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author:("rosendaal, S.")
1.  Towards a clinically useful diagnosis for mild-to-moderate conditions of medically unexplained symptoms in general practice: a mixed methods study 
BMC Family Practice  2014;15:118.
Background
Symptoms that cannot be attributed to any known conventionally defined disease are highly prevalent in general practice. Yet, only severe cases are captured by the current diagnostic classifications of medically unexplained symptoms (MUS). This study explores the clinical usefulness of a proposed new diagnostic category for mild-to-moderate conditions of MUS labelled ‘multiple symptoms’.
Methods
A mixed methods approach was used. For two weeks, 20 general practitioners (GPs) classified symptoms presented in consecutive consultations according to the International Classification of Primary Care (ICPC) supplemented with the new diagnostic category ‘multiple symptoms’. The GPs’ experiences were subsequently explored by focus group interviews. Interview data were analysed according to ethnographic principles.
Results
In 33% of patients, GPs classified symptoms as medically unexplained, but applied the category of ‘multiple symptoms’ only in 2.8%. The category was described as a useful tool for promoting communication and creating better awareness of patients with MUS; as such, the category was perceived to reduce the risk of unnecessary tests and referrals of these patients. Three main themes were found to affect the clinical usefulness of the diagnostic category of ‘multiple symptoms’: 1) lack of consensus on categorisation practices, 2) high complexity of patient cases and 3) relational continuity (i.e. continuity in the doctor-patient relationship over time). The first two were seen as barriers to usefulness, the latter as a prerequisite for application. The GPs’ diagnostic classifications were found to be informed by the GPs’ subjective pre-formed concepts of patients with MUS, which reflected more severe conditions than actually intended by the new category of ‘multiple symptoms’.
Conclusions
The study demonstrated possible clinical benefits of the category of ‘multiple symptoms’, such as GPs’ increased awareness and informational continuity in partnership practices. The use of the category was challenged by the GPs’ conceptual understanding of MUS and was applied only to a minority of patients. The study demonstrates a need for addressing these issues if sub-threshold categories for MUS are to be applied in routine care. The category of ‘multiple symptoms’ may profitably be used in the future as a risk indicator rather than a diagnostic category.
doi:10.1186/1471-2296-15-118
PMCID: PMC4075929  PMID: 24924564
Somatoform disorders; Signs and symptoms; Classification; Diagnosis; Focus groups; General practice; Primary health care
2.  Spatial and temporal patterns of porcine reproductive and respiratory syndrome virus (PRRSV) genotypes in Ontario, Canada, 2004–2007 
Background
The spread of PRRSV among pig herds has been investigated experimentally, but few observational studies have investigated this subject. Because PRRSV is endemic and live modified vaccines are used in Ontario, the spatial and temporal distributions of 6 PRRSV genotypes were investigated in the province during the period from 2004–2007. The purpose was to find evidence of spread of PRRSV genotypes and determine if spread could be attributed to supplier or ownership connections between herds. Sequence information from PRRSV ORF5 and related source-herd demographic information were obtained from diagnostic submissions to the Animal Health Laboratory, University of Guelph.
Results
A spatial cluster that could not be attributed to supplier or ownership connections among herds in the cluster was detected for RFLP type 1-3-4. Because of genetic dissimilarity among members of the cluster, it was considered to be a result of past spread of the RFLP type. A spatio-temporal cluster detected for RFLP type 1-18-4 was attributed to a shared gilt supplier among the herds in the cluster. Significant spatio-temporal patterns detected for RFLP type 2-5-2, which is considered to be a vaccine-type virus were most likely due to grouping of herds in an ownership that used the corresponding vaccine. Clustering within herd-ownership was a risk factor for presence of five of the six genotypes investigated in the present study.
Conclusions
Although the literature indicates that PRRSV can spread via aerosol between pig herds, the present study found no strong evidence of this occurring in Ontario. The evidence pointed toward transmission of PRRSV occurring in this population by common sources of animals or similarity of herd ownership, which is a proxy measure for other connections between herds. It is also apparent that the recognition and testing of these connections between herds is a necessary part of interpreting spatio-temporal patterns of PRRSV genotypes.
doi:10.1186/1746-6148-10-83
PMCID: PMC4005473  PMID: 24708804
PRRSV; Area spread; Cluster; Clustering; Aerosol; Swine; Pig
3.  Sick-leave decisions for patients with severe subjective health complaints presenting in primary care: A cross-sectional study in Norway, Sweden, and Denmark 
Abstract
Objectives
The primary objective of this study was to explore whether general practitioners (GPs) in Norway, Sweden, and Denmark make similar or different decisions regarding sick leave for patients with severe subjective health complaints (SHC). The secondary objective was to investigate if patient diagnoses, the reasons attributed for patient complaints, and GP demographics could explain variations in sick leave decisions.
Design
A cross-sectional study.
Method
Video vignettes of GP consultations with nine different patients.
Subjects
126 GPs in Norway, Sweden, and Denmark.
Setting
Primary care in Norway, Sweden, and Denmark.
Main outcome measure
Sick leave decisions made by GPs.
Results
“Psychological” diagnoses in Sweden were related to lower odds ratio (OR) of granting sick leave than in Norway (OR = 0.07; 95% CI = 0.01–0.83) Assessments of patient health, the risk of deterioration, and their ability to work predicted sick leave decisions. Specialists in general medicine grant significantly fewer sick leaves than non-specialists.
Conclusion
Sick-leave decisions made by GPs in the three countries were relatively similar. However, Swedish GPs were more reluctant to grant sick leave for patients with “psychological” diagnoses. Assessments regarding health-related factors were more important than diagnoses in sick-leave decisions. Specialist training may be of importance for sick-leave decisions.
doi:10.3109/02813432.2013.844412
PMCID: PMC3860299  PMID: 24164371
Diagnosis; family practice; general practice; medically unexplained symptoms; Norway; primary health care; sick leave; somatoform disorder
4.  Psychological and social problems in primary care patients - general practitioners’ assessment and classification 
Abstract
Objective. To estimate the frequency of psychological and social classification codes employed by general practitioners (GPs) and to explore the extent to which GPs ascribed health problems to biomedical, psychological, or social factors. Design. A cross-sectional survey based on questionnaire data from GPs. Setting. Danish primary care. Subjects. 387 GPs and their face-to-face contacts with 5543 patients. Main outcome measures. GPs registered consecutive patients on registration forms including reason for encounter, diagnostic classification of main problem, and a GP assessment of biomedical, psychological, and social factors’ influence on the contact. Results. The GP-stated reasons for encounter largely overlapped with their classification of the managed problem. Using the International Classification of Primary Care (ICPC-2-R), GPs classified 600 (11%) patients with psychological problems and 30 (0.5%) with social problems. Both codes for problems/complaints and specific disorders were used as the GP's diagnostic classification of the main problem. Two problems (depression and acute stress reaction/adjustment disorder) accounted for 51% of all psychological classifications made. GPs generally emphasized biomedical aspects of the contacts. Psychological aspects were given greater importance in follow-up consultations than in first-episode consultations, whereas social factors were rarely seen as essential to the consultation. Conclusion. Psychological problems are frequently seen and managed in primary care and most are classified within a few diagnostic categories. Social matters are rarely considered or classified.
doi:10.3109/02813432.2012.751688
PMCID: PMC3587306  PMID: 23281962
Classification; Denmark; diagnosis; general practice; ICPC; mental disorders; primary health care; social problems
5.  The General Practitioner's Consultation Approaches to Medically Unexplained Symptoms: A Qualitative Study 
ISRN Family Medicine  2012;2013:541604.
Background. The prevalence of medically unexplained symptoms (MUSs) in primary care is about 10–15%. The definition of MUS is descriptive and there are no specific diagnostic criteria for MUS in primary care. Furthermore, a general practitioner's (GP's) categorisation of patients with MUS shows large variation. The aim of the present study is to investigate how GPs employ the definition of MUS and how they manage patients with MUS in daily practice. Methods. With a grounded theory approach five focus group interviews with GPs were performed. The interviews addressed how GPs managed MUS and their reflections on the course and prognosis for MUS patients. Results. Consultations about MUS develop around the individual patient and usually include several appointments. We identified three different types of consultations: (1) “searching for a disease,” (2) “going by the routine,” and (3) “following various paths.” These types of consultations spanned from a biomedical approach to an approach where multiple explanations were offered to explain the patient's problem. The choice of consultation types was influenced by the GP, the patient and contextual factors which, in turn, affected the diagnostic process. Conclusions. A diagnosis of MUS is contextually embedded and the diagnostic process is shaped by the consultation.
doi:10.5402/2013/541604
PMCID: PMC4041244  PMID: 24967320
6.  Exogenous pyruvate accelerates glycolysis and promotes capacitation in human spermatozoa 
Human Reproduction (Oxford, England)  2011;26(12):3249-3263.
BACKGROUND
There has been an ongoing debate in the reproductive field about whether mammalian spermatozoa rely on glycolysis, oxidative phosphorylation or both for their energy production. Recent studies have proposed that human spermatozoa depend mainly on glucose for motility and fertilization but the mechanism behind an efficient glycolysis in human spermatozoa is not well understood. Here, we demonstrate how human spermatozoa utilize exogenous pyruvate to enhance glycolytic ATP production, motility, hyperactivation and capacitation, events that are crucial for male fertility.
METHODS
Purified human spermatozoa from healthy donors were incubated under capacitating conditions (including albumin, bicarbonate and glucose) and tested for changes in ATP levels, motility, hyperactivation and tyrosine phosphorylation after treatment with pyruvate. The experiments were repeated in the presence of sodium cyanide in order to assess the contribution from mitochondrial respiration. The metabolism of 13C labeled glucose and pyruvate was traced by a combination of liquid chromatography and mass spectrometry.
RESULTS
The treatment of human spermatozoa with exogenous pyruvate increased intracellular ATP levels, progressive motility and hyperactivation by 56, 21 and 130%, respectively. In addition, added pyruvate induced a significant increase in tyrosine phosphorylation levels. Blocking of the electron transport chain did not markedly affect the results, indicating that the mechanism is independent of oxidative phosphorylation. However, the observed effects could be counteracted by oxamate, an inhibitor of lactate dehydrogenase (LDH). Metabolic tracing experiments revealed that the observed rise in ATP concentration resulted from an enhanced glycolytic flux, which was increased by more than 50% in the presence of exogenous pyruvate. Moreover, all consumed 13C labeled pyruvate added was converted to lactate rather than oxidized in the tricarboxylic acid cycle.
CONCLUSIONS
Human spermatozoa seem to rely mainly, if not entirely, on glycolysis as the source of ATP fueling the energy-demanding processes of motility and capacitation. The efficient glycolysis is dependent on exogenous pyruvate, which indirectly feeds the accelerated glycolysis with NAD+ through the LDH-mediated conversion of pyruvate to lactate. Pyruvate is present in the human female reproductive tract at concentrations in accordance with our results. As seen in other mammals, the motility and fertility of human spermatozoa seem to be dictated by the available energy substrates present in the conspecific female.
doi:10.1093/humrep/der317
PMCID: PMC3212877  PMID: 21946930
capacitation; glycolysis; human spermatozoa; pyruvate; sperm metabolism
7.  G-patch domain and KOW motifs-containing protein, GPKOW; a nuclear RNA-binding protein regulated by protein kinase A 
Background
Post-transcriptional processing of pre-mRNA takes place in several steps and requires involvement of a number of RNA-binding proteins. How pre-mRNA processing is regulated is in large enigmatic. The catalytic (C) subunit of protein kinase A (PKA) is a serine/threonine kinase, which regulates numerous cellular processes including pre-mRNA splicing. Despite that a significant fraction of the C subunit is found in splicing factor compartments in the nucleus, there are no indications of a direct interaction between RNA and PKA. Based on this we speculate if the specificity of the C subunit in regulating pre-mRNA splicing may be mediated indirectly through other nuclear proteins.
Results
Using yeast two-hybrid screening with the PKA C subunit Cbeta2 as bait, we identified the G-patch domain and KOW motifs-containing protein (GPKOW), also known as the T54 protein or MOS2 homolog, as an interaction partner for Cbeta2. We demonstrate that GPKOW, which contains one G-patch domain and two KOW motifs, is a nuclear RNA-binding protein conserved between species. GPKOW contains two sites that are phosphorylated by PKA in vitro. By RNA immunoprecipitation and site directed mutagenesis of the PKA phosphorylation sites we revealed that GPKOW binds RNA in vivo in a PKA sensitive fashion.
Conclusion
GPKOW is a RNA-binding protein that binds RNA in a PKA regulated fashion. Together with our previous results demonstrating that PKA regulates pre-mRNA splicing, our results suggest that PKA phosphorylation is involved in regulating RNA processing at several steps.
doi:10.1186/1750-2187-6-10
PMCID: PMC3179746  PMID: 21880142
RNA processing; phosphorylation; PKA catalytic subunit; GPKOW
8.  Effect of gene dosage on single-cell hippocampal electrophysiology in a murine model of SSADH deficiency (γ-hydroxybutyric aciduria) 
Epilepsy research  2010;90(1-2):39-46.
Summary
Human and murine succinic semialdehyde dehydrogenase (SSADH; gamma-hydroxybutyric (GHB) aciduria) deficiency represents an epileptic disorder associated with hyperGABA- and hyperGHB-ergic states. Despite significant neurotransmitters alterations, well-defined single-cell electrophysiological studies, aimed to provide insight into regional neuropathology, have been lacking. In this study, we characterized the effect of residual SSADH enzyme function/increased GABA levels on single-cell hippocampal electrophysiology in SSADH+/+ (wild-type; WT), SSADH+/− (heterozygous; HET), and SSADH−/− (knock-out; KO) mice. Tonic extrasynaptic GABAA receptor (GABAAR)-mediated currents were elevated in HET and KO mice, whereas phasic synaptic GABAAR currents were unaltered in dentate gyrus granule cells. Similarly, tonic GABAAR-mediated currents were increased in dentate gyrus interneurons of KO animals, while phasic GABAergic neurotransmission was unaffected in the same cells. Our results indicate global disruption of cortical networks in SSADH KO mice, affecting both excitatory and inhibitory neurons. Our findings provide new clues concerning seizure evolution in the murine model (absence→tonic-clonic→status epilepticus), and extend pathophysiological insight into human SSADH deficiency.
doi:10.1016/j.eplepsyres.2010.03.005
PMCID: PMC3155419  PMID: 20363598
Dentate gyrus; Granule cell; Interneuron; GABA; GABAA receptor; Mouse
9.  Children diagnosed with congenital cardiac malformations at the national university departments of pediatric cardiology: positive predictive values of data in the Danish National Patient Registry 
Clinical Epidemiology  2011;3:61-66.
Introduction:
The present study was conducted to establish the positive predictive value of congenital cardiac malformation diagnoses registered in the Danish National Patient Registry (NPR), thereby exploring whether the NPR can serve as a valid tool for epidemiologic studies of congenital cardiac malformations.
Materials and methods:
The study population comprised every individual born from 2000 to 2008 who was registered in the NPR with a congenital cardiac malformation diagnosis and treated at one of the two national departments of pediatric cardiology. Positive predictive values were established comparing NPR information with the clinical record of each individual.
Results:
A total of 2952 patients with a total of 3536 diagnoses were eligible for validation. Review of their clinical records unveiled no patient without cardiac malformation. In 98% (98%–99%) of the cases, the NPR diagnosis could be found as the discharge diagnosis in the patient’s clinical record, and in 90% (89%–91%) of the cases the NPR diagnosis was considered a true reflection of the patient’s actual malformation.
Conclusions:
Our study verifies that the present study population retrieved from the NPR is a valid tool for epidemiological research within the topic of congenital cardiac malformations, given that the research question is not dependent on a fully established sensitivity of the NPR. Precautions should be made regarding cardiac malformations characterized by low prevalence or poor predictive values, and the reported validity should not be extrapolated beyond the study period.
doi:10.2147/CLEP.S15627
PMCID: PMC3046186  PMID: 21386975
congenital cardiac malformation; registry; validation
10.  Spread of porcine circovirus associated disease (PCVAD) in Ontario (Canada) swine herds: Part I. Exploratory spatial analysis 
Background
The systemic form of porcine circovirus associated disease (PCVAD), also known as postweaning multisystemic wasting syndrome (PMWS) was initially detected in the early 1990s. Starting in 2004, the Canadian swine industry experienced considerable losses due to PCVAD, concurrent with a shift in genotype of porcine circovirus type 2 (PCV2). Objectives of the current study were to explore spatial characteristics of self-reported PCVAD distribution in Ontario between 2004 and 2008, and to investigate the existence and nature of local spread.
Results
The study included 278 swine herds from a large disease-monitoring project that included porcine reproductive and respiratory syndrome (PRRS) virus-positive herds identified by the diagnostic laboratory, and PRRS virus-negative herds directly from the target population. Herds were included if they had growing pigs present on-site and available geographical coordinates for the sampling site. Furthermore, herds were defined as PCVAD-positive if a producer reported an outbreak of circovirus associated disease, or as PCVAD-negative if no outbreak was noted. Spatial trend was investigated using generalized additive models and time to PCVAD outbreak in a herd using Cox's proportional hazard model; spatial and spatio-temporal clustering was explored using K-functions; and location of most likely spatial and spatio-temporal clusters was investigated using scan statistics. Over the study period, the risk of reporting a PCVAD-positive herd tended to be higher in the eastern part of the province after adjustment for herd PRRS status (P = 0.05). This was partly confirmed for spread (Partial P < 0.01). Local spread also appeared to exist, as suggested by the tentative (P = 0.06) existence of spatio-temporal clustering of PCVAD and detection of a spatio-temporal cluster (P = 0.04).
Conclusions
In Ontario, PCVAD has shown a general trend, spreading from east-to-west. We interpret the existence of spatio-temporal clustering as evidence of spatio-temporal aggregation of PCVAD-positive cases above expectations and, together with the existence of spatio-temporal and spatial clusters, as suggestive of apparent local spread of PCVAD. Clustering was detected at small spatial and temporal scales. Other patterns of spread could not be detected; however, survival rates in discrete Ontario zones, as well as a lack of a clear spatial pattern in the most likely spatio-temporal clusters, suggest other between-herd transmission mechanisms.
doi:10.1186/1746-6148-6-59
PMCID: PMC3024231  PMID: 21190587
11.  Spread of porcine circovirus associated disease (PCVAD) in Ontario (Canada) swine herds: Part II. Matched case-control study 
Background
The emergence of porcine circovirus associated disease (PCVAD) was associated with high mortality in swine populations worldwide. Studies performed in different regions identified spatial, temporal, and spatio-temporal trends as factors contributing to patterns of the disease spread. Patterns consistent with spatial trend and spatio-temporal clustering were already identified in this dataset. On the basis of these results, we have further investigated the nature of local spread in this report. The primary objective of this study was to evaluate risk factors for incidence cases of reported PCVAD.
Results
A time-matched case-control study was used as a study design approach, and conditional logistic regression as the analytical method. The main exposure of interest was local spread, which was defined as an unidentified mechanism of PCVAD spread between premises located within 3 kilometers of the Euclidean distance. Various modifications of variables indicative of local spread were also evaluated. The dataset contained 278 swine herds from Ontario originally sampled either from diagnostic laboratory submissions or directly from the target population. A PCVAD case was defined on the basis of the producer's recall. Existence of apparent local spread over the entire study period was confirmed (OR = 2.26, 95% CI: 1.06, 4.83), and was further identified to be time-varying in nature - herds experiencing outbreaks in the later part of the epidemic were more likely than control herds to be exposed to neighboring herds experiencing recent PCVAD outbreaks. More importantly, the pattern of local spread was driven by concurrent occurrence of PCVAD on premises under the same ownership (OREXACTwithin ownership = 25.6, 95% CI: 3.4, +inf; OREXACToutside ownership = 1.3, 95% CI: 0.45, 3.3). Other significant factors included PRRSv status of a herd (OREXACT = 1.9, 95% CI: 1.0, 3.9), after adjusting for geographical location by including the binary effect of the easting coordinate (Easting > 600 km = 1; OREXACT = 1.8, 95% CI: 0.5, 5.6).
Conclusions
These results preclude any conclusion regarding the existence of a mechanism of local spread through airborne transmission or indirectly through contaminated fomites or vectors, as simultaneous emergence of PCVAD could also be a result of concurrent change in contributing factors due to other mechanisms within ownerships.
doi:10.1186/1746-6148-6-58
PMCID: PMC3023701  PMID: 21190586
12.  Clinical signs and their association with herd demographics and porcine reproductive and respiratory syndrome (PRRS) control strategies in PRRS PCR-positive swine herds in Ontario 
The purposes of this study were to describe the clinical signs observed in PRRS positive herds during a porcine reproductive and respiratory syndrome (PRRS) outbreak in Ontario and to determine associations between these clinical signs and herd demographics and PRRS control strategies. All PRRS polymerase chain reaction-(PCR)-positive submissions to a diagnostic laboratory between September 1, 2004 and August 31, 2007 were identified (n = 1864). After meeting eligibility requirements and agreeing to voluntary study participation, producers from 455 of these submissions were surveyed for information on clinical signs observed in their herds, herd demographics, and PRRS control strategies used in their herds at the time that the PCR-positive samples were taken. Larger herd size was associated with an increased risk of reporting abortion, weakborn piglets, off-feed sows, and sow mortality in sow herds, and with an increased risk of reporting mortality in finishing herds. When disease control strategies were examined, use of a commercial PRRS vaccine in sows and gilts was associated with a decreased risk of reporting weakborn pigs and high pre-weaning mortality, while the use of serum inoculation in breeding animals was associated with an increased risk of reporting off-feed sows and sow mortality. Providing biofeedback of stillborn/mummified piglets, placenta or feces to gilts was associated with an increased risk of reporting respiratory disease and mortality in finishing pigs while all-in/all-out flow in farrowing rooms was associated with an increased risk of reporting sow mortality and weakborn piglets.
PMCID: PMC2896797  PMID: 20885840
13.  Distribution of genotypes of porcine reproductive and respiratory syndrome virus in Ontario during 2004–2007 and the association between genotype and clinical signs of disease 
Restriction fragment length polymorphism (RFLP) was first proposed to classify porcine reproductive and respiratory syndrome virus (PRRSV) in 1998. The primary objective of this study was to identify associations between different PRRSV RFLP types in swine herds in southern Ontario and clinical signs of disease in those herds. Herds included in the study submitted samples to the Animal Health Laboratory at the University of Guelph between September 2004 and August 2007. Each farm owner was surveyed to describe the clinical disease in the herd and the RFLP pattern of an isolate of PRRSV was obtained from a diagnostic sample. The most frequent isolates were RFLP types 1_4 (25.1%), 252 (14.7%), 134 (12%), and 1_2 (7.7%). The distribution of RFLP types in this study was found to be different from a previous investigation in Ontario. Those RFLP types most associated with clinical disease in the farrowing phase of production were 1_4, 1_2, and 134. The only virus type to be significantly associated with disease in the finisher phase was RFLP type 262. During the study period RFLP type 184 emerged in the population in November 2005.
PMCID: PMC2851721  PMID: 20592841
14.  Prevalence of Actinobacillus pleuropneumoniae, Actinobacillus suis, Haemophilus parasuis, Pasteurella multocida, and Streptococcus suis in representative Ontario swine herds 
Tonsillar and nasal swabs were collected from weanling pigs in 50 representative Ontario swine herds and tested for the presence of 5 important bacterial upper respiratory tract pathogens. All but 1 herd (2%) tested positive for Streptococcus suis by polymerase chain reaction (PCR); 48% of herds were S. suis serovar 2, 1/2 positive. In all but 2 herds there was evidence of Haemophilus parasuis infection. In contrast, toxigenic strains of Pasteurella multocida were detected by a P. multocida — enzyme-linked immunosorbant assay (PMT-ELISA) in only one herd. Seventy-eight percent of the herds were diagnosed positive for Actinobacillus pleuropneumoniae by apxIV PCR. Sera from finishing pigs on the same farms were also collected and tested by ELISA for the presence of A. pleuropneumoniae antibodies. Seventy percent of the herds tested had evidence of antibodies to A. pleuropneumoniae including serovars 1–9–11 (2%), 2 (4%), 3–6–8–15 (15%), 5 (6%), 4–7 (26%), and 12 (17%). This likely represents a shift from previous years when infection with A. pleuropneumoniae serovars 1, 5, and 7 predominated. At least 16% and possibly as many as 94% of the herds tested were Actinobacillus suis positive; only 3 of the 50 herds were both A. pleuropneumoniae and A. suis negative as judged by the absence of a positive PCR test for apxII. Taken together, these data suggest that over the past 10 years, there has been a shift in the presence of pathogenic bacteria carried by healthy Ontario swine with the virtual elimination of toxigenic strains of P. multocida and a move to less virulent A. pleuropneumoniae serovars. As well, there appears to be an increase in prevalence of S. suis serovar 2, 1/2, but this may be a reflection of the use of a more sensitive detection method.
PMCID: PMC2327245  PMID: 18505187
17.  Diagnosis of somatisation: effect of an educational intervention in a cluster randomised controlled trial. 
BACKGROUND: Somatisation is highly prevalent in primary care (present in 25% of visiting patients) but often goes unrecognised. Non-recognition may lead to ineffective treatment, risk of iatrogenic harm, and excessive use of healthcare services. AIM: To examine the effect of training on diagnosis of somatisation in routine clinical practice by general practitioners (GPs). DESIGN OF STUDY: Cluster randomised controlled trial, with practices as the randomisation unit. SETTING: Twenty-seven general practices (with a total of 43 GPs) in Vejle County, Denmark. METHOD: Intervention consisted of a multifaceted training programme (the TERM [The Extended Reattribution and Management] model). Patients were enrolled consecutively over a period of 13 working days. Psychiatric morbidity was assessed by means of a screening questionnaire. GPs categorised their diagnoses in another questionnaire. The primary outcome was GP diagnosis of somatisation and agreement with the screening questionnaire. RESULTS: GPs diagnosed somatisation less frequently than had previously been observed, but there was substantial variation between GPs. The difference between groups in the number of diagnoses of somatisation failed to reach the 5% significance (P = 0.094). However, the rate of diagnoses of medically unexplained physical symptoms was twice as high in the intervention group as in the control group (7.7% and 3.9%, respectively, P = 0.007). Examination of the agreement between GPs' diagnoses and the screening questionnaire revealed no significant difference between groups. CONCLUSION: Brief training increased GPs' awareness of medically unexplained physical symptoms. Diagnostic accuracy according to a screening questionnaire remained unaffected but was difficult to evaluate, as there is no agreement on a gold standard for somatisation in general practice.
PMCID: PMC1314743  PMID: 14960214
18.  The Growth-Regulatory Protein HCRP1/hVps37A Is a Subunit of Mammalian ESCRT-I and Mediates Receptor Down-Regulation 
Molecular Biology of the Cell  2004;15(9):4337-4346.
The biogenesis of multivesicular bodies and endosomal sorting of membrane cargo are driven forward by the endosomal sorting complexes required for transport, ESCRT-I, -II, and -III. ESCRT-I is characterized in yeast as a complex consisting of Vps23, Vps28, and Vps37. Whereas mammalian homologues of Vps23 and Vps28 (named Tsg101 and hVps28, respectively) have been identified and characterized, a mammalian counterpart of Vps37 has not yet been identified. Here, we show that a regulator of proliferation, hepatocellular carcinoma related protein 1 (HCRP1), interacts with Tsg101, hVps28, and their upstream regulator Hrs. The ability of HCRP1 (which we assign the alternative name hVps37A) to interact with Tsg101 is conferred by its mod(r) domain and is shared with hVps37B and hVps37C, two other mod(r) domain-containing proteins. HCRP1 cofractionates with Tsg101 and hVps28 by size exclusion chromatography and colocalizes with hVps28 on LAMP1-positive endosomes. Whereas depletion of Tsg101 by siRNA reduces cellular levels of both hVps28 and HCRP1, depletion of HCRP1 has no effect on Tsg101 or hVps28. Nevertheless, HCRP1 depletion strongly retards epidermal growth factor (EGF) receptor degradation. Together, these results indicate that HCRP1 is a subunit of mammalian ESCRT-I and that its function is essential for lysosomal sorting of EGF receptors.
doi:10.1091/mbc.E04-03-0250
PMCID: PMC515363  PMID: 15240819
19.  Stroke service in the Netherlands: an exploratory study on effectiveness, patient satisfaction and utilisation of healthcare 
Abstract
Objective
To assess whether shared care for stroke patients results in better patient outcome, higher patient satisfaction and different use of healthcare services.
Design
Prospective, comparative cohort study.
Setting
Two regions in the Netherlands with different healthcare models for stroke patients: a shared care model (stroke service) and a usual care setting.
Patients
Stroke patients with a survival rate of more than six months, who initially were admitted to the Stroke Service of the University Hospital Maastricht (experimental group) in the second half of 1997 and to a middle sized hospital in the western part of the Netherlands between March 1997 and March 1999 (control group).
Main outcome measures
Functional health status according to the SIP-68, EuroQol, Barthel Index and Rankin Scale, patient satisfaction and use of healthcare services.
Results
In total 103 patients were included in this study: 58 in the experimental group and 45 in the control group. Six months after stroke, 64% of the surviving patients in the experimental group had returned home, compared to 42% in the control group (p<0.05). This difference could not be explained by differences in health status, which was comparable at that time. Patients in the shared care model scored higher on patient satisfaction, whereas patients in the usual care group received a higher volume of home care.
Conclusions
The Stroke Service Maastricht resulted in a higher number of patients who returned home after stroke, but not in a better health status. Since patients in the usual care group received a higher volume of healthcare in the period of rehabilitation, the Stroke Service Maastricht might be more efficient.
PMCID: PMC1480390  PMID: 16896372
transmural care; shared care; stroke service; effectiveness
20.  Can shared care deliver better outcomes for patients undergoing total hip replacement? 
Abstract
Objectives
To assess whether shared care for patients undergoing total hip replacement delivers better outcomes compared to care as usual.
Design
Prospective, observational cohort study.
Setting
Two regions in the Netherlands where different organisational health care models have been implemented: a shared care setting (experimental group) and a care as usual setting (control group).
Patients
One hundred and fifteen patients undergoing total hip replacement: 56 in the experimental group and 59 in the control group.
Main measures
Functional health status according to the sickness impact profile, hip function, patient satisfaction and use of health care services.
Results
Two weeks before hip replacement both groups were comparable concerning patient characteristics, hip function and health status. The mean improvement of the total sickness impact profile score between two weeks before hip replacement and six months after was −1.92 in the shared care group, compared to −5.11 in care as usual group, a difference in favour of the control group (p=0.02). The mean length of hospital stay was comparable in both settings: 12.8 days in the shared care group and 13.2 days in the care as usual group. After hip replacement, compared to care as usual, patients in the shared care group received more homecare, with a higher frequency, and for a longer period of time. No differences in patient satisfaction between the two groups were found.
Conclusions
Six months after hip replacement, the health status of patients in the care as usual group, using significantly less home care, was better than the status of patients in the shared care group.
Discussion
The utilisation of home care after hip replacement should be critically appraised in view of the need to stimulate patients' independence.
PMCID: PMC1534008  PMID: 16902701
shared care; total hip replacement; effectiveness
21.  The associations of viral and mycoplasmal antibody titers with respiratory disease and weight gain in feedlot calves. 
The Canadian Veterinary Journal  1999;40(8):560-570.
Blood samples from 32 groups of calves (n = 700) were taken on arrival and after 28-35 days at the feedlot. Eleven groups were housed in feedlots in Ontario, and 21 groups in feedlots in Alberta. Serum antibody titers to bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), parainfluenza virus type 3 (PIV-3), infectious bovine rhinotracheitis virus (IBRV), Mycoplasma dispar and M. bovis, plus data on bovine corona virus (BCV) from a previous study were investigated for their association with the risk of bovine respiratory disease (BRD), and with 28-day weight change, both before and after controlling for titers to Pasteurella haemolytica and Haemophilus somnus. Exposure to IBRV and M. bovis was infrequent, and although exposure to PIV-3 was more common, none of these agents had important associations with BRD. Higher titers to BVDV, BRSV, and BCV on arrival were associated with reduced risks of BRD and increased weight gains. However, there was some variation in these relationships and higher arrival titers to BVDV and BRSV in a subset of the calves were associated with increased risks of BRD. Titer increases to BVDV were associated with a higher risk of BRD and lower weight gains. Titer increases to BRSV were not usually associated with the occurrence of BRD, but titer increases to BRSV in a subset of calves that were vaccinated against BRSV, on arrival, were associated with an elevated risk of BRD. Of all the agents studied, BVDV had the most consistent associations with elevated risk of BRD and lower weight gains. Higher BRSV arrival titers were related to lower risk of BRD and higher weight gains; in some instances titer increases to BRSV were associated with higher BRD risk. Higher titers to BCV on arrival were related to reduced risks of BRD. Practical ways of adequately preventing the negative effects of these agents are still needed.
PMCID: PMC1539768  PMID: 12001336
22.  Actinobacillus suis strains isolated from healthy and diseased swine are clonal and carry apxICABDvar. suis and apxIICAvar. suis toxin genes. 
Journal of Clinical Microbiology  1997;35(5):1131-1137.
Actinobacillus suis isolates recovered from both healthy and diseased pigs were characterized by biochemical testing, serotyping, restriction endonuclease fingerprinting, and apx toxin gene typing. The clinical isolates analyzed were collected over a 10-year period from approximately 40 different locations in southwestern Ontario, Canada. Little variation in the biochemical profiles of these isolates was seen, and all isolates reacted strongly with rabbit antisera prepared against one of the strains. Similarly, by using BamHI and BglII for restriction endonuclease fingerprinting (REF) analysis, all isolates were found to belong to a single REF group. Minor variations could be detected, especially in the BglII fingerprints, but overall the patterns were remarkably similar. Sequences that could be amplified by PCR with primers to the apxICA and apxIICA genes of Actinobacillus pleuropneumoniae were detected in all strains. Although no amplification was obtained with primers to the A. pleuropneumoniae apxIBD genes, sequences with homology to apxIBD were detected by hybridization. There was no evidence of apxIII homologs. Taken together, these data suggest that A. suis isolates are genotypically and phenotypically very similar, regardless of their source, and that they contain genes similar to, but not identical to, the apxICABD and apxIICA genes of A. pleuropneumoniae.
PMCID: PMC232716  PMID: 9114394
23.  Antibody- and cell-mediated immune responses of Actinobacillus pleuropneumoniae-infected and bacterin-vaccinated pigs. 
Infection and Immunity  1997;65(2):358-365.
Current porcine pleuropneumonia bacterins afford only partial protection by decreasing mortality but not morbidity. In order to better understand the type(s) of immune response associated with protection, antibody- and cell-mediated immune responses (CMIR) were compared for piglets before and after administration of a commercial bacterin, which confers partial protection, or a low-dose (10(5) CFU/ml) aerosol challenge with Actinobacillus pleuropneumoniae CM5 (LD), which induces complete protection. Control groups received phosphate-buffered saline or adjuvant. Serum antibody response, antibody avidity, delayed-type hypersensitivity (DTH), and lymphocyte blastogenic responses were measured and compared among treatment groups to the lipopolysaccharide (LPS), capsular polysaccharide (CPS), hemolysin (HLY), and outer membrane proteins (OMP) of A. pleuropneumoniae. Peripheral blood lymphocytes and sera were collected prior to and following primary and secondary immunization-infection and high-dose A. pleuropneumoniae CM5 (10(7) CFU/ml) aerosol challenge. Serum antibody and DTH, particularly that to HLY, differed significantly between treatment groups, and increases were associated with protection. LD-infected piglets had higher antibody responses (P < or = 0.01) and antibody avidity (P < or = 0.10) than bacterin-vaccinated and control groups. Anti-HLY antibodies were consistently associated with protection, whereas anti-LPS and anti-CPS antibodies were not. LD-infected animals had higher DTH responses, particularly to HLY, than bacterin-vaccinated pigs (P < or = 0.03). The LD-infected group maintained consistent blastogenic responses to HLY, LPS, CPS, and OMP over the course of infection, unlike the bacterin-vaccinated and control animals. These data suggest that the immune responses induced by a commercial bacterin are very different from those induced by LD aerosol infection and that current bacterins may be modified, for instance, by addition of HLY, so as to stimulate responses which better reflect those induced by LD infection.
PMCID: PMC174603  PMID: 9009283
24.  Pasteurella multocida toxin induces IL-6, but not IL-1 alpha or TNF alpha in fibroblasts. 
Pasteurella multocida toxin (PMT) is the major virulence factor in Progressive Atrophic Rhinitis of swine. Other workers' previous findings that PMT was mitogenic for 3T3 fibroblasts, were confirmed in the present study. In addition, PMT stimulated 3T3 cells to release IL-6, but IL-1 alpha or TNF alpha were not detected in fibroblast supernatants sampled 24, 48, or 72 h after stimulation. In view of the role of IL-6 in osteoclastic bone resorption, these findings provide a new working hypothesis for investigations into the molecular pathogenesis of this important disease.
PMCID: PMC1263754  PMID: 7648529
25.  Effect of time of exposure to rat coronavirus and Mycoplasma pulmonis on respiratory tract lesions in the Wistar rat. 
The effects of time of exposure on the progression of pulmonary lesions in rats inoculated with Mycoplasma pulmonis and the rat coronavirus, sialodacryoadenitis virus (SDAV) were studied, using six groups of 18 SPF Wistar rats (n = 108). Rats were inoculated intranasally as follows: Group 1, sterile medium only; Group 2, sterile medium followed one week later by 150 TCID50 SDAV; Group 3, sterile medium followed by 10(5.7) colony forming units of M. pulmonis; Group 4, SDAV followed one week later by M. pulmonis; Group 5, M. pulmonis followed one week later by SDAV; Group 6, M. pulmonis followed two weeks later by SDAV. Six rats from each group were euthanized at one, two and three weeks after the final inoculation. In a separate experiment, six additional animals were inoculated in each of groups 3, 5 and 6 (n = 18) and were sampled at five weeks after they had received M. pulmonis. Bronchoalveolar lavage and quantitative lung mycoplasma cultures were conducted on two-thirds of the rats. Histopathological examination and scoring of lesion severity were performed on all animals. Based on the prevalence and extent of histopathological lesions, bronchoalveolar lavage cell numbers, neutrophil differential cell counts and the isolation of M. pulmonis, the most severe disease occurred in the groups that received both agents. There was no significant difference in lesion severity between the groups receiving both agents other than in those examined during the acute stages of SDAV infection. Based on these results, it is evident that SDAV enhances lower respiratory tract disease in Wistar rats whether exposure occurs at one week prior to or at various intervals following M. pulmonis infections.
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PMCID: PMC1263735  PMID: 7704844

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