Subjective and objective evaluations of horses for fit-to-compete or unfit-to-compete judgement.

At Fédération Equestre Internationale (FEI) competitions, horses undergo veterinary inspection for judgement of 'fit-to-compete'. However, FEI Veterinary Delegates (VDs) often differ in opinion. The aim of the present study was to evaluate intra- and inter-observer agreements of fit-to-compete judgement and compare these with objective gait analysis measurements. Twelve horses were evaluated by three experienced VDs and one veterinary specialist and video-recorded for re-evaluation later. Simultaneously, quantitative gait analysis measurements were acquired. Inter-observer agreement during live evaluations was fair (κ = 0.395, 58% agreement). Intra-observer agreement between live observations and videos at one and 12 months was 71% and 73% respectively. Sensitivity and specificity of motion symmetry measured with quantitative gait analysis system were 83.3% and 66.7% respectively, against the consensus of all observers as a reference. These findings might suggest that more VDs should be used to adequately judge fit-to-compete. Quantitative-gait-analysis may be useful to support decision making during fit-to-compete judgement.

Caudal cervical vertebral morphological variation is not associated with clinical signs in Warmblood horses.

BACKGROUND: Variation in equine caudal cervical spine morphology at C6 and C7 has high prevalence in Warmblood horses and is suspected to be associated with pain in a large mixed-breed group of horses. At present no data exist on the relationship between radiographic phenotype and clinical presentation in Warmblood horses in a case-control study. OBJECTIVES: To establish the frequency of radiographically visible morphologic variation in a large group of Warmblood horses with clinical signs and compare this with a group without clinical signs. We hypothesised that occurrence of morphologic variation in the case group would not differ from the control group, indicating there is no association between clinical signs and morphologic variation. STUDY DESIGN: Retrospective case-control. METHODS: Radiographic presence or absence of morphologic variation of cervical vertebrae C6 and C7 was recorded in case (n = 245) and control horses (n = 132). Case and control groups were compared by univariable Pearson's Chi-square and multivariable logistic regression for measurement variables age, sex, breed, degenerative joint disease and morphologic variation at C6 and C7. Odds ratio and confidence intervals were obtained. A P≤0.05 was considered statistically significant. RESULTS: Morphologic variation at C6 and C7 (n = 108/377 = 28.6%; Cases 58/245 = 23.7%; Control 50/132 = 38%) was less frequent in horses with clinical signs in univariable testing (OR 0.48, 95% CI 0.3-0.8, P = 0.001). Age, sex, breed and degenerative joint disease were not retained in the final multivariable logistic regression step whereas morphologic variation remained significantly less present in horses with clinical signs. MAIN LIMITATIONS: Possible demographic differences between equine clinics. CONCLUSIONS: Morphologic variation in the caudal cervical spine was detected more frequently in horses without clinical signs. Therefore, radiographic presence of such variation does not necessarily implicate the presence of clinical signs.

Quantitative and qualitative aspects of standing-up behavior and the prevalence of osteochondrosis in Warmblood foals on different farms: could there be a link?

BACKGROUND: Osteochondrosis (OC) is a common, clinically important joint disorder in which endochondral ossification is focally disturbed. Reduced blood supply to growing cartilage is considered an important cause of the condition, which has both genetic and environmental origins. Housing conditions can influence cartilage injury through peak-pressure changes during limb sliding. Additionally, circulatory perturbation can cause the avascular necrosis of cartilage. In this study, we evaluated the type and frequency of limb sliding during standing up and the occurrence of OC in foals aged up to 12 months on different farms. METHODS: Standing-up behavior was observed in 50 weaned, group-housed, Dutch Warmblood foals aged 6-9 months at five farms using black-and-white surveillance cameras, and their standing-up behavior was scored using a predetermined ethogram. OC was scored using a categorical scale between 6 and 12 months of age in 50 foals in the weanling period, and in 48 from the weanling to yearling periods because two foals died in this time. RESULTS: At both 6 and 12 months of age, the total prevalence of OC differed between the farms: the lowest prevalence was observed on a farm with no sliding, and the highest prevalence was evident on a farm with a higher sliding frequency. The mean ratio of sliding versus normal standing-up behavior was 29% (range: 0-50%); i.e., foals experienced limb sliding during around 29% of standing-up maneuvres. The frequency of sliding instead of normal standing-up behavior differed significantly between the farms (range: 0-50%; P < 0.05), but significantly decreased when foals could better prepare themselves to stand, e.g., when there was an obvious provocation such as the announced approach of another foal (P < 0.05). CONCLUSIONS: Small but significant differences exist between farms in the sliding frequency and total OC incidence in Warmblood foals, but whether environmental factors are causally related to these differences requires further elucidation.

Quantitative motor unit action potential analysis in 2 paraspinal neck muscles in adult Royal Dutch Sport horses.

BACKGROUND: Reference values for quantitative electromyography (QEMG) in neck muscles of Royal Dutch Sport horses are lacking. OBJECTIVE: Determine normative data on quantitative motor unit action potential (QMUP) analysis of serratus ventralis cervicis (SV) and brachiocephalicus (BC) muscle. ANIMALS: Seven adult normal horses (mean age 9.5 standard deviation [SD] ± 2.3 years, mean height 1.64 SD ± 4.5 cm, and mean rectal temperature 37.6 SD ± 0.3°C). METHODS: An observational study on QMUP analysis in 6 segments of each muscle was performed with commercial electromyography equipment. Measurements were made according to formerly published methods. Natural logarithm transformed data were tested with ANOVA and posthoc testing according to Bonferroni. RESULTS: Mean duration, amplitude, phases, turns, area, and size index (SI) did not differ significantly among the 6 segments in each muscle. Mean amplitude, number of phases, and SI were significantly (P < .002) higher in SV than BC, 520 versus 448 µV, 3.0 versus 2.8 µV, and 0.48 versus 0.30 µV, respectively. In SV 95% confidence intervals (CI) for amplitude, duration, number of phases, turns, polyphasia area, and SI were 488-551 µV, 4.3-4.6 ms, 2.9-3.0, 2.4-2.6, 7-12%, 382-448, and 0.26-0.70, respectively; in BC this was 412-483 µV, 4.3-4.7 ms, 2.7-2.8, 2.4-2.6, 4-7%, 393-469, and 0.27-0.34, respectively. Maximal voluntary activity expressed by turns/second did not differ significantly between SV and BC with a 95% CI of 132-173 and 137-198, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: The establishment of normative data makes objective QEMG of paraspinal muscles in horses suspected of cervical neurogenic disorders possible. Differences between muscles should be taken into account.

The propagation of induced tendon lesions in the equine superficial digital flexor tendon: an ex vivo study.

REASONS FOR PERFORMING STUDY: Clinical tendon lesions usually enlarge during the first days to weeks after sustaining the injury due to enzymatic and biomechanical influences. Limiting this enlargement would positively influence prognosis related to lesion size. OBJECTIVES: To investigate the effect of cyclic loading on the propagation of enzymatically and physically induced tendon lesions and to assess the effect of immobilisation thereon in an ex vivo model. METHODS: Equine cadaver limbs with either physically or collagenase-induced SDFT lesions were placed in a pneumatic loading device. Groups consisted of unloaded limbs, cyclically loaded limbs and cyclically loaded limbs with fibreglass cast immobilisation. Lesion size was evaluated ultrasonographically and macroscopically and load at failure was determined for groups where lesions enlarged. RESULTS: Physically induced lesions did not propagate after cyclical loading and were not further investigated. Collagenase-induced lesions propagated significantly more after cyclical loading compared to unloaded limbs. This propagation could effectively be reduced by immobilisation through a lower limb cast. Immobilisation did not influence load at failure. CONCLUSIONS: The combination of enzymatic and mechanical stimulation caused the lesions to propagate most. Casting appeared effectively to reduce the enlargement of the original tendon lesions in this ex vivo model, while it did not affect ultimate tendon strength. POTENTIAL RELEVANCE: As prognosis of tendon injuries is related to lesion size, the outcome of this study warrants further investigations in vivo.

Prevalence of various radiographic manifestations of osteochondrosis and their correlations between and within joints in Dutch warmblood horses.

REASONS FOR PERFORMING STUDY: Osteochondrosis (OC) is the most important orthopaedic developmental disorder in horses and may manifest in several different forms. No detailed study on the prevalence and/or interrelation of these forms is available, even though these data are a prerequisite for conclusive genetic studies. OBJECTIVES: To assess the prevalence of the various manifestations of OC as detected radiographically and to evaluate possible relationships between their occurrence within the same joint and between different joints. METHODS: The FP (femoropatellar), TC (tarsocrural) and MCP/MTP (metacarpophalangeal/metatarsophalangeal) joints of 811 yearlings selected randomly, descending from 32 representative stallions, were radiographed and scored for the presence and grade of osteochondrotic lesions. Results were compared at the sire, animal, joint and predilection site levels. RESULTS: In the FP joint, the percentage of animals showing normal joint contours in all sites was 60.7%. For the TC joint and the combined MCP/MTP joints, these figures were 68.6 and 64.6%, respectively. For all joints combined, the percentage dropped to 30.5%. Sedation improved detection of OC lesions in the FP joint. There was a high correlation between the right and left joints. The correlation between flattened bone contours and fragments was considerably less. CONCLUSIONS: Scoring on a detailed scale is necessary to achieve good insight into the prevalence of OC. Observations on the right and left joints can be combined in further analyses, whereas flattened bone contours and fragments should be evaluated as statistically different disorders. POTENTIAL RELEVANCE: This study provides insight into the prevalences of various manifestations of OC and their relationships, within and between joints. These results form the basis for detailed quantitative and/or molecular genetic studies that should lead to the establishment of breeding indices and/or genetic marker sets for OC.

Subclinical hypocalcaemia in captive Asian elephants (Elephas maximus).

The hypothesis that hypocalcaemia may play a role in dystocia in captive Asian elephants (Elephas maximus) was investigated. The objectives of the study were to measure the total calcium concentration in elephant plasma; assess the changes in parameters of calcium metabolism during a feeding trial; investigate a possible relationship between calcium metabolism and dystocia; and assess bone mineralisation in captive Asian elephants in vivo. The following parameters were measured: total and ionised calcium, inorganic phosphorous and magnesium, the fractional excretions of these minerals, intact parathyroid hormone, 25-OH-D(3) and 1,25-OH-D(3). Radiographs were taken from tail vertebrae for assessment of bone mineralisation. The mean (sd) heparinised plasma total calcium concentration was 2.7 (0.33) mmol/l (n=43) ranging from 0.84 to 3.08 mmol/l in 11 Asian elephants. There was no significant correlation between plasma total calcium concentration and age. Following feeding of a calcium rich ration to four captive Asian elephant cows, plasma total and ionised calcium peaked at 3.6 (0.24) mmol/l (range 3.4 to 3.9 mmol/l) and 1.25 (0.07) mmol/l (range 1.17 to 1.32 mmol/l), respectively. Plasma ionised calcium concentrations around parturition in four Asian elephant cows ranged from 0.37 to 1.1 mmol/l only. The present study indicates that captive Asian elephants might be hypocalcaemic, and that, in captive Asian elephants, the normal plasma concentration of total calcium should actually be around 3.6 mmol/l and normal plasma concentration of ionised calcium around 1.25 mmol/l. Given the fact that elephants absorb dietary calcium mainly from the intestine, it could be concluded that elephants should be fed calcium-rich diets at all times, and particularly around parturition. In addition, normal values for ionised calcium in captive Asian elephants should be reassessed.

Phenotypic diagnosis of dwarfism in six Friesian horses.

An extreme form of abnormal development, dwarfism, is common in man and some animals, but has not been officially reported in horses. Within the Friesian horse breed, congenital dwarfism has been recognised for many years, but no detailed report exists on its phenotype. The most salient feature of the dwarf syndrome is the physeal growth retardation in both limbs and ribs. Affected animals have approximately 25% shorter fore- and hindlimbs and approximately 50% reduced bodyweight. Postnatal growth is still possible in these animals, albeit at a slower rate: the head and back grow faster than the limbs and ribs leading to the characteristic disproportional growth disturbance. Thus, adult dwarfs exhibit a normal, but a relatively larger head conformation, a broader chest with narrowing at the costochondral junction, a disproportionally long back, abnormally short limbs, hyperextension of the fetlocks and narrow long-toed hooves. Furthermore, a dysplastic metaphysis of the distal metacarpus and metatarsus is radiographically evident. Microscopic analysis of the growth plates at the costochondral junction shows an irregular transition from cartilage to bone, and thickening and disturbed formation of chondrocyte columns, which is similar to findings in osteochondrodysplasia.

Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism.

BACKGROUND: Low molecular weight heparins (LMWH) have been shown to be effective and safe in preventing venous thromboembolism (VTE), and may also be effective for the initial treatment of VTE. OBJECTIVES: To determine the effect of LMWH compared with unfractionated heparin (UFH) for the initial treatment of VTE. SEARCH STRATEGY: Trials were identified from the Cochrane Peripheral Vascular Diseases Group's Specialised Register, CENTRAL and LILACS. Colleagues and pharmaceutical companies were contacted for additional information. SELECTION CRITERIA: Randomised controlled trials comparing fixed dose subcutaneous LMWH with adjusted dose intravenous or subcutaneous UFH in people with VTE. DATA COLLECTION AND ANALYSIS: At least two reviewers assessed trials for inclusion and quality, and extracted data independently. MAIN RESULTS: Twenty-two studies were included (n = 8867). Thrombotic complications occurred in 151/4181 (3.6%) participants treated with LMWH, compared with 211/3941 (5.4%) participants treated with UFH (odds ratio (OR) 0.68; 95% confidence intervals (CI) 0.55 to 0.84, 18 trials). Thrombus size was reduced in 53% of participants treated with LMWH and 45% treated with UFH (OR 0.69; 95% CI 0.59 to 0.81, 12 trials). Major haemorrhages occurred in 41/3500 (1.2%) participants treated with LMWH, compared with 73/3624 (2.0%) participants treated with UFH (OR 0.57; 95% CI 0.39 to 0.83, 19 trials). In eighteen trials, 187/4193 (4.5%) participants treated with LMWH died, compared with 233/3861 (6.0%) participants treated with UFH (OR 0.76; 95% CI 0.62 to 0.92). Nine studies (n = 4451) examined proximal thrombosis; 2192 participants treated with LMWH and 2259 with UFH. Subgroup analysis showed statistically significant reductions favouring LMWH in thrombotic complications and major haemorrhage. By the end of follow up, 80 (3.6%) participants treated with LMWH had thrombotic complications, compared with 143 (6.3%) treated with UFH (OR 0.57; 95% CI 0.44 to 0.75). Major haemorrhage occurred in 18 (1.0%) participants treated with LMWH, compared with 37 (2.1%) treated with UFH (OR 0.50; 95% CI 0.29 to 0.85). Nine studies (n = 4157) showed a statistically significant reduction favouring LMWH with respect to mortality. By the end of follow up, 3.3% (70/2094) of participants treated with LMWH had died, compared with 5.3% (110/2063) of participants treated with UFH (OR 0.62; 95% CI 0.46 to 0.84). REVIEWERS' CONCLUSIONS: LMWH is more effective than UFH for the initial treatment of VTE. LMWH significantly reduces the occurrence of major haemorrhage during initial treatment and overall mortality at follow up.

Identification and phenotyping of leukocytes in bovine bronchoalveolar lavage fluid.

A method is proposed to identify leukocyte subpopulations in bovine bronchoalveolar lavage fluid by dual-laser flow cytometry. The technique uses several parameters, i.e., exclusion of highly autofluorescent alveolar macrophages and inclusion of leukocytes on the basis of labeling by specific antibodies and light scatter characteristics.

The role of electromyography in clinical diagnosis of neuromuscular locomotor problems in the horse.

REASONS FOR PERFORMING STUDY: Systematically performed EMG needle examination of muscles provides essential information about the functional aspects of the motor unit. However, clinical studies in which information is given on the diagnostic and discriminative values of electromyography (EMG) in the horse are scarce. OBJECTIVES: To determine to what extent inclusion of EMG analysis in clinical examination contributes to determination of type and localisation of abnormality. METHODS: EMG analysis, complete clinical examination and diagnosis of 108 horses (mean +/- s.d. age 75 +/- 3.8 years; bodyweight 548 +/- 86 kg; height 1.67 +/- 0.07 m) were performed, and results without and with EMG analysis compared. RESULTS: Without EMG, myopathy and neuropathy were diagnosed in 20 and 58 horses, respectively, and with EMG in 17 and 82 horses. EMG changed localisation in myopathy and neuropathy in 12 and 37% of cases, respectively. Lesions in the C1-T2, T2-L3 and L3-S3 segments were, respectively, diagnosed without EMG in 7, 11 and 30%, and with EMG in 27, 7 and 17% of cases. Where no clinical diagnosis could be made prior to EMG, many patients appeared to be suffering from localised cervical lesions (29%) or generalised neuropathy (54%). CONCLUSIONS AND POTENTIAL RELEVANCE: The assistance of EMG in discriminating between normal, neuropathy and myopathy, and in locating pathology, contributes to diagnosis of neuromuscular problems.

Brain abscesses as a metastatic manifestation of strangles: symptomatology and the use of magnetic resonance imaging as a diagnostic aid.

REASONS FOR PERFORMING STUDY: The occurrence of unexpectedly high numbers of horses with neurological signs during two outbreaks of strangles required prompt in-depth researching of these cases, including the exploration of magnetic resonance imaging (MRI) as a possible diagnostic technique. OBJECTIVES: To describe the case series and assess the usefulness of MRI as an imaging modality for cases suspected of space-occupying lesions in the cerebral cavity. METHODS: Four cases suspected of suffering from cerebral damage due to Streptococcus equi subsp. equi infection were examined clinically, pathologically, bacteriologically, by clinical chemistry (3 cases) and MRI (2 cases). In one case, MRI findings were compared to images acquired using computer tomography (CT). RESULTS: In all cases, cerebral abscesses positive for Streptococcus equi subsp. equi were found, which explained the clinical signs. Although the lesions could be visualised with CT, MRI images were superior in representing the exact anatomic reality of the soft tissue lesions. CONCLUSIONS: The diagnosis of bastard strangles characterised by metastatic brain abscesses was confirmed. MRI appeared to be an excellent tool for the imaging of cerebral lesions in the horse. POTENTIAL CLINICAL RELEVANCE: The high incidence of neurological complications could not be explained but possibly indicated a change in virulence of certain strains of Streptococcus equi subsp. equi. MRI images were very detailed, permitting visualisation of much smaller lesions than demonstrated in this study and this could allow prompt clinical intervention in less advanced cases with a better prognosis. Further, MRI could assist in the surgical treatment of brain abscesses, as has been described earlier for CT.

Relationships of age and shape of the navicular bone to the development of navicular disease: a radiological study.

Estimating the shape of the proximal articular border of the navicular bone and grading the radiological navicular bone condition (grades 3 and 4 representing the most severe changes), the aim of this study was to assess potential age-related implications of the previously reported shape predisposition to navicular disease in 746 normal and 174 clinically affected Dutch Warmbloods age 3-19 years. A significant, age-independent, shape-grade association found in normal and affected horses emphasises the fundamental character of the shape predisposition to navicular disease. A significant age-related increase of the least susceptible shape prevalence was found in elderly normal horses. A shape-independent low grades 3 and 4 prevalence (mean 15%) was found in normal horses, vs. a high grades 3 and 4 prevalence (mean 85%) in the affected horses. Therefore, the clinical manifestation of the disease is grade-rather than shape-dependent. A significant age-related appearance of inverted flask-shaped channels and enthesophytes was found in the clinically affected horses. However, considering the significant shape-radiological features association previously reported in 3-year-old normal horses, this association may be shape- rather than age-dependent.

Transmodulation of epidermal growth factor receptor mediates IL-1 beta-induced MMP-1 expression in cultured human keratinocytes.

Ultraviolet (UV) irradiation causes human skin aging and skin cancer through the activation of matrix metalloproteinases (MMPs) which are responsible for the degradation of collagen and tumor progression in human skin. The molecular mechanisms of UV-induced MMPs are yet to be defined. Our previous studies and others suggest that i) the transient activation of cell surface receptors and subsequent activation of MAP kinase cascade contributes to the transcriptional up-regulation of MMPs; and ii) UV-induced expression of pro-inflammatory cytokines such as IL-1 beta and TNF-alpha may also account for the expression of MMPs. However, signaling pathway through which cytokines induce MMP expression remains to be unraveled. In this study, we investigated the pathway that leads to the IL-1 beta-induced up-regulation of MMP-1 in human keratinocytes. IL-1 beta activated epidermal growth factor (EGF) receptor in cultured human keratinocytes in a time- and dose-dependent manner. IL-1 beta-induced EGF receptor tyrosine phosphorylation started at 5 min and peaked at 10 min and remained elevated up to 40 min post IL-1 beta treatment. EGF receptor kinase inhibitor PD153035 and AG1478 inhibited IL-1 beta-induced EGF receptor tyrosine phosphorylation. To test the effect of EGF receptor transactivation on downstream components, we examined the ERK activation by IL-1 beta. We found that IL-1 beta-induced ERK phosphorylation, PD153035 and MEK inhibitor PD98059 blocked IL-1 beta-induced ERK activity. Furthermore, both inhibitors also dramatically reduced IL-1 beta-induced expression of c-jun and c-fos mRNA which are required for up-regulation of MMPs. EGF receptor kinase inhibitor PD153035 and AG1478 and MEK inhibitor PD98059 also blocked IL-1 beta induction of MMP-1 in cultured human keratinocytes. Collectively, our data indicate that IL-1 beta-induced expression of MMP-1 is mediated by transactivation of EGF receptor and through ERK pathway in human keratinocytes.

The radiographic development of the distal and proximal double contours of the equine navicular bone on dorsoproximal-palmarodistal oblique (upright pedal) radiographs, from age 1 to 11 months.

The aim of this study was to monitor the postnatal radiographic development of the proximal and distal double contours and the modelling of the shape of the proximal articular border. In mature horses, the proximal and distal contours of the navicular bone on dorsopalmar dorsoproximal-palmarodistal oblique (upright pedal) radiographs are commonly visualised as 2 lines, one being the articular border and the second representing the border of the cortex facing the deep digital flexor tendon (flexor border). The shape of the proximal articular border may be concave, undulating, straight or convex in the mature animal. These shapes have been found to be hereditary and to constitute a predisposing factor in the pathogenesis of navicular disease. This predisposing role may result from a shape dependent distribution of the biomechanical forces exerted on this region. There is no agreement in the literature with respect to the moment when the navicular bone takes its mature radiographic appearance. Upright pedal radiographs of the left front foot of 19 Dutch Warmblood foals were made at age 1 month and subsequently at intervals of 4 weeks, until the age of 11 months. The distal double contour developed soon after birth and the radiographic visibility of the articular border improved from ill-defined at 1 or 2 months to clear manifestation at 3 or 4 months. The proximal double contour developed later. The articular border became usually visible at age 3 or 4 months and was clearly visible from age 9 months. The mature shape of the proximal articular border usually became recognisable from age 7 months and was always obvious between 9 and 11 months. This development was associated with a gradual modelling of the lateral and medial extremities of the navicular bone. It was concluded that the navicular bone adopts its mature radiological appearance during the first year postpartum. Considering this early manifestation of the mature shape of the proximal articular border and its previously demonstrated inheritance, a force-dependent development of this shape, as predicted by the trajectional theory/Wolffs law, is improbable. The predisposing role of this shape in the pathogenesis of navicular disease may therefore be explained by a shape-dependent distribution of the biomechanical forces exerted on the navicular bone. Considering the potential application of these findings, from age 1 year shape determination enables identification of the individual and breed susceptibility for the development of navicular disease.

Movement characteristics of persons with prader-willi syndrome rising from supine.

PURPOSE: The purposes of this study were to: 1) determine if previously published descriptors of the supine to stand rising task in healthy individuals could be applied to the movements of persons with Prader-Willi Syndrome (PWS); and 2) assess upper extremity (UE), axial region (AX), and lower extremity (LE) movements among subjects with PWS compared with controls. METHODS: Nine subjects with PWS (seven-36 years of age) and matched controls were videotaped performing 10 rising trials. The UE, AX, and LE movements were classified using published descriptors. Occurrence frequencies of movement patterns, duration of movement, and the relationships among body region movement score, BMI, and age were determined. RESULTS: Subjects with PWS utilized developmentally less advanced asymmetrical rising patterns, took longer to rise, and demonstrated less within subject variability than controls. CONCLUSIONS: Categorical descriptors, with minor modifications, can be used to describe rising movements in persons with PWS. Knowledge of successful rising patterns may assist PTs when examining or planning intervention strategies for teaching the rising task.

Duration of oral anticoagulant treatment in patients with venous thromboembolism and a deficiency of antithrombin, protein C or protein S--a decision analysis.

Patients with a first venous thromboembolic event and a deficiency of the coagulation inhibitors antithrombin, protein C or protein S have an increased risk of recurrent venous thromboembolism compared to patients without such a deficiency. A decision analysis was performed to assess the effect of continuing treatment with vitamin K antagonists on mortality by a reduction in fatal recurrent pulmonary embolism and an induction of fatal haemorrhages associated with their use. The treatment decision involves continuation or discontinuation of vitamin K antagonists in patients with a first spontaneous or secondary venous thromboembolism and an antithrombin, protein C or S deficiency. Although the efficiency of oral anticoagulation is high in all age groups early after the first thromboembolic event, it decreases over time. Our analysis indicates that the optimal treatment duration will vary, depending on the type of the initial event (spontaneous or secondary; deep venous thrombosis or pulmonary embolism), age, and time passed since the initial thromboembolic episode. Moreover, life-long duration of the prophylaxis seems not warranted in all patients.

Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism.

BACKGROUND: Low molecular weight heparins have been shown to be effective and safe for prevention of venous thromboembolism. There is accumulating evidence that these new anticoagulants are also effective and safe for treatment of venous thromboembolism. OBJECTIVES: The objective of this review was to determine the effect of fixed-dose, subcutaneous low molecular weight heparins compared with adjusted-dose, intravenous or subcutaneous, unfractionated heparin for initial treatment of acute deep venous thrombosis or pulmonary embolism. SEARCH STRATEGY: Trials were identified from the Cochrane Peripheral Vascular Diseases Group trials register and LILACS. The reviewers contacted colleagues and representatives of pharmaceutical companies for additional information about trials. SELECTION CRITERIA: Randomised trials comparing fixed-dose, subcutaneous low molecular weight heparin with adjusted-dose, intravenous or subcutaneous, unfractionated heparin in patients with venous thromboembolism. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trials for inclusion and quality, and extracted data independently. MAIN RESULTS: Fourteen studies with a total of 4754 patients were included. By the end of follow up in ten trials, thrombotic complications occurred in 86 (4.3%) of the 1998 patients treated with low molecular weight heparin, compared with 113 (5.6%) of the 2021 patients treated with unfractionated heparin (odds ratio 0.76, 95% confidence interval 0.57 to 1.01). In eight trials a reduction in thrombus size was shown by 60% treated with low molecular weight heparin and 54% treated with unfractionated heparin (odds ratio 0.77, 95% confidence interval 0.61 to 0.97). At the end of the initial treatment period, in all 14 of the trials, major haemorrhages occurred in 30 (1.3%) of the 2353 patients treated with low molecular weight heparin, compared with 51 (2.1%) of the 2401 patients treated with unfractionated heparin (odds ratio 0.60, 95% confidence interval 0.39 to 0.93). By the end of follow up in 11 trials, 135 (6.4%) of the 2108 patients treated with low molecular weight heparin had died, compared with 172 (8.0%) of the 2137 patients treated with unfractionated heparin (odds ratio 0.78, 95% confidence interval 0.62 to 0.99). Five studies with a total of 1636 patients examined proximal (above the knee) thrombosis; 814 treated with low molecular weight heparin and 822 with unfractionated heparin. A sub-analysis of these trials showed statistically significant reductions favouring the action of low molecular weight heparin in three areas: thrombotic complications; major haemorrhages; and overall mortality. By the end of follow up 39 (4. 8%) patients treated with low molecular weight heparin had thrombotic complications, compared with 64 (7.8%) treated with unfractionated heparin (odds ratio 0.60, 95% confidence interval 0. 40 to 0.89). Major haemorrhages occurred in 8 (1.0%) treated with low molecular weight heparin, compared with 68 (8.3%) treated with unfractionated heparin (odds ratio 0.44, 95% confidence interval 0. 21 to 0.95). By the end of follow up, 44 (5.4%) treated with low molecular weight heparin had died, compared with 68 (8.3%) treated with unfractionated heparin (odds ratio 0.64, 95% confidence interval 0.43 to 0.93). REVIEWER'S CONCLUSIONS: Low molecular weight heparin is at least as effective as unfractionated heparin in preventing recurrent venous thromboembolism, and significantly reduces the occurrence of major haemorrhage during initial treatment and overall mortality at the end of follow-up. It can be adopted safely as the standard therapy for deep venous thrombosis, and studies comparing individual low molecular weight heparins are merited.

The nuclear transcription factor NF-kappaB mediates interleukin-1beta-induced expression of cyclooxygenase-2 in human myometrial cells.

OBJECTIVE: Up-regulation of prostaglandin production by gestational tissues in the setting of intrauterine infection has been implicated as an important contributor to preterm labor and parturition. In this study we investigated the possible role of the nuclear transcription factor NF-kappaB in interleukin-1 signaling, leading to the expression of cyclooxygenase 2 and prostaglandin production in human myometrial cell cultures. STUDY DESIGN: Human myometrial smooth muscle cells from an immortalized line were used as a model system between passages 20 and 35. Growth-arrested cell cultures were stimulated with human recombinant interleukin 1, and the activation of NF-kappaB was assessed by the degradation of the inhibitory protein IkappaB-alpha (Western analysis), as well as by nuclear binding of NF-kappaB by using an electrophoretic mobility shift assay. The abundance of cyclooxygenase-2 messenger ribonucleic acid and protein was measured by Northern and Western analyses, whereas prostaglandin (prostaglandin I(2 ) and prostaglandin E(2 )) production was determined by specific radioimmunoassays. RESULTS: Within 15 minutes of stimulation with interleukin 1, 90% of IkappaB-alpha was degraded. This was temporally associated with nuclear translocation and binding of NF-kappaB. Within 30 minutes, cyclooxygenase 2 messenger ribonucleic acid appeared, with steady-state levels increasing up to 4 hours. This was followed by an up to 80-fold increase in cyclooxygenase 2 protein and a corresponding time-dependent increase in prostaglandin production. When IkappaB-alpha degradation was blocked with calpain I inhibitor, NF-kappaB translocation, cyclooxygenase 2 messenger ribonucleic acid and protein expression, and prostaglandin synthesis were also inhibited. CONCLUSION: Stimulation of human myometrial cells with interleukin 1 leads to rapid activation of the transcription factor NF-kappaB, which is functionally linked to the expression of cyclooxygenase 2 messenger ribonucleic acid, protein, and prostaglandin synthesis.

Replacing inpatient care by outpatient care in the treatment of deep venous thrombosis--an economic evaluation. TASMAN Study Group.

Two clinical trials in patients with acute deep venous thrombosis have indicated that the outpatient management with fixed-dose, subcutaneous low-molecular-weight heparin is at least as effective and safe as inpatient treatment with unfractionated intravenous heparin with respect to recurrent venous thromboembolism and major bleeding. We performed an economic evaluation alongside one of these trials to assess the cost consequences of the outpatient management strategy. Data were collected through case record forms, complemented by a prospective questionnaire in 78 consecutive patients, interviews with health care providers, and hospital data bases. Our study demonstrated that seventy-five percent of patients allocated to low-molecular-weight heparin received treatment either entirely at home or after a brief hospital stay. Fifteen percent of these patients required professional domiciliary care. Within-centre comparisons of resource utilisation in terms of natural units showed that outpatient management with low-molecular-weight heparin reduced the average number of hospital days in the initial treatment period in nine centres by 59 percent (95% CI: 43 to 71 percent) accompanied by a limited increase in outpatient and professional domiciliary care. The average reduction in hospital days at the end of follow up was 40 percent (95% CI: 25 to 54 percent). A cost-minimisation analysis, focusing on resource utilisation directly related to the treatment of deep venous thrombosis and associated costs in one centre demonstrated a cost reduction of 64 percent (95% CI: 56 to 72 percent) with the outpatient management with low-molecular-weight heparin. These data suggest that outpatient management of patients with proximal venous thrombosis using low-molecular-weight heparin reduces resource utilisation and total treatment cost. Implementation should be preceded by a cautious evaluation of a potential cost shifting and organisational prerequisites.