Triple aim improvement for individuals, services and society in dementia care : The DementiaNet collaborative care approach.

BACKGROUND: A redesigning of primary care is required to meet dementia patients' needs. In the Netherlands, current dementia care still falls short in areas including ad hoc collaboration, lack of feedback on quality to professionals involved, and insufficient implementation of established multidisciplinary guidelines. OBJECTIVE: DementiaNet is a collaborative care approach, which aims to reduce the burden of the disease on individuals, healthcare services and society via network-based care that encourages collaboration, enhances knowledge and skills and stimulates quality improvement cycles. MATERIAL AND METHODS: DementiaNet was developed to support primary care networks through implementation of five core processes: network-based care, clinical leadership, quality improvement cycles, interprofessional practice-based training and communication support tools, following a stepwise tailor-made approach. Alongside this, a mixed method study was designed to evaluate innovation and effectiveness. RESULTS: Currently, 18 networks have been formed. These vary in quality of care and strength of collaboration due to local circumstances. Initial activities and goals of each network also vary, ranging from acquaintance to shared care plans. Ongoing research will identify barriers, facilitators and merits of the approach in increasing quality of care and ultimately improving outcomes for patient, carer, health service and society. CONCLUSION: Initial results show that clinical practice varies and the DementiaNet approach can lead to quality improvement. Complexity and variety of local care requires complex interventions and evaluation methods that account for this in order to safeguard the value for practice. Strict methodology lessens external validity.

Bladder cancer survival: Women only fare worse in the first two years after diagnosis.

OBJECTIVES: It has consistently been shown that women who are diagnosed with bladder cancer have lower survival than men, but the exact mechanism remains unknown. Most studies assumed that the sex-specific mortality ratio is constant over time, possibly resulting in inaccurate estimates in various periods of follow-up. This study aimed to investigate the sex-specific excess mortality in bladder cancer patients and its variation over follow-up time. METHODS: Observational cohort study. Using data from the population-based Netherlands Cancer Registry, we studied 24,169 patients diagnosed between 2003 and 2014 with histologically confirmed ≥T1 bladder cancer with follow-up until January 2018. We used flexible parametric relative survival models to estimate excess mortality as a function of time for each sex and to explore the effect of covariates on these functions. RESULTS: Female patients (24%) had worse clinical tumor, node, and metastasis-stage at diagnosis and more often a nonurothelial tumor histology. The excess mortality ratio of sex was not constant over time; in the first two years after diagnosis excess mortality rates for women were higher than for men, but lower thereafter; this applied to both nonmuscle-invasive and muscle-invasive bladder cancer subgroups. Baseline differences in age, tumor, node, and metastasis-stage and histology accounted for only part of the excess mortality gap. CONCLUSIONS: The assumption of proportional hazards over time leads to underestimation of the excess mortality ratio for women in the first two years and overestimation thereafter, when excess mortality is comparable for women and men. Clinicians should incorporate the initial sex-specific poorer outcome in their considerations regarding prognosis and treatment options for female patients, e.g., more invasive treatment and neo-adjuvant treatment. These findings also point towards a mechanism of micrometastatic disease, warranting assessment of sex-specific efficacy in randomized controlled trials on treatments in this patient population.

Androgen influence on lacrimal gland apoptosis, necrosis, and lymphocytic infiltration.

PURPOSE: Previous studies have shown that ovariectomy and hypophysectomy cause regression of the lacrimal gland and have implicated androgens as trophic hormones that support the gland. The purposes of this study were to test the hypothesis that glandular regression after ovariectomy is due to apoptosis, to identify the cell type or types that undergo apoptosis, to survey the time course of the apoptosis, and to determine whether ovariectomy-induced apoptosis could be prevented by dihydrotestosterone (DHT) treatment. METHODS: Groups of sexually mature female New Zealand White rabbits were ovariectomized and killed at various time periods up to 9 days. Additional groups of ovariectomized rabbits were treated with 4 mg/kg DHT per day. At each time period, sham-operated rabbits were used as controls. Lacrimal glands were removed and processed for analysis of apoptosis as assessed by DNA fragmentation and for morphologic examination. DNA fragmentation was determined using the TdT-dUTP terminal nick-end labeling assay and by agarose gel electrophoresis. Labeled nuclei were quantified by automated densitometry. Sections were also stained for RTLA (rabbit thymic lymphocyte antigen), rabbit CD18, and La antigen. Morphology was evaluated by both light and electron microscopy. RESULTS: The time course of apoptosis exhibited two phases, a rapid and transient phase and a second prolonged phase. A transient phase peaked at approximately 4 to 6 hours after ovariectomy. The values for degraded DNA as a percentage of total nuclear area were 4.29%+/-0.79% and 4.26%+/-0.54%, respectively. The values for sham-operated controls examined at the same time periods were 1.77%+/-0.08% and 0.82%+/-0.21%, respectively. The percentage of degraded DNA at 24 hours after ovariectomy was not different from controls examined at the same interval after sham operation. The percentage of degraded DNA 6 days after ovariectomy was significantly increased (8.5%+/-2.4%), compared with sham-operated animals at the same time period (0.68%+/-0.03%). DNA laddering was more pronounced after ovariectomy. Dihydrotestosterone treatment in ovariectomized rabbits suppressed the increase in DNA degradation. Morphologic examination of lacrimal gland sections indicated that ovariectomy caused apoptosis of interstitial cells rather than acinar or ductal epithelial cells. Tissue taken 4 hours and 6 days after ovariectomy showed nuclear chromatin condensation principally in plasma cells. Increased numbers of macrophages were also evident. Significant levels of cell degeneration and cell debris, characteristic of necrosis, were observed in acinar regions 6 days after ovariectomy. Dihydrotestosterone prevented this necrosis. Increased numbers of RTLA+, CD18+, and La+ interstitial cells were also evident 6 days after ovariectomy. In addition, ovariectomy increased La expression in ductal cells. Dihydrotestosterone treatment prevented the increase in numbers of lymphoid cells and La expression. Dihydrotestosterone also promoted the appearance of mitotic figures in acinar cells and increased the sizes of acini by 43% (P < 0.05). CONCLUSIONS: Glandular atrophy observed after ovariectomy is likely to proceed by necrosis of acinar cells rather than apoptosis. This process begins with an apparent time lag after a rapid phase of interstitial cell apoptosis. These processes are accompanied by increased lymphocytic infiltration. These results suggest that a critical level of androgen is necessary to maintain lacrimal gland structure and function and that a decrease in available androgen below this level could trigger lacrimal gland apoptosis and necrosis, and an autoimmune response. Because apoptotic and necrotic cell fragments may be sources of autoantigens that can be processed and presented to initiate an autoimmune reaction, we surmise that cell death triggered by androgen withdrawal may trigger an autoimmune response such as that encountered in Sjögren's syndrome. (ABSTRACT TRUNCATED)

Air pollutants and the facilitation of cancer metastasis.

Studies have been carried out to determine whether the inhalation of ambient levels of nitrogen dioxide (NO2), a common air pollutant, could influence the frequency of blood-borne cancer cell metastasis to the lungs. B16 mouse melanoma cells were used as an in vivo test model. the results have indicated that animals inhaling ambient levels of NO2 developed a significantly higher number of melanoma nodules in their lungs than the animals inhaling filtered air. Thus, a new concept for the action of air pollutants is proposed. The question is raised whether similar events are taking place in urban human populations.

Retroviral vector-mediated gene expression in hematopoietic cells.

Gene transfer vectors based on simple retroviruses and more complex lentiviruses are currently the most reliable tools for stable establishment of transgenes in hematopoietic cells. While important hurdles in basic gene transfer technologies have been overcome in recent years, there is still some uncertainty in the choice of the cis-regulatory elements of the vector. These elements dictate the overall level, clonal variability, response to differentiation and persistence of transgene expression in vivo and thus have a significant influence on the outcome of therapeutic applications of somatic gene transfer. The rationale underlying the further improvement of such cis-elements is reviewed here.

Chronic glandular bronchitis in young individuals residing in a metropolitan area.

A study of 161 Los Angeles County residents aged 12-28 years old who had died sudden violent deaths showed frequent and severe chronic glandular bronchitis (CGB), that is to say grade > or =5 (0-10) chronic inflammation involving at least one, half or more, and all submucosal glands in 53.4%, 21%, and 4.4% of the main stem bronchi, respectively. The mean plasma cell/gland/bronchus was high (> or =5) for 22 subjects (13.7%), while only 2 bronchi (1.2%) had a correspondingly high lymphocyte mean (P<0.001). Of the bronchi, 75.2% were affected by glandular atrophy (> or =5 in 8.1%), 10.6% had neutrophil infiltration of glands, and 3.1% had acute sialadenitis. Of the total of 1040 glands, CGB was found in 83.8% (> or =5 in 26.5%). Of 25 non-smokers identified, 14 (56%) had some degree of CGB in > or =50% of the glands, severe in 7 (26%). Severe CGB in many young individuals raises concern that a subpopulation of living cohorts may have an increased susceptibility to disease and a rising incidence of chronic lung disease. Demographic analysis is pending, but respiratory infection, smoking, adverse socioeconomic factors, and air pollution are all potential causative factors. Since pollution in Los Angeles frequently exceeds air quality standards, an ongoing multicity study is attempting to distinguish between the suspected effects of air pollution and confounding variables.

Centriacinar region inflammatory disease in young individuals: a comparative study of Miami and Los Angeles residents.

Semiquantitative measurements of chronic inflammation of the centriacinar region (proximal acinus of lung) were compared between 20 Miami and 18 Los Angeles residents (ages 11-30 years) for whom smoking histories were available. Mean extent and severity scores of four lung sites were higher for Los Angeles than Miami residents, with effect of city statistically significant for extent (P=0.02). Also, maximum scores for extent and severity by city were significantly greater for Los Angeles residents (P=0.02, each), but not by smoking history. Smokers did have higher scores for mean extent and severity (by lung site and smoking history), but neither this nor inclusion of smoking and city in the model reached significance. With respect to maximum extent and maximum severity scores, a stratified comparison of cities by smoking history showed a trend (not significant) toward higher scores for Los Angeles residents. Mean extent and severity scores for the lower lobe were higher for basilar sections than for apical sections (each P<0.001). Cumulative data indicate that expanded pathologic studies are essential for efforts to complete a convergence of epidemiological and experimental data implicating exceedences of the Federal ozone standard as a contributor to human lung injury.

Nitrogen dioxide (NO2) inhalation, formation of microthrombi in lungs and cancer metastasis.

It is recognized that cancer cells may be introduced into circulation during surgical removal of a malignant neoplasm. The fate of these cells depends upon many factors. In this paper we present findings from an animal model which indicate that inhalation of nitrogen dioxide facilitates blood-borne cancer cell metastasis to lungs by injuring lung capillary endothelium and formation of microthrombi. Lung capillaries were evaluated by light and electron microscopy. The main lesions observed were microthrombi and injury to capillary endothelial cells, following 6 weeks of 0.35 +/- 0.05 ppm NO2 exposure. The blood-borne cancer cell metastasis was studied utilizing B16 melanoma cells in C57Bl/6J mice. A correlation was observed between increased incidence of microthrombi, endothelial cell injury and lung metastasis in exposed animals. Other adverse NO2 effects such as impairment of immune system may also participate. Inhalation of nitrogen dioxide and other air pollutants may play a significant role in enhancement of metastasis and blood vessel associated disorders.

The relationship between inhalation of nitrogen dioxide, the immune system, and progression of a spontaneously occurring lymphoma in AKR mice.

The effects of exposure to an ambient level of nitrogen dioxide (NO2) on the development and progression of the spontaneous T-cell lymphoma in AKR/cum mice are evaluated. The animals were exposed to 0.25 ppm +/- 0.05 ppm NO2 for 7 hr/day, 5 days/week for up to 181 days. Following exposure periods of 37, 71, 111, 141, and 181 days, the extent of lymphoma was determined microscopically in histologic sections of the thymus, spleen, lymph nodes, lung, and liver. In addition, T-lymphocyte subpopulations were quantitated by flow cytometry. The results indicate that the development and progression of lymphoma in mice was influenced by intermittent inhalation of NO2. The lymphoma was detectable earlier in control animals and the survival of the NO2-exposed group was significantly higher. The T-lymphocyte subpopulations were significantly lower in NO2-exposed animals following 37 and 181 days of NO2 exposure. The T-helper/inducer (CD4+) lymphocytes were adversely affected to the greatest extent, explaining in part the more aggressive behavior of the lymphoma in the control animals. Most importantly, these studies provide additional evidence that in vivo exposure to a level of NO2 commonly encountered in polluted metropolitan areas adversely affects cells of the immune system. In the case of the AKR mouse, the adverse effect of NO2 on CD4+ cells manifested itself by retarding development and progression of the spontaneous lymphoma. Our data suggest that this neoplasm may be dependent on growth factors such as interleukin 2, produced by CD4+ lymphocytes in the early stages.

Spleen cellularity shifts from the inhalation of 0.25-0.35 PPM nitrogen dioxide.

The effects of ambient level (0.25-0.35 ppm)NO2 on percent spleen cell counts, relative percentages of spleen lymphocyte subpopulations, spleen lymphoid nodule size, and differential peripheral blood cell counts were investigated in 170 young adult male mice following various NO2 exposure periods. The total spleen cell counts, surface IgM-positive lymphocytes and spleen mean lymphoid nodule area were all significantly decreased in the groups exposed to NO2 following extended time periods. The relative percentages of peripheral blood lymphocytes were also significantly decreased in the groups exposed to NO2 for 8 weeks. The mechanism for these observed spleen changes following ambient level NO2 exposure remains unclear, but the results warrant further investigation and concern, especially since such changes may reflect altered immune responsiveness.

Influence of ambient level NO2 exposure on newborn and adult mice body weights.

A study of the effects of NO2 inhalation on body weights of newborn and adult mice was carried out. A total of 1590 adult mice and 450 newborn mice were evaluated. The level of NO2 exposure was in the ambient range and varied between 0.17 and 0.80 +/- 0.05 ppm depending on experimental design. The duration of exposure was three to twelve weeks, depending upon specific experimental design. The results have indicated that newborn mice are more sensitive than adults to the inhalation of ambient level NO2 and showed significantly lower body weight gains. The findings were interpreted as being indicative of adverse systemic NO2 effects on newborn animals.

A new relationship between air pollutant inhalation and cancer.

Many studies have been conducted to investigate the effects of different air pollutants on health. Our studies have focused on the effects of nitrogen dioxide (NO2), and recently we reported that inhalation of low levels of NO2 can facilitate cancer cell metastasis. The study described herein utilized the same B16 mouse melanoma metastasis model of previous investigations, but under different NO2 exposure conditions. The results provide further evidence that inhalation of ambient level NO2 (0.4 ppm) or polluted urban ambient air play a role in facilitation of blood-borne cancer cell metastasis. In addition, results show different patterns of melanoma cell distribution in the lungs of NO2- and ambient-air exposed animals. They also indicate that extended periods of clean air between NO2 exposures may diminish the severity of the insult in the less sensitive animals. It is our conclusion that the results provide strong support for the need of improved air quality and for reduction of noxious pollutants in urban ambient air.

Inhalation of NO2 and blood borne cancer cell spread to the lungs.

An experimental model was designed where the frequency of blood-borne cancer cell metastases to the lungs of animals was used as an indicator to detect adverse effects of inhaled nitrogen dioxide (NO2). Animals were exposed to air containing 0.40 +/- 0.05 ppm or 0.80 +/- 0.05 ppm of NO2. After the appropriate exposure periods, the animals were infused intravenously with B16 mouse melanoma cells. At 3 wk post-infusion the animals were killed and the lungs were examined for melanoma nodule development. The lungs of the NO2-exposed animals contained a significantly higher number of melanoma nodules than the lungs of control animals (P less than .0025). These results indicate that inhalation of ambient or near ambient levels of NO2 influences the metastasis of blood-borne cancer cells. This raises the possibility that similar events may occur in the human population.

Ambient level ozone effects on subpopulations of thymocytes and spleen T lymphocytes.

The effects of ozone on thymocyte and spleen T lymphocyte subpopulations were studied. Balb/c mice were exposed to clean air or to 0.3 +/- 0.05 ppm ozone for 1-3 wk. Thymocytes and spleen T cells were stained with fluorochrome conjugated monoclonal antibodies against surface differentiation markers and/or propidium iodide for deoxyribonucleic acid (DNA). The cells were then analyzed by fluorescence activated cell sorter. The percentages of certain thymocyte and spleen T lymphocyte subtypes and DNA synthesizing spleen T cells were lower following 1 wk of ozone exposure. After 3 wk exposure, the thymocyte percentages were higher in ozone-exposed mice, whereas the absolute number remained lower, and spleen T lymphocytes showed no changes. The findings suggest that short-term ozone inhalation can affect the T cell immune system adversely, particularly the CD4+ cells.

Incidence of and risk factors for persistent gram-positive bacteraemia and catheter-related thrombosis in haematopoietic stem cell transplantation.

A cohort of 439 haematopoietic SCT recipients was analysed to determine the incidence of Gram-positive coccal bacteraemia and thromboembolic events associated with the use of central venous catheters (CVCs) and to determine risk factors for these complications. The incidences of persistent coagulase-negative staphylococcal (CoNS) bacteraemia, symptomatic thrombosis and thrombophlebitis were 25%, 9.6% and 6.6%, respectively. Duration of neutropenia (in days, odds ratio (OR) 1.02; P=0.04) and left-sided placement of the CVCs (OR 1.73; P=0.03) were independent risk factors for the occurrence of persistent CoNS bacteraemia, whereas the use of less mucotoxic conditioning regimens was associated with a lower risk (high-dose melphalan (HDM)/BEAM vs other regimens, OR 0.24; P<0.001). Use of TBI, persistent CoNS bacteraemia and tip colonisation were all significantly associated with an increased risk of symptomatic thrombosis (OR 6.03, 3.36 and 2.80, respectively; P0.02). The risk factors found in this cohort of SCT recipients differed from those found in the general cancer population, showing an important role for persisting bacteraemia in the pathogenesis of CVC-associated thrombosis. Therefore, we constructed a new algorithm in order to improve catheter management and prevent these CVC-related complications.