both tests appeared valuable for routine diagnostic purposes, we found the DIF analysis on tissue sections somewhat more discriminative, especially in detection of heavy chain restriction in B-NHL.