Treatment of bone metastasis induced by MDA-MB-231 breast cancer cells with an antibody against bone sialoprotein

The extracellular bone matrix protein bone sialoprotein (BSP) is considered to play an important role in the pathogenesis of lytic skeletal lesions which are associated with severe morbidity in breast, prostate or lung cancer patients. In addition to in vitro studies, nude rats were implanted with 10(5) MDA-MB-231 cells transfected with GFP into a small branch of the femoral artery. Osteolytic lesions of the respective hind leg were detected by X-ray and CT analysis as well as by immunohistochemistry. Exposure of MDA-MB-231GFP cells in vitro to an antibody against BSP (0-400 microg/ml) decreased proliferation, colony formation and migration of these cells by up to 95, 83 and 89 T/C%, respectively. In nude rats, pre-incubation of MDA-MB-231GFP cells prior to inoculation (25-100 microg/ml) reduced the mean osteolytic lesion size to 22 T/C% after 90 days of observation (p<0.05). Treatment of overt lytic metastasis with the anti-BSP antibody (10 mg/kg) resulted in a significantly smaller mean lesion size of 57 T/C% at the end of the observation period (p<0.05) as well as in new bone formation. Immunohistochemical analysis revealed the presence of BSP in MDA-MB-231GFP cells and in vessel endothelium cells during processes such as migration and invasion. In conclusion, an anti-BSP antibody decreased proliferation, colony formation and migration of MDA-MB-231GFP cells in vitro and reduced osteolysis besides inducing bone formation in a nude rat model.     

Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma

We have recently shown that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (CB(1) and CB(2)). In the current study, the role of each receptor and the signal transduction triggered by receptor ligation were investigated. Induction of apoptosis after treatment with the synthetic agonists R(+)-methanandamide [R(+)-MA] and Win55,212-2 (Win55; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone) was dependent on both cannabinoid receptors, because pretreatment with N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) and N-((1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) (SR144528), specific antagonists to CB(1) and CB(2), respectively, abrogated caspase-3 activity. Preincubation with the inhibitors 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) and 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB202190) showed that phosphorylation of MAPK p38 was implicated in the signal transduction leading to apoptosis. Treatment with R(+)-MA and Win55 was associated with accumulation of ceramide, and pharmacological inhibition of ceramide synthesis de novo prevented both p38 activation and mitochondria depolarization assessed by binding of 3,3'-dihexyloxacarbocyanine iodide (DiOC(6)). In contrast, the pancaspase inhibitor z-Val-Ala-Asp(Ome)-CH(2)F (z-VAD-FMK) did not protect the mitochondrial integrity. Taken together, these results suggest that concurrent ligation of CB(1) and CB(2) with either R(+)-MA or Win55 induces apoptosis via a sequence of events in MCL cells: accumulation of ceramide, phosphorylation of p38, depolarization of the mitochondrial membrane, and caspase activation. Although induction of apoptosis was observed in both MCL cell lines and primary MCL, normal B cells remained unaffected. The present data suggest that targeting CB(1)/CB(2) may have therapeutic potential for the treatment of mantle cell lymphoma.     

Capacity building in environmental health research in India and Nepal

The Fogarty International Training and Research Program in Environmental and Occupational Health at UC Berkeley concentrates on two major environmental health issues in the Indian subcontinent: arsenic in drinking water in West Bengal, India, and indoor air pollution in India and Nepal. Local trainees and researchers have had the opportunity to work on related research. Concerning arsenic in drinking water, projects included studies of skin lesions, pulmonary effects, reproductive outcomes, and child development, as well as mitigation approaches to reduce exposures. Activities in the indoor air pollution project have emphasized quantifying exposures to smoke from cooking and heating as well as their associations with tuberculosis and eye disease. Training has focused on developing skills necessary to address these problems. The training emphasizes in-country mentoring of trainees related to their research projects, and intensive short courses at partner institutions. The focus of capacity building in environmental health research in countries in economic and environmental transition should be on country-based research projects with embedded training efforts.     

Peer education in HIV prevention: an evaluation in schools

BACKGROUND: In recent years a number of publications have come out about the peer education method used as a tool in HIV prevention for young people. Our survey aimed at testing the effectiveness of the peer education method in HIV prevention in high school settings through a pilot intervention. METHODS: A peer education intervention took place in 10 high schools in Athens over a 1 year period. A cohort of 702 students was surveyed (n = 493 intervention group, n = 209 control group) from 13 high schools through anonymous questionnaires based on the KABPs model, pre- and post-intervention. The statistical package used was SPSS using the chi(2)-test. RESULTS: Compared with control students, the intervention students were slightly empowered: (i) to increase their personal responsibility; and (ii) to adopt a safer behaviour in sexual practice. Knowledge did not show any significant modification between the two groups. However, discrimination about certain groups of people, the attitude about condoms and initiation of sexual relations did not appear to be influenced. CONCLUSIONS: The peer education approach can influence the behaviour of young people regarding their personal protection from HIV infection. In order to test its effectiveness, peer education should be further evaluated as a health education method in HIV prevention in high schools, other youth settings and community interventions, where the aim is behavioural change.     

Maternal health in pregnancy and intellectual disability in the offspring: a population-based study

PURPOSE: The aim of the study is to investigate the relationship between common maternal conditions and intellectual disability (ID) of unknown cause in the offspring. METHODS: Information about the maternal health of children with and without ID was obtained by using record linkage. For mothers with specific medical conditions, proportions of children with mild to moderate ID, severe ID, and autism spectrum disorder (ASD) with ID were compared with those who did not have ID. RESULTS: There was an increased risk for mild to moderate ID in children of mothers with asthma (odds ratio [OR], 1.52; confidence interval [CI], 1.26-1.83]), diabetes (OR, 1.69; CI, 1.26-2.27), a renal or urinary condition (OR, 2.09; CI, 1.39-3.14), and epilepsy (OR, 3.53; CI, 2.56-4.84). ASD risk was increased for children of women with diabetes (OR, 2.89; CI, 1.28-6.51) and epilepsy (OR, 4.57; CI, 1.69-12.31). For anemia (n = 1101), there was an increased risk for severe ID (OR, 5.26; CI, 2.16-12.80). CONCLUSIONS: The increased risk for ID in offspring of mothers with such conditions as asthma and diabetes is particularly important for disadvantaged or ethnic populations, for whom these conditions are more prevalent and may be less well managed.     

Predictors of mortality for lower respiratory infections in nursing home residents with dementia were validated transnationally

BACKGROUND AND OBJECTIVE: Generalizability of clinical predictors for mortality from lower respiratory infection (LRI) in nursing home residents has not been assessed for residents with dementia. STUDY DESIGN AND SETTING: In prospective cohort studies of LRI in 61 nursing homes in the Netherlands (n = 541) and 36 nursing homes in Missouri, USA (n = 564), we examined 14-day and 1- and 3-month mortality in residents with dementia who were treated with antibiotics. RESULTS: A logistic model predicting 14-day mortality derived from Dutch data included eating dependency, elevated pulse, decreased alertness, respiratory difficulty, insufficient fluid intake, high respiratory rate, male gender, and pressure sores. After adjusting coefficients with the heuristic shrinkage factor, the 14-day model showed good discrimination and calibration in both datasets. The apparent c-statistic for the original Dutch model was 0.80 (after correction for optimism, it was 0.75); the c-statistic was 0.74 in the U.S. validation population. The models predicting 1- and 3-month mortality showed moderate performance. A scoring system for estimating 14-day mortality performed equally well as the original model. CONCLUSION: We identified a set of credible clinical predictors that are easily assessed and demonstrated validity in identifying residents at low risk of dying from LRI across different nursing home populations. This tool should inform decision-making for families and doctors.     

Wagga Wagga specialist outreach palliative medicine service: a report on the first 12 months of service

OBJECTIVE: This paper reports on and discusses the development of a visiting palliative medicine specialist outreach service for Wagga Wagga New South Wales, Australia, and presents initial data and three case vignettes for reflection. The visiting doctor was flown from Sydney each fortnight for a day and integrated with the local nursing based palliative care team. METHODS: Demographic data was collected over the initial 12 months of service, which included the location of the consult (hospital, home, nursing home), whom the consult was from (specialist, GP), age of the patient, location of death, type of cancer, as well as the complexity of consultation from the perspective of one of the authors. RESULTS: The majority of referrals were for advice on cancer pain control (62.3%) and other symptoms (26.7%) confirming the expectation. Those patients referred were considered appropriate, with over 75% having a palliative care issue that was considered appropriate for direct patient contact by the specialist in palliative medicine. CONCLUSIONS: The provision of a visiting palliative medicine specialist to rural areas has been developed over the last few years in New South Wales and the reporting of the success of this particular service aims to provide evidence for the need and the development of further services, as it is expected that this service would continue but with an increasing number of referrals as the service became increasingly known.     

Do older adults using NSAIDs have a reduced risk of colorectal cancer?

BACKGROUND AND OBJECTIVES: Colorectal cancer (CRC) is primarily a disease of older adults. Although NSAIDs are thought to protect from CRC, and long-term use of NSAIDs is common in the elderly, little is known about the impact of NSAID use on CRC risk at advanced age. We specifically reviewed current evidence regarding the effects of NSAIDs on CRC risk in individuals aged > or =65 years, a rapidly growing age group. STUDY DESIGN: We searched all articles in PubMed published before August 2005. Studies were included if a subgroup analysis of older adults (> or =65 years of age) was performed, or if long-term use of NSAIDs for > or =5 years and CRC risk was investigated. From the selected studies, relevant information, including sample characteristics and association with CRC risk, was extracted and compared. RESULTS: Altogether 19 studies were identified. Only four studies specifically considered NSAID use in people > or =65 years of age; of these, two showed risk reduction for CRC comparable to that seen in younger age groups or in all age groups. The most informative observational studies found decreasing relative risk of CRC with increasing duration of NSAID use, suggesting substantial risk reduction after 10-20 years of regular use. CONCLUSIONS: The available data on long-term effects of NSAID use in elderly people are sparse but predominantly indicate risk reduction for CRC comparable to that seen in younger age groups or all ages. Whether and to what degree initiating NSAID use in old age prevents CRC is essentially unknown. In light of the potential adverse effects of NSAIDs, including recent data on adverse cardiovascular outcomes, more information is needed on the minimum effective dose of NSAIDs and the duration of use required in order to evaluate individual risks and benefits in older adults.