Cancer prevalence higher in stroke patients than in the general population: the Dutch String-of-Pearls Institute (PSI) Stroke study.

BACKGROUND AND PURPOSE: The aim of this study was to assess the prevalence of cancer and its characteristics in patients with ischemic stroke and to compare this with cancer prevalence in the general population. METHODS: This was a multicenter cohort study with 2736 patients presenting with ischemic stroke or transient ischemic attack. The prevalence of cancer was assessed by interview and verified by reviewing all medical records. In stroke patients with a history of cancer, we studied the subtype of cancer and its treatment characteristics. We used the national database of The Netherlands Cancer Registry to calculate population-based age and sex cancer standardized prevalence ratios (SPRs) for patients with ischemic stroke. RESULTS: Cancer prevalence in ischemic stroke patients was 12%, corresponding to an SPR of 1.2 [95% confidence interval (CI), 1.0-1.3]. Increased SPRs were observed for cancer of the central nervous system (SPR, 18.2; 95% CI, 9.0-27.4), head and neck (SPR, 3.4; 95% CI, 2.3-4.6), lower respiratory tract (SPR, 2.4; 95% CI, 1.5-3.3) and urinary tract (SPR, 2.1; 95% CI, 1.4-2.9), but not for other cancer types. Cardiovascular risk factors, stroke etiology, treatment and outcome were not different between patients with or without a history of cancer. CONCLUSIONS: In stroke patients, the prevalence of cancer, most prominently cancer of the central nervous system, head and neck, lower respiratory and urinary tract, was higher than in the general population. Medical treatment for the prevention of stroke in cancer survivors deserves further study.

Early renin-angiotensin system intervention is more beneficial than late intervention in delaying end-stage renal disease in patients with type 2 diabetes.

AIMS: To develop and validate a model to simulate progression of diabetic kidney disease (DKD) from early onset until end-stage renal disease (ESRD), and to assess the effect of renin-angiotensin system (RAS) intervention in early, intermediate and advanced stages of DKD. METHODS: We used data from the BENEDICT, IRMA-2, RENAAL and IDNT trials that assessed effects of RAS intervention in patients with type 2 diabetes. We built a model with discrete disease stages based on albuminuria and estimated glomerular filtration rate (eGFR). Using survival analyses, we assessed the effect of RAS intervention on delaying ESRD in early [eGFR>60 ml/min/1.73 m(2) and albumin:creatinine ratio (ACR) <30 mg/g], intermediate (eGFR 30-60 ml/min/1.73 m(2) or ACR 30-300 mg/g) and advanced (eGFR <30 ml/min/1.73 m(2) or ACR >300 mg/g) stages of DKD for patients in different age groups. RESULTS: For patients at early, intermediate and advanced stage of disease, whose mean age was 60 years and who received placebo, the median time to ESRD was 21.4, 10.8 and 4.7 years, respectively. RAS intervention delayed the predicted time to ESRD by 4.2, 3.6 and 1.4 years, respectively. The benefit of early RAS intervention was more pronounced in younger patients; for example, for patients with a mean age of 45 years, RAS intervention at early, intermediate or advanced stage delayed ESRD by 5.9, 4.0 and 1.1 years versus placebo. CONCLUSIONS: RAS intervention early in the course of proteinuric DKD is more beneficial than late intervention in delaying ESRD.

A phase II study of cediranib as palliative treatment in patients with symptomatic malignant ascites or pleural effusion.

Malignant ascites and pleural effusion are challenging clinical problems, with a major impact on quality of life. We conducted a randomized phase II trial to assess the palliative value of cediranib, an oral vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). After a baseline paracentesis or thoracentesis (on day 0), patients with symptomatic malignant ascites and/or pleural effusion were randomized between immediate treatment with cediranib (Immediate Cediranib) or delayed treatment with cediranib (Delayed Cediranib) on day 29, or after a new puncture was needed. The primary objective of the study was the puncture-free survival, defined as the time from study start (day 1) to the first need for paracentesis or thoracentesis, or time to death, whichever event occurred first. Twelve patients were enrolled. The median puncture-free survival was 45 days (range 10-368) in the Immediate Cediranib patients and 7 days (range 4-13) in the Delayed Cediranib patients (P = 0.011). The change in puncture-free interval (the puncture-free survival after study start minus the puncture-free interval before study start) increased with a median of 31 days in the Immediate Cediranib patients and shortened with a median of 3 days in the Delayed Cediranib patients (P = 0.015). The most common adverse events were fatigue and anorexia. In conclusion, cediranib increased the puncture-free survival and puncture-free interval with an acceptable toxicity profile. This is the first study in which an oral VEGFR TKI showed beneficial palliative effects in patients with malignant effusions.

Subcutaneous angiomatoid fibrous histiocytoma mimicking metastatic melanoma.

Angiomatoid fibrous histiocytoma is an uncommon soft-tissue tumor of intermediate malignancy that is often misdiagnosed initially. As there is not one immunohistochemical marker that consequently stains positive or negative for angiomatoid fibrous histiocytoma, molecular diagnostics are becoming more widely used. So far three translocations have been reported to arise in angiomatoid fibrous histiocytoma: FUS-ATF1, EWSR1-CREB1, or EWSR1-ATF1. We present a case of angiomatoid fibrous histiocytoma on the upper arm of a 40-year-old female, which was initially misdiagnosed as metastatic melanoma in a lymph node. Revision of the pathology revealed an angiomatoid fibrous histiocytoma, which was later confirmed by a EWSR1-CREB1 translocation with molecular diagnostics. Furthermore, we review the relevant literature and provide an overview of all available case reports in the past ten years. This case report illustrates the importance for pathologists of knowing the typical pathology features of AFH and integrating immunohistochemical and molecular findings in order to prevent overdiagnosis of lymph node metastasis of a malignancy.

Staircase falls: high-risk groups and injury characteristics in 464 patients.

INTRODUCTION: Few data are available about the epidemiology and injury characteristics in staircase falls. The available literature mainly concerns children and autopsy studies. OBJECTIVE: To describe the epidemiology and injury characteristics of staircase falls, and to identify high-risk groups for these falls. METHODS: All patients who reported to an academic Accident & Emergency (A&E) department in 2005 after a staircase fall were selected in the Dutch Injury Surveillance System These data were linked to the hospital Trauma Registry database. RESULTS: Four hundred and sixty-four patients (42% male, p=0.001), with a median age of 35 years were included. Children under five suffered significantly more head injuries. Male patients showed significantly more thoracic injuries than female patients. Spinal column fractures were only seen in patients over 25 years of age. Older patients tended to accumulate more rib fractures and lower extremity fractures and were admitted more frequently than the younger patients. Sixty-one patients (13%) required admission. Two patients, both with severe traumatic brain injury (TBI), died. National data on staircase falls were comparable with our hospital data. However, in comparison to the national population data, senior citizens in this study had an incidence that was markedly higher than in the younger patients. CONCLUSION: Injuries due to staircase falls occur in all age groups, however, children under five years are relatively over-represented with higher rates of head injury. Senior citizens showed a markedly higher incidence than younger patients. Most injuries occur to the distal extremities and are relatively mild.

Alternative approaches to derive disability weights in injuries: do they make a difference?

BACKGROUND: In burden of disease studies, several approaches are used to assess disability weights, a scaling factor necessary to compute years lived with disability (YLD). The aim of this study was to quantify disability weights for injury consequences with two competing approaches, (a) standard QALY/DALY model (SQM) which derives disability weights from patient survey data and (b) the annual profile model (APM) which derives weights for the same patient data valued by a panel. METHODS: Disability weights were assessed using (a) EQ-5D data from a postal survey among 8,564 injury patients 2(1/2), 5, and 9 months after attending the Emergency Department, and (b) preferences of 143 laymen elicited with the time trade-off method. RESULTS: Compared with APM, SQM disability weights were consistently higher. YLD calculated with SQM disability weights was more than three times higher compared with YLD calculated with APM disability weights, for mild injuries with short duration, this increase was six fold. CONCLUSIONS: The APM seems the preferred method in burden of injury studies that includes mild conditions with a rapid course, since the SQM approach might overestimate the impact of the latter. The APM, however, might underestimate the impact of injury consequences, especially in case of severe injuries.

Improved competence after a palliative care course for internal medicine residents.

Residents report that they received inadequate teaching in palliative care and low levels of comfort and skills when taking care of dying patients. This study describes the effects of a problem-based palliative care course on perceived competence and knowledge in a representative Dutch cohort of residents in internal medicine. Before and after the course, we carried out a questionnaire survey and knowledge test in 91 residents. The results show that many residents felt they had limited competence or were incompetent when taking care of patients in the palliative care phase. This was particularly true with respect to communication concerning euthanasia and physician-assisted suicide or hastened death (86% and 85% respectively reported limited competence or incompetence). Participants reported that they received inadequate training in palliative care and believed that specific education would make them feel more competent. The number of times that residents were engaged in palliative care situations and the years of clinical experience had a positive influence on perceived competence. Participating in the course improved perceived competence and knowledge in palliative care. No correlation was found between perceived competence and knowledge of palliative care.

Novel empirical disability weights to assess the burden of non-fatal injury.

BACKGROUND: Disability weights are necessary to estimate the disability component (years lived with disability, YLDs) of disability-adjusted life years. The original global burden of disease approach to deriving disability weights ignores temporary consequences of injury. OBJECTIVES: To develop and apply novel empirical disability weights to improve estimates of the non-fatal burden of injury. METHODS: A set of 45 disability weights was derived for both permanent and temporary consequences of injury, using the annual profile approach. A population panel (n = 143) provided the values. The novel set of disability weights was then linked to epidemiological surveillance data on the incidence of injury in The Netherlands to calculate YLD resulting from permanent and temporary consequences of injury. RESULTS: The empirical disability weights for injury consequences varied from minor (corneal abrasion, 0.004) to very severe (quadriplegia, 0.719) health loss. Increasing disability weights by level of severity were found, as illustrated by concussion (0.02), versus moderate brain injury (0.193), versus severe brain injury (0.540). Application of these new disability weights showed a 36% increase in YLD as the result of unintentional injury. CONCLUSIONS: YLD calculations based on global burden of disease disability weights underestimate the size of the injury problem by ignoring temporary health consequences. Application of novel empirical disability weights, derived using the annual profile approach, may improve calculations on the burden of non-fatal injury.

Methodological issues in comparing injury incidence across countries.

The primary objective was to describe the methodological challenges and devise solutions to compare injury incidence across countries. The research design was a mixed methods study, consisting of a consultation with an expert group and comparison of injury surveillance systems and data from ten European countries. A subset of fractures, selected radiologically verifiable fractures and a method of checking the national representativeness of sample emergency department data were devised and are proposed for further development. These methodological considerations and developments will be further refined and tested and should prove useful tools for those who need to compare injury incidence data across countries.

Most probable origin of coeliac disease is low immune globulin A in the intestine caused by malfunction of Peyer's patches.

Coeliac disease frequency increases by obscure reasons and affects in some Western countries as much as 1% of the populations. The second one of monozygotic twins does not develop the disease in 100% but only in 20-50%. To unravel these mysteries, literature was searched to determine the disease background and find suggestions for research and prevention. The causal antigen of coeliac disease is gluten of wheat that is neutralised in the intestine by secretory immune globulin A (sIgA). SIgA is secreted by the secondary (lymphoid) immune system that develops in a newborn infant after the primary (central) immune organs thymus and bone marrow have been primed with antigens of the intestine. Predisposed infants are sensitive for development of coeliac disease during the time without sIgA secretion into the intestine. The risk of the disease diminishes when sIgA cycles of gluten neutralisation develop. Peyer's patches (PP) of the secondary immune system play a central role in the cycles and possibly do not function well in the case of coeliac disease. Coeliac disease in predisposed infants may be prevented by delay of bread consumption till the time of normal sIgA secretion and by application of a challenge period with gluten (see Discussion). It is concluded that sIgA secretion into body cavities and malfunction of immune cells in PP should be included in the future research of coeliac disease as well as in more allergic diseases (type 1 diabetes, Crohn disease, asthma, hay fever).

Multicenter validation of the cppB gene as a PCR target for detection of Neisseria gonorrhoeae.

The cppB gene is often used as a target for detection of Neisseria gonorrhoeae by PCR. Using a coded panel of 500 DNA samples, we determined that the cppB gene is missing in 5.8% of N. gonorrhoeae strains, and therefore we consider the cppB gene to be an unsuitable target.

Multicentre quality control study for detection of Mycobacterium tuberculosis in clinical samples by nucleic amplification methods.

The aim of this study was to evaluate the laboratory performance of nucleic acid amplification tests (NATs) for detection of the Mycobacterium tuberculosis complex. A proficiency panel consisting of eight sputum specimens and four specimens diluted in phosphate-buffered saline (PBS) was sent to 82 laboratories in 23 countries by the Quality Control for Molecular Diagnostics (QCMD) TB programme. The performance of different NATs was analysed in combination with a questionnaire on the applied methods. Seventy-eight participants (95.2%) contributed a total of 85 evaluable data sets. The percentage of correct results on the eight sputum samples was 86.3% (586/679). Of the sputum specimens considered as 'smear-negatives' (650 CFU/250 micro L), only 61.2% (104/170) were reported positive. The percentage of correct results for the three scored PBS samples was 75.7% (193/255). The total number of false-positive results was 11 (4.3%); these were reported for seven (8.2%) of the 85 data sets. In 32 (37.6%) data sets an 'in-house' NAT method was used, and in 53 (62.4%) sets a commercial assay was tested. The percentage of data sets achieving correct results on all sputum samples was 35.3% and 37.8%, respectively. For the PBS samples this was 45.8% and 41.5%. Overall, the results of this study demonstrated that the performance of NATs for the detection of M. tuberculosis has improved since previous studies. The percentage of false-positives has decreased considerably. However, a large number of procedures still lack sufficient sensitivity for application to smear-negative samples.

Setting priorities in injury prevention: the application of an incidence based cost model.

OBJECTIVES: To make detailed calculations on the direct medical costs of injuries in the Netherlands to support priority setting in prevention. METHODS: A computerised, incidence based model for cost calculations was developed and incidence figures derived from the Dutch Injury Surveillance System (LIS) which provides national estimates of the annual number of patients treated at an emergency department. A comprehensive set of cost elements (that is, health care segments) was obtained from health care registrations and a LIS patient survey. Patients were assigned to specific groups based on LIS characteristics (for example, age, injury type). Average costs per patient group were calculated for each cost element and total costs estimated by adding costs for all patient groups. RESULTS: The direct costs of injury average 2000 guilders per injury patient attending an emergency department. Home and leisure injuries account for over half of the costs, although cost per patient is highest for motor vehicle injuries. Injuries to the lower extremities account for almost half of the total costs and are incurred mainly in the home or recreation. Motor vehicle crashes are the major cause of head injuries. CONCLUSIONS: The model permits continuous and detailed monitoring of injury costs. Estimates can be compiled for any LIS patient group or injury subcategory. The results can be used to rank injuries for prioritisation of prevention by injury categories (for example, traffic, home, or leisure), or by specific scenarios (for example, fall at home).

Unethical ethics? Reflections on intercultural research practices.

The notion that there is a universal ethics is commonly supposed, but less often explicitly discussed, in protocols for ethical procedures in research. In this article, the authors reflect on their action-research with women farmers in a Bolivian highland province. Their project aims to propose ways in which local health services could better serve these women's expressed sexual and reproductive health needs. A series of field experiences led the authors to question the adequacy of pre-established institutional protocols for informed consent. Cultural understandings in this context made for situations where supposedly ethical procedures led to unethical effects. While recognising the value of precautionary measures to avoid abuse of research subjects, the authors challenge the assumption of subjects' essential vulnerability in fieldwork relations. They found that they too, as researchers and outsiders to the community, could be assigned less than adult status by research subjects seeking empowerment in their own terms. The paper concludes that consent protocols, rather than relying on standardised procedures, should provide flexible alternatives to facilitate negotiation with subjects about whether and how they will participate at different stages of a research project.

Microwell hybridization assay for detection of PCR products from Mycobacterium tuberculosis complex and the recombinant Mycobacterium smegmatis strain 1008 used as an internal control.

A microwell hybridization assay was developed for the detection of the PCR products from both Mycobacterium tuberculosis complex bacteria and the recombinant Mycobacterium smegmatis strain 1008 that is used as an internal control to monitor inhibition in the PCR based on the M. tuberculosis complex-specific insertion sequence IS6110. The test is based on specific detection with digoxigenin-labeled oligonucleotide probes of biotinylated PCR products which are captured in a microtiter plate coated with streptavidin. The captured PCR products are hybridized separately with two probes, one specific for the PCR product from IS6110 from M. tuberculosis complex and the other specific for the PCR fragment from the modified IS6110 fragment from the recombinant M. smegmatis 1008. The microwell hybridization assay discriminates perfectly between the two types of amplicon. The amount of PCR product that can be detected by this assay is 10 times less than that which can be detected by agarose gel electrophoresis. The test can be performed in 2 h. It is much faster and less laborious than Southern blot hybridization. Furthermore, the interpretation of results is objective. The assay was used with 172 clinical samples in a routine microbiology laboratory, and the results were in complete agreement with those of agarose gel electrophoresis and Southern blot hybridization.

Routine application of the polymerase chain reaction for detection of Mycobacterium tuberculosis in clinical samples.

AIM: To investigate the use of the polymerase chain reaction (PCR) in the routine laboratory for the detection of Mycobacterium tuberculosis in clinical samples. METHODS: Samples were divided and processed separately for the detection of M tuberculosis by microscopy, culture and PCR. After DNA extraction, PCR was performed with primers specific for the insertion element IS6110 and the product was analysed by agarose gel electrophoresis, Southern blotting or dot blotting and hybridisation with a digoxigenin labelled internal probe. Each sample was tested for inhibitors of Taq polymerase with the aid of an internal control. Multiple negative and positive controls were used to monitor each step of the procedure. RESULTS: The data from two laboratories, using the same operating procedures, were combined. Of 1957 specimens, 79 (4%) were culture and PCR positive, while 1839 (93.9%) were negative in both tests. Thirty specimens (1.5%) were PCR positive only and nine (0.5%) were culture positive but PCR negative. CONCLUSION: Using culture and clinical history as the gold standard, sensitivity and specificity for PCR were 92.1% and 99.8%, respectively. With elaborate precautions, PCR is a suitable and reliable method for the detection of M tuberculosis in clinical samples in a routine microbiology laboratory.

Lysophosphatidic acid-induced Ca2+ mobilization in human A431 cells: structure-activity analysis.

Lysophosphatidic acid (LPA; 1-acyl-sn-glycero-3-phosphate) is a platelet-derived lipid mediator that activates its own G-protein-coupled receptor to trigger phospholipase C-mediated Ca2+ mobilization and other effector pathways in numerous cell types. In this study we have examined the structural features of LPA that are important for activation of the Ca(2+)-mobilizing receptor in human A431 carcinoma cells, which show an EC50 for oleoyl-LPA as low as 0.2 nM. When the acyl chain at the sn-1 position is altered, the rank order of potency is oleoyl-LPA > arachidonoyl-LPA > linolenoyl-LPA > linoleoyl-LPA > stearoyl-LPA = palmitoyl-LPA > myristoyl-LPA. The shorter-chain species, lauroyl- and decanoyl-LPA, show little or no activity. Ether-linked LPA (1-O-hexadecyl-sn-glycero-3-phosphate) is somewhat less potent than the corresponding ester-linked LPA; its stereoisomer is about equally active. Deletion of the glycerol backbone causes a 1000-fold decrease in potency. Replacement of the phosphate group in palmitoyl-LPA by a hydrogen- or methyl-phosphonate moiety results in complete loss of activity. A phosphonate analogue with a methylene group replacing the oxygen at sn-3 has strongly decreased activity. All three phosphonate analogues induce cell lysis at doses > 15 microM. Similarly, the methyl and ethyl esters of palmitoyl-LPA are virtually inactive and become cytotoxic at micromolar doses. None of the LPA analogues tested has antagonist activity. Sphingosine 1-phosphate, a putative messenger with some structural similarities to LPA, elicits a transient rise in intracellular [Ca2+] only at micromolar doses; however, cross-desensitization experiments indicate that sphingosine 1-phosphate does not act through the LPA receptor. The results indicate that, although many features of the LPA structure are important for optimal activity, the phosphate group is most critical, suggesting that this moiety is directly involved in receptor activation.