First aid and basic life support: a questionnaire survey of medical schools in the Netherlands.

PURPOSE: Adequate education in first aid and basic life support (BLS) should be considered as an essential aspect of the medical curriculum. The objective of this study was to investigate the current medical training in first aid and BLS at all 8 medical schools in the Netherlands. SUMMARY: An evaluation was made, by sending a questionnaire to all medical schools, regarding whether the medical training was performed in accordance with the national Dutch guidelines for medical education. The response was 100%. Seven of the eight medical schools train their students in first aid and BLS during the medical curriculum. An average of only 38% of the clinical pictures and diseases and 69% of the skills were mastered at the level-defined national Dutch guidelines. CONCLUSION: The medical education in the Netherlands does not meet the required objectives as stated in the national Dutch guidelines concerning first aid and BLS.

Validation of two methods to measure posterior tilt in femoral neck fractures.

INTRODUCTION: Posterior tilt of the femoral head in femoral neck fractures (FNF) may influence stability of the fracture and may therefore affect the treatment outcome. Posterior tilt can be measured with different methods. The Lateral Garden Angle (LGA) has been used for this purpose for decades and more recently the Posterior Tilt Measurement (PTM) was introduced. Despite the fact that both methods (LGA and PTM) are used in multiple studies, they have never been compared for reliability in a direct study. The aim of this study is to analyze the intra and inter observer reliability of the LGA described by Garden and the PTM according to Palm. METHODS: Four observers measured the posterior tilt on the radiographs of 50 FNF two times with both methods. Intra and inter observer reliability were determined for the LGA and the PTM. RESULTS: The intra observer reliability for both methods is substantial with an intra class coefficient of 0.75. The inter observer reliability of the PTM is also substantial with an intra class coefficient of 0.75 compared to a moderate reliability of the LGA with an intraclass coefficient of 0.60. CONCLUSION: Based on our results we believe the LGA and the PTM are both reliable methods to measure posterior tilt. Yet the Posterior Tilt Measurement seems to have a better inter observer reliability and therefore has a slight preference over the Lateral Garden Angle.

Disruption of the 11-cis-retinol dehydrogenase gene leads to accumulation of cis-retinols and cis-retinyl esters.

To elucidate the possible role of 11-cis-retinol dehydrogenase in the visual cycle and/or 9-cis-retinoic acid biosynthesis, we generated mice carrying a targeted disruption of the 11-cis-retinol dehydrogenase gene. Homozygous 11-cis-retinol dehydrogenase mutants developed normally, including their retinas. There was no appreciable loss of photoreceptors. Recently, mutations in the 11-cis-retinol dehydrogenase gene in humans have been associated with fundus albipunctatus. In 11-cis-retinol dehydrogenase knockout mice, the appearance of the fundus was normal and punctata typical of this human hereditary ocular disease were not present. A second typical symptom associated with this disease is delayed dark adaptation. Homozygous 11-cis-retinol dehydrogenase mutants showed normal rod and cone responses. 11-cis-Retinol dehydrogenase knockout mice were capable of dark adaptation. At bleaching levels under which patients suffering from fundus albipunctatus could be detected unequivocally, 11-cis-retinol dehydrogenase knockout animals displayed normal dark adaptation kinetics. However, at high bleaching levels, delayed dark adaptation in 11-cis-retinol dehydrogenase knockout mice was noticed. Reduced 11-cis-retinol oxidation capacity resulted in 11-cis-retinol/13-cis-retinol and 11-cis-retinyl/13-cis-retinyl ester accumulation. Compared with wild-type mice, a large increase in the 11-cis-retinyl ester concentration was noticed in 11-cis-retinol dehydrogenase knockout mice. In the murine retinal pigment epithelium, there has to be an additional mechanism for the biosynthesis of 11-cis-retinal which partially compensates for the loss of the 11-cis-retinol dehydrogenase activity. 11-cis-Retinyl ester formation is an important part of this adaptation process. Functional consequences of the loss of 11-cis-retinol dehydrogenase activity illustrate important differences in the compensation mechanisms between mice and humans. We furthermore demonstrate that upon 11-cis-retinol accumulation, the 13-cis-retinol concentration also increases. This retinoid is inapplicable to the visual processes, and we therefore speculate that it could be an important catabolic metabolite and its biosynthesis could be part of a process involved in regulating 11-cis-retinol concentrations within the retinal pigment epithelium of 11-cis-retinol dehydrogenase knockout mice.

[Walking in the sun: heat stroke and heat exhaustion during the Four-Day March in Nijmegen, in 2006]. / Wandelen in de zon: hitteberoerte en hitte-uitputting tijdens de Nijmeegse Vierdaagse 2006.

The annual Four-Day March in Nijmegen, The Netherlands, in July 2006 was cancelled after the first day because two participants had died, men aged 65 and 57 years, and many had become unwell while walking in unusually high ambient temperatures. However, the cause of death of the two who died turned out to be cardiovascular and not heat-related. The case of two of the people that became unwell, men aged 58 and 59 years, respectively, shows that heat stroke and heat exhaustion were important causative conditions. Heat-related illnesses are relatively uncommon in the Netherlands due to its temperate climate. Heat stroke is the most severe of these and associated with a high mortality rate if not recognised and treated promptly. The primary cause is accumulation of heat due either to diminished loss or increased endogenous heat production, such as by physical exertion. Heat exhaustion is caused by salt or water depletion.

Patients either contacting a general practice cooperative or accident and emergency department out of hours: a comparison.

INTRODUCTION: Lack of collaboration between general practice (GP) cooperatives and accident and emergency (A&E) departments and many self referrals may lead to inefficient out-of-hours care. METHODS: We retrospectively analysed the records of all patients contacting the GP cooperative and all patients self referring to the A&E department out of hours in a region in the Netherlands. RESULTS: 258 patients contacted the GP cooperative and 43 self referred to the A&E department per 1000 patients per year. A wide range of problems were seen in the GP cooperative, mainly related to infections (26.2%). The A&E department had a smaller range of problems, mainly related to trauma (66.1%). Relatively few urgent problems were seen in the GP cooperative (4.6%) or for self referrals in the A&E department (6.1%). Women, children, the elderly, and rural patients chose the GP cooperative significantly more often, as did men and patients with less urgent complaints, infections, and heart and airway problems. DISCUSSION: The contact frequency of self referrals to the A&E department is much lower than that at the GP cooperative. Care is complementary: the A&E department focuses on trauma while the GP cooperative deals with a wide range of problems. The self referrals concern mostly minor, non-urgent problems and can generally be treated by the general practitioner, by a nurse, or by advice over the telephone, particularly in the case of optimal collaboration in an integrated care facility of GP cooperatives and A&E departments with one access point to medical care for all patients.

[Protocols for trauma care and the missing of injuries in severely injured accident victims during the prehospital phase]. / Protocollering van traumazorg en het missen van letsels bij ernstig gewonde ongevalspatiënten in de prehospitale fase.

Standardizing trauma care according to internationally accepted life-support principles is being increasingly implemented in the prehospital as well as the intramural setting. In the primary survey it is important to distinguish between aspects of major and minor importance, without losing sight of details. In prehospital care it is of little use to be focused on the complete diagnoses and the approach should be related to signs and symptoms. First attention should be paid to the mechanism of injury, related potential vital impairment and obvious visible injuries. The goal should be effective treatment, focused on the stabilization of vital functions and triage related to the choice of facility necessary for definitive care.

[Navigation surgery and fracture treatment]. / Navigatiechirurgie en fractuurbehandeling.

During operative fracture treatment the surgeon depends on fluoroscopic or X-ray radiological images as well as CT scans or MRI scans. This means that the surgeon sees only images at a given moment. Continuous imaging is technically complex and is accompanied by considerable exposure to radiation. Between images the surgeon has to depend on his or her knowledge of anatomical relationships and three-dimensional orientation. This may lead to the incorrect positioning of implants with ensuing morbidity and sometimes even death. Throughout the surgical procedure, computer assisted surgery (CAS) informs the surgeon of the exact position of the instruments in relation to the affected bone. The concept can be compared to that of the global positioning system (GPS) that is used by motorists. Clinical applications of CAS have been described for the operative treatment of vertebral fractures as well as fractures of the pelvis, hip and long bones. In reconstructive surgery, CAS is used for positioning the patient for total hip and knee surgery. The potential advantages of CAS are: increased accuracy, safety and reproducibility combined with lower radiation levels. Currently CAS is not widely used. There are a number of reasons for this. The technique is expensive and complex although the newer systems are more user friendly. It is possible that in the future CAS will be in standard use in orthopaedic and trauma surgery.

[Damage control surgery in polytraumatized patients]. / 'Damage control surgery' bij polytraumapatiënten.

Care for the polytraumatized patient in the pre-hospital phase has improved rapidly in recent years. This has resulted in more patients being alive on arrival at the hospital. The treatment of polytraumatized patients requires a different approach to that of regular trauma patients because they are threatened not only by the injuries themselves but also by the metabolic disruptions that follow. Therefore, the concept of damage control surgery (DCS) has been developed with the primary aim of controlling the life-threatening situation without immediate definitive repair of the sustained injuries. DCS describes a triphasic approach for abdominal and thoracic injuries and for injuries of the pelvic and extremities. The first phase aims at surgical intervention to stop the bleeding and to prevent further contamination. The second phase consists of resuscitation on the Intensive Care Unit and the third phase aims at definitive repair of the sustained injuries. Despite the low level of evidence found in the literature, DCS seems to reduce mortality rates in polytraumatized patients. Therefore, when initiated correctly and at the right moment, it appears to be a promising technique.

Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor beta 3.

Mucositis is a common, dose-limiting complication in patients receiving cancer chemotherapy, which appears to be a consequence of the rate of epithelial proliferation. The beta transforming growth factors have been shown to be negative regulators of epithelial cell proliferation. Here we show that transforming growth factor beta 3 administration reduced proliferation of oral epithelium in vitro and in vivo. Topical application of transforming growth factor beta 3 to the oral mucosa of the Syrian golden hamster prior to chemotherapy significantly reduced the incidence, severity, and duration of oral mucositis, reduced chemotherapy-associated weight loss, and increased survival.

Incidence and prognostic factors of chronic pain after isolated musculoskeletal extremity injury.

BACKGROUND: Chronic pain in patients is usually related to an episode of pain following acute injury, emphasizing the need to prevent progression from acute to chronic pain. Multiple factors in the acute phase might be responsible for perpetuating the pain. The presentation of patients at the emergency department (ED) presents a prime opportunity to identify patients at high risk for chronic pain and to start appropriate treatment. METHODS: The PROTACT study is a prospective follow-up study aiming to estimate the incidence and prognostic factors responsible for the development of chronic pain after musculoskeletal injury. Data including sociodemographic, pain, clinical, injury- or treatment-related and psychological factors of 435 patients were collected from registries and questionnaires at ED visit, 6-week, 3- and 6-month follow-up. RESULTS: At 6 months post-injury, 43.9% of the patients had some degree of pain (Numeric Rating Scale (NRS) ≥1) and 10.1% had chronic pain (NRS ≥4). Patients aged over 40 years, in poor physical health, with pre-injury chronic pain, pain catastrophizing, high urgency level and severe pain at discharge were found to be at high risk for chronic pain. CONCLUSIONS: Two prognostic factors, severe pain at discharge and pain catastrophizing, are potentially modifiable. The implementation of a pain protocol in the ED and the use of cognitive-behavioural techniques involving reducing catastrophizing might be useful.

Cloning and structural analysis of the murine GCN5L1 gene.

We recently cloned the murine 11-cis retinol dehydrogenase gene. A second gene, the murine GCN5L1 gene, was found to be situated upstream of the murine 11-cis retinol dehydrogenase gene. We have isolated and sequenced the complete coding sequence of the murine GCN5L1 gene. The distance between the 3'-end of the murine GCN5L1 gene and the 5'-end of the 11-cis retinol dehydrogenase gene is only 776 nt. The murine GCNSL1 gene consists of four exons encompassing approximately 3.5 kb of genomic DNA. Intron/exon splice sites conform to the GT/AG rule. The open reading frame consists of 375 nucleotides encoding a 14 kDa protein. The murine GCN5L1, like the human GCN5L1 protein, displays weak homology (27%) to yeast GCN5. The distance between the murine, human and bovine GCN5L1 and 11-cis retinol dehydrogenase genes appeared to be conserved.

The visual cycle retinol dehydrogenase: possible involvement in the 9-cis retinoic acid biosynthetic pathway.

The 11-cis-retinol dehydrogenase (11-cis-RoDH) gene encodes the short-chain alcohol dehydrogenase responsible for 11-cis-retinol oxidation in the visual cycle. The structure of the murine 11-cis-RoDH gene was used to reinvestigate its transcription pattern. An 11-cis-RoDH gene transcript was detected in several non-ocular tissues. The question regarding the substrate specificity of the enzyme was therefore addressed. Recombinant 11-cis-RoDH was found capable of oxidizing and reducing 9-cis-, 11-cis- and 13-cis-isomers of retinol and retinaldehyde, respectively. Dodecyl-beta-1-maltoside used to solubilize the enzyme was found to affect the substrate specificity. This is the first report on a visual cycle enzyme also present in non-retinal ocular and non-ocular tissues. A possible role in addition to its role in the visual cycle is being discussed.

Characterization of monoclonal antibodies recognizing retinal pigment epithelial antigens.

PURPOSE: To purify and characterize retinal pigment epithelial proteins exhibiting uveitogenic characteristics after immunization of Lewis rats, a broad panel of monoclonal antibodies directed against retinal pigment epithelial (RPE) protein antigens, was isolated. METHODS: Bovine RPE detergent extracts were used to isolate monoclonal antibodies against RPE antigens. Species and tissue specificity within the eye was tested through immunocytochemical analysis. Western blot analysis was used to determine the molecular weight of the RPE antigens. RESULTS: Several RPE-reactive antibodies were obtained. At least four monoclonal antibodies were isolated that reacted with different RPE antigen types. Against most of the antigens more than one hybridoma cell line was isolated. Two hybridoma lines were isolated producing antibodies, which on immunocytochemical analysis showed strong reactivity with the RPE and eye muscle tissue. The latter monoclonal antibody recognizes a 32 kD protein in RPE cells. Five monoclonal antibodies recognize a protein with an apparent molecular weight of 65 kD. One cell line was isolated that produced antibodies showing an irregular reaction pattern with both iris and ciliary body. CONCLUSIONS: RPE cells, striated eye muscle and smooth muscle cells share a 32 kD antigenic protein. This antigen is present in almost all ocular epithelial cells. Based on reaction patterns on Western blot and immunocytochemical analysis, there are at least three different 65 kD RPE antigens, two of which are RPE-specific and one of which is also present in the kidney epithelium.

Cloning and expression of a cDNA encoding bovine retinal pigment epithelial 11-cis retinol dehydrogenase.

PURPOSE: Identification of a 32-kd protein in the bovine retinal pigment epithelium. METHODS: A bovine retinal pigment epithelium cDNA library was constructed in the bacteriophage lambda ZAP Express. A monoclonal antibody, designated 21-C3/AV, was used to isolate the cDNA encoding the 21-C3/AV antigen. A positive full-length clone, designated 21-C3RDH/CD, was sequenced. Northern blot analysis was used to determine the length of the mRNA and the tissue expression pattern. The entire open reading frame of clone 21-C3RDH/CD was used to isolate a recombinant baculovirus clone and expressed in Spodoptera frugiperda insect cells. Enzymatic activity toward 11-cis retinaldehyde was investigated. RESULTS: The complete nucleotide sequence of 21-C3RDH/CD was obtained. The deduced amino acid sequence reveals homology with short-chain alcohol dehydrogenases. Northern blot analysis detected a 1.2-kb transcript. Although the monoclonal antibody used to isolate 21-C3RDH/CD also reacts with other ocular and nonocular tissues, the authors were unable to demonstrate any reactivity with RNA samples isolated from different (non)ocular tissues. Recombinant baculovirus-infected insect cells synthesized the 21-C3/AV antigen. This protein showed 11-cis retinol dehydrogenase activity. CONCLUSIONS: Homology to the human D-beta-hydroxybutyrate dehydrogenase precursor and other alcohol dehydrogenases shows that 21-C3RDH/CD encodes a short-chain alcohol dehydrogenase. Furthermore, tissue specificity and molecular weight of the antigen suggest that 21-C3RDH/CD encodes the bovine retinal pigment epithelial 11-cis retinol dehydrogenase. Direct proof came from experiments in which we used the baculovirus-based expression system for in vitro synthesis of the protein encoded by 21-C3RDH/CD. Protein extracts obtained from recombinant baculovirus-infected insect cells were found capable of reducing 11-cis retinaldehyde.

Retinoic acid delays transcription of human retinal pigment neuroepithelium marker genes in ARPE-19 cells.

The effect of retinoic acid on the differentiation of a human retinal pigment epithelium-derived cell line ARPE-19 was studied. Differentiation of ARPE-19 cells is delayed by retinoic acid. The minimum all-trans-retinoic acid concentration needed for delay of ARPE-19 differentiation is 1 microM. A delay of differentiation was also observed using 1 microM 9-cis or 13-cis-retinoic acid. Differentiation at the molecular level was studied by analyzing transcription of two RPE-marker genes, RPE65 and peropsin. In the presence of 1 microM retinoic acid the onset of transcription of both genes was delayed by 2-3 weeks. We conclude that all-trans-, 9-cis-, and 13-cis-retinoic acid delay differentiation of ARPE-19 cells into cells that phenotypically resemble cells from the human retinal pigment epithelium.

Lipid kinases are novel effectors of the GTPase Rac1.

We have found that a complex consisting of a type I PIPK and a DGK associates with the GTPase Rac1. Binding of the lipid kinase complex is through the C-terminus of Rac. Complex formation is augmented in the presence of specific phospholipids. The complex also associates with Rho GDI, through Rac. Based on the role of PtdIns-4,5-P2 in regulating proteins that influence actin structures we propose that the Rac-associated lipid kinase complex functions to generate locally high concentrations of PtdIns-4,5-P2 in a Rac-dependent manner. There are many possible roles PtdIns-4,5-P2 might play. A likely role is binding to barbed-end actin capping proteins. This would release the capping protein, providing free barbed ends for actin polymerization. Uncapping would occur at the membrane so that additional actin polymerization would result in membrane protrusions and lamellapodia, in a Brownian ratchet model. It is also possible that PtdIns-4,5-P2 has other roles, such as promoting the release of G actin from profilin or promoting the cross-linking of actin or its anchorage to the plasma membrane. Studies are currently underway to determine the role of this lipid kinase complex in Rac signaling and actin regulation in vivo.

Rhodopsin-induced experimental autoimmune uveoretinitis in monkeys.

We present the first evidence that purified rhodopsin can induce experimental autoimmune uveoretinitis (EAU) in monkeys. Injection of a highly purified lipid-free rhodopsin preparation provokes severe chorioretinitis with concomitant anterior uveitis. The onset of disease is earlier, its frequency is higher, and the inflammation is considerably more severe than in EAU induced under similar conditions by opsin. The first inflammatory cells are observed in the ciliary body and pars plana. Within a few days the inflammation extends into the anterior chamber, choroid, and retina. Retinitis predominates in the central area, while chorioretinitis is observed in the periphery, both accompanied by damage to and elimination of the photoreceptor cells. The monkeys develop high cellular and humoral immune responses against rhodopsin and opsin. The cellular response maximum just precedes the onset of EAU. This may indicate that cellular immunity has an important role in the pathogenesis of rhodopsin-induced EAU.

Transforming growth factor-beta 3 mediated modulation of cell cycling and attenuation of 5-fluorouracil induced oral mucositis.

Mucositis is a common, dose-limiting complication in patients receiving cancer chemotherapy, which derives from damage to the epithelial cell layer. We have shown that transforming growth factor-beta 3 (TGF-beta 3) negatively regulates epithelial cell proliferation and reduces the incidence of oral mucositis. Here, we report the findings of a large study examining the effects of TGF-beta 3 administration in a hamster model on oral epithelial cell cycling in vivo, on oral mucositis, on weight retention and on survival. Topical application of TGF-beta 3 to the buccal mucosa significantly reduced basal cell proliferation, as measured by proliferating cell nuclear antigen (PCNA) immunohistochemistry and DNA ploidy. Administration of topical TGF-beta 3 prior to chemotherapy with 5-fluorouracil (5-FU) significantly reduced the severity of mucositis with respect to time, reduced chemotherapy-associated weight loss and increased survival.

Posterolateral dislocation of the elbow joint. Relationship to medial instability.

BACKGROUND: Dislocation of the elbow joint is the second most common dislocation in the upper extremity, dislocation of the shoulder being the most common. It has been reported that uncomplicated dislocation of the elbow joint may be associated with a decreased range of motion, degenerative changes in the elbow joint, ectopic calcification, or neurological deficits. As the medial collateral ligament complex can be completely disrupted during dislocation, we evaluated the association between the long-term results of treatment of simple posterolateral dislocation of the elbow and the presence of persistent medial or valgus elbow instability. METHODS: Fifty patients who had a mean age of thirty-three years (range, eighteen to fifty-eight years) had closed reduction of a posterolateral dislocation of the elbow without associated fractures. The extremity was immobilized in an above-the-elbow plaster cast for three weeks. After a mean duration of follow-up of nine years (range, six to thirteen years), forty-one patients were evaluated with an interview, a physical examination, and radiographs made while a valgus load was applied to the elbow. RESULTS: The average score according to the system of The Hospital for Special Surgery was 91 points (range, 49 to 100 points), and thirty-one patients described their elbow function as good or excellent. Twenty-four patients had evidence of medial instability on radiographs made while a valgus load was applied to the elbow. Twenty-one patients had signs of degeneration of the joint, and twenty-five patients had ectopic ossification. Magnetic resonance imaging combined with arthrography was performed for the first twenty patients; eight had evidence of rupture of the medial collateral ligament, seven had generalized degenerative changes of the cartilage, and four had a chondral defect of the capitellum. (The study could not be completed for the remaining patient.) Medial instability on radiographs was correlated with signs of degeneration (p = 0.001), ectopic ossification (p = 0.01), a worse score according to the system of The Hospital for Special Surgery (p = 0.002), and persistent pain (p = 0.04). CONCLUSIONS: Posterolateral dislocation of the elbow joint can lead to persistent valgus instability that is associated with a worse overall clinical and radiographic result.

Opsin-induced experimental autoimmune retinitis in rats.

Experimental autoimmune retinitis has been induced in Lewis rats by injection of opsin in mycobacterial adjuvant and Hemophilus pertussis adjuvant. Clinical, histopathological and immunological parameters of the disease are reported. Two types of opsin were prepared from purified bovine retina outer segments, one type in Triton X-100 and the other in lithium dodecyl sulfate. Both preparations were free from S-antigen. Dodecyl sulfate-denaturated-opsin displayed lower antigenicity and pathogenicity than Triton-opsin. Triton-opsin (250 micrograms) induced moderate to severe non-granulomatous uveitis (predominantly retinitis) in 70% of the Lewis rats at the end of the second week after injection. The photoreceptor cell layer was destructed within a few days. This group displayed high responses to opsin in the lymphocyte transformation test. In view of observed histological features, the possible early involvement of vasoactive factors is discussed. Low opsin doses (50 or 100 micrograms) seldomly induced severe retinitis, while the incidence of mild pathology was low. Lewis rats appeared to be more susceptible for the development of experimental autoimmune retinitis than Wistar rats.