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We present an infant with ETV6-NTRK3 fusion-positive congenital-infantile-fibrosarcoma (CIFS) and very delayed response to conventional chemotherapy, avoiding TRK-inhibition. Although CIFS is rare, it represents one of the commonest non-rhabdomyosarcoma soft-tissue-sarcomas in infancy and whilst potentially highly-aggressive locally, they infrequently metastasize (1-13%) and carry favorable overall-survival[1]. Hallmark ETV6-NTRK fusions are present in 87% of CIFS[1], as well as in congenital-mesoblastic-nephroma[2] and leukemia[3]. The European-pediatric-Soft-tissue-sarcoma-Study-Group (EpSSG) developed therapeutic recommendations for CIFS according to resectability at initial presentation[1]. Complete macroscopic resection is first-line treatment and where not possible, systemic treatment with Vincristine/Actinomycin (VA) chemotherapy is standard[1,4], with good rates of response using RECIST criteria[5] and survival[1]. Interestingly, spontaneous regression of CIFS has also been reported[6,7], possibly related to the high apoptotic and low proliferative index in infantile tumors[8].

Blood cells are organized as a hierarchy with hematopoietic stem cells (HSCs) at the root. The advent of genomic technologies has opened the way for global characterization of the molecular landscape of HSCs and their progeny, both in mouse and human models, at the genetic, transcriptomic, epigenetic, and proteomics levels. Here, we outline our current understanding of the molecular programs that govern human HSCs and how dynamic changes occurring during HSC differentiation are necessary for well-regulated blood formation under homeostasis and upon injury. A large body of evidence is accumulating on how the programs of normal hematopoiesis are modified in acute myeloid leukemia, an aggressive adult malignancy driven by leukemic stem cells. We summarize these findings and their clinical implications.

Xanthoma disseminatum (XD) is a rare, benign, non-Langerhans cell histiocytosis characterized by disseminated xanthomatous lesions with a predilection for the face, flexures, and mucosae. Approximately 100 cases have been reported in the literature. We report XD in an 8-year-old boy with symmetric synovitis and arthritis involving the wrists and knees. This case is interesting in view of the association between arthritis and synovitis and XD, which to our knowledge has not been reported in the literature. This case has to be differentiated from multicentric histiocytosis, another non-Langerhans cell histiocytosis, in which joint involvement is common.

Blood cells are organized as a hierarchy with hematopoietic stem cells (HSCs) at the root. The advent of genomic technologies has opened the way for global characterization of the molecular landscape of HSCs and their progeny, both in mouse and human models, at the genetic, transcriptomic, epigenetic, and proteomics levels. Here, we outline our current understanding of the molecular programs that govern human HSCs and how dynamic changes occurring during HSC differentiation are necessary for well-regulated blood formation under homeostasis and upon injury. A large body of evidence is accumulating on how the programs of normal hematopoiesis are modified in acute myeloid leukemia, an aggressive adult malignancy driven by leukemic stem cells. We summarize these findings and their clinical implications.

Background: NHS Library Services are utilised by NHS staff and junior trainees to locate scientific papers that provide them with the evidence base required for modern medical practice. The cost of accessing articles can be considerable particularly for junior trainees. Objectives: This survey looks at variations in cost of journal article loans and investigates access to particular orthopaedic journals across the country. Methods: A national survey of UK Health Libraries was performed. Access to and costs of journals and interlibrary loan services were assessed. Availability of five wide-reaching orthopaedic journals was investigated. Results: Seven hundred and ten libraries were identified. One hundred and ten libraries completed the questionnaire (16.7%). Of these, 96.2% reported free access to scientific journals for users. 99.1% of libraries used interlibrary loan services with 38.2% passing costs on to the user at an average of £2.99 per article. 72.7% of libraries supported orthopaedic services. Journal of Bone and Joint Surgery (British) had greatest onsite availability. Conclusions: The study demonstrates fluctuations in cost of access to interlibrary loan services and variation in access to important orthopaedic journals. It provides a reflection of current policy of charging for the acquisition of medical evidence by libraries in the UK.

The purpose of this study is to determine whether, in low-risk febrile neutropenic paediatric populations, oral antibiotics are as effective as intravenous antibiotics in obtaining resolution of the febrile neutropenic episode. A comprehensive literature search of MEDLINE, EMBASE and CENTRAL identified prospective, randomised controlled trials comparing oral antibiotics with intravenous antibiotics in the treatment of febrile neutropenic episodes in low-risk paediatric oncology patients. Outcomes assessed were mortality, rate of treatment failure, length of the febrile neutropenic episode and adverse events. The random effects model was used to calculate risk ratios (RRs) for dichotomous data and mean difference with standard deviation for continuous data. Seven trials were included in the overall analysis, which included 934 episodes of febrile neutropenia in 676 patients aged between 9 months and 20 years. The overall treatment failure rates were not significantly different between oral and intravenous antibiotics (RR: 1.02, 95% confidence interval 0.78-1.32, P= 0.91). In carefully selected low-risk febrile neutropenic children, empiric treatment with oral antibiotics is a safe and effective alternative to intravenous antibiotics as they lower the cost of treatment as well as psychosocial burden on these children and their families.

Although age-related changes in cancellous bone structure in human are relatively well characterized, few studies have addressed changes in cortical bone. We have investigated age-related changes in iliac crest bone biopsy specimens from 54 normal subjects, 23 men and 31 women, aged 18–90 years. A significant decrease in cortical width and area was seen (P = 0.002 and

Summary The Standardbred trotter must pull a considerable load when racing and, consequently, draught loading is a common method of training in the Standardbred and the effects of loading and fatigue due to loading on the locomotor pattern was the purpose of this investigation. Four mature healthy Standardbred horses trotted with and without a horizontal-pulling loading of 34 kg until the horses were no longer willing to keep pace with the treadmill despite encouragement. Heart rate was monitored every min using a bipolar electrocardiogram. The kinematics for 5 consecutive strides were filmed. Horses exercised on the treadmill for 7–10 mins. The mean heart rate was 206 beats/min at the end of the exercise. Due to draught loading, the horses reduced significantly the time of the stance phase in both the fore- and hindlimb. Three of the 4 horses reduced their stride lengths as the result of increased loading. The general movement pattern of the horses remained similar. More dramatic changes in the movement pattern were observed because of fatigue. The limbs of the horse were significantly more compressed as the result of greater joint excursion during the stance phase. Furthermore, the length of stride was significantly increased as the result of fatigue. The results show that both loading and fatigue change the locomotor pattern of the Standardbred trotter. Although the horizontal loading was. considerable, the horse maintained similar joint movement with increases in stride frequency. During fatigue the horse seems to be unable to maintain stride frequency, probably due to a compromised power capacity of the muscles. The increase in joint excursion due to fatigue may have an important influence on certain types of injury to the locomotor system of the racehorse.

Wolbachia is an intracellular endosymbiont of Brugia malayi parasite whose presence is essential for the survival of the parasite. Treatment of B. malayi-infected jirds with tetracycline eliminates Wolbachia, which affects parasite survival and fitness. In the present study we have tried to identify parasite proteins that are affected when Wolbachia is targeted by tetracycline. For this Wolbachia depleted parasites (B. malayi) were obtained by tetracycline treatment of infected Mongolian jirds (Meriones unguiculatus) and their protein profile after 2-DE separation was compared with that of untreated parasites harboring Wolbachia. Approximately 100 protein spots could be visualized followed by CBB staining of 2-D gel and included for comparative analysis. Of these, 54 showed differential expressions, while two new protein spots emerged (of 90.3 and 64.4 kDa). These proteins were subjected to further analysis by MALDI-TOF for their identification using Brugia coding sequence database composed of both genomic and EST sequences. Our study unravels two crucial findings: (i) the parasite or Wolbachia proteins, which disappeared/down-regulated appear be essential for parasite survival and may be used as drug targets and (ii) tetracycline treatment interferes with the regulatory machinery vital for parasites cellular integrity and defense and thus could possibly be a molecular mechanism for the killing of filarial parasite. This is the first proteomic study substantiating the wolbachial genome integrity with its nematode host and providing functional genomic data of human lymphatic filarial parasite B. malayi.

Use of activation frequency as a measure of remodeling rate assumes co-regulation of remodeling rate and remodeling balance. In iliac crest biopsy specimens from 57 healthy subjects 19–80 yr of age, no correlations were shown between these variables, an observation that challenges the use of activation frequency as an estimate of remodeling rate. Introduction: The histomorphometric derivation of activation frequency assumes that the remodeling rate is dependent on the duration of the remodeling cycle and the amount of bone formed in individual remodeling units. This implies that remodeling balance and remodeling rate are co-regulated. We tested this assumption in normal human adult cancellous bone. Materials and Methods: Relationships between indices of bone formation at the basic multicellular unit (BMU) level (wall width and mineral apposition rate) and indices of remodeling rate (mineralizing perimeter and osteoid perimeter) were examined in iliac crest biopsies obtained from 57 healthy adults (24 men) 19–80 yr of age. Results: Univariate analysis revealed a negative correlation between wall width and osteoid perimeter (r = −0.38; p = 0.0004), but there was no correlation between wall width and mineralizing perimeter or between mineral apposition rate and either mineralizing or osteoid perimeter. After adjustment for age and sex, the association between wall width and osteoid perimeter was no longer observed. Both wall width and mineral apposition rate correlated negatively with age (r = −0.75, p < 0.0001 and r = −0.27, p = 0.05, respectively). Conclusions: Our results indicate that remodeling balance and remodeling rate are not co-regulated in adult human bone. Activation frequency, as currently derived from histomorphometric variables, may therefore be unreliable as an indicator of remodeling rate.

The opioid neuropeptide haemorphin-7 was measured, by immunoreactivity, in Standardbred horses during low-speed (7 m/s) and high-speed (10 m/s) endurance exercises, lasting 49-58 and 12-16 min respectively. In parallel, heart rate, muscle temperature and plasma lactate concentrations were measured. The profile of the low-speed exercise showed significantly increased heart rate after 10 min [154 beats per minute (bpm)]. After the exercise, muscle temperature (42.1 degrees C) and plasma lactate (4.8 mmol/l) were significantly increased. The profile of the high-speed exercise was comparatively characterized by a higher increase of heart rate after 5 min (194 bpm) and higher increases of muscle temperature (43.2 degrees C) and lactate levels (15.8 mmol/l) after the exercise. The horses were probably exhausted by glycogen depletion in the low-speed exercise and by muscle pH decrease in the high-speed exercise. Haemorphin-7 increased significantly during the high-speed exercise (274.8 fmol/ml) but not during low speed (108.3 fmol/ml), coincident with the results of lactate. These results suggest that plasma haemorphin-7 is measurable in the horse by immunoreactivity, and that intense exercise stimulates release of this opioid. Such endogenous opioids are most likely involved in regulatory functions associated with pain, physical effort, inflammation, and blood pressure variation in horses, as have been established in other species.

This article assesses some of the major premises of neo-institutionalist explanations of decentralization policy and practices, but focuses especially on the relationship between decentralization and democracy, in the context of the recent and ongoing Indonesian experience with decentralization. In the last two decades 'decentralization' has become, along with 'civil society', 'social capital' and 'good governance', an integral part of the contemporary neo-institutionalist lexicon, especially that part which is intended to draw greater attention to 'social' development. The concern of this article is to demystify how, as a policy objective, decentralization has come to embody a barely acknowledged political, not just theoretical, agenda. It also suggests alternative ways of understanding why decentralization has often failed to achieve its stated aims in terms of promoting democracy, 'good governance', and the like. What is offered is an understanding of decentralization processes that more fully incorporates the factors of power, struggle and interests, which tend to be overlooked by neo-institutionalist perspectives. The current Indonesian experience clearly illustrates the way in which institutions can be hijacked by a wide range of interests that may sideline those that champion the worldview of 'technocratic rationality'. © Institute of Social Studies 2004.

Vertebral fractures (VFX) are caused by low bone mass and microstructural deterioration of bone tissue. The latter is not well defined. We investigated bone structure in transiliac biopsy specimens from 88 volunteers. Biopsy specimens were obtained at baseline in the Multiple Outcomes of Raloxifene Evaluation trail, a prospective study in osteoporotic (BMD < or = -2.5 T score) postmenopausal women without or with VFX on standardized lateral spinal radiographs. Bone biopsy specimens were embedded in methylmethacrylate (MMA). Histomorphometry was done in 8 microns (U.S.A.) or 5 microns (Europe) Goldner stained sections. Vertebral fracture status (yes/no) was the outcome variable in logistic regression models adjusted for age and biopsy specimen origin (U.S.A. vs. Europe). Patients with and without VFX (26/62) were similar regarding age (69.2 +/- 5.2 years vs. 67.3 +/- 6.7 years), bone volume (BV/TV; 17.7 +/- 4.7% vs. 19.0 +/- 5.8%), and bone surface (BS/TV; 2.7 +/- 0.6 mm2/mm3 vs. 2.8 +/- 0.6 mm2/mm3). A lower cortical thickness (C.Th; 652 +/- 267 microns vs. 822 +/- 325 microns), total strut length (TSL; 826 +/- 226 microns/mm2 vs. 922 +/- 256 microns/mm2), node-to-loop (Nd-Lp) strut length (10.1 +/- 10.3% vs. 15.0 +/- 13.6%), together with a higher node-to-terminus (Nd-Tm) strut length (45.6 +/- 9.7% vs. 39.1 +/- 9.3%) were each associated with prevalent VFX (0.01 < p < 0.10). Differences in BV/TV did not explain these associations. In conclusion, cortical thinning and disruption of trabecular lattice are possible pathogenic mechanisms in patients with VFX.

Summary The aim was to investigate metabolic response in muscle during submaximal treadmill exercise to fatigue, with a special emphasis on adenine nucleotide degradation products such as inosine monophosphate (IMP) in muscle and hypoxanthine, xanthine and uric acid in plasma. Five Standardbred trotters performed treadmill exercise on 2 occasions, once at 7 m/s and once at 10 m/s. Venous blood samples were taken at rest, during exercise and at the end of exercise. Muscle biopsies were taken before and after exercise and muscle temperature was measured before and after exercise. Running time differed among horses and was 48–58 min at 7 m/s and 10–15.5 min at 10 m/s. Both lactate and uric acid concentrations in plasma showed a gradual increase during exercise at both 7 and 10 m/s. At the end of exercise, values for uric acid were higher and values for lactate lower at 7 m/s compared with at 10 m/s. No marked changes were seen in plasma concentrations of hypoxanthine or xanthine with exercise. Muscle glycogen decreased after exercise at both 7 and 10 m/s with a marked depletion seen in some fibres. Muscle lactate concentrations increased after exercise at both 7 m/s and at 10 m/s. No significant changes were seen in adenosine triphosphate (ATP), ADP and AMP concentrations, whereas IMP concentrations increased after exercise at both 7 m/s and at 10 m/s. The results of this study indicate that AMP deamination occurs with submaximal exercise and that development of fatigue may be related to adenine nucleotide degradation in muscle.

Organ transplantation is associated with increased bone loss and high fracture risk, but the pathophysiological mechanisms responsible have not been established. We have performed a histomorphometric analysis of bone remodeling before and 3 months after liver transplantation in 21 patients (14 male, 7 female) aged 38-68 years with chronic liver disease. Eight-micrometer undecalcified sections of trans-iliac biopsies were assessed using image analysis. Preoperatively, bone turnover was low with a tendency toward reduced wall width and erosion depth. The bone formation rate increased from 0.021 +/- 0.016 (mean +/- SD) to 0.067 +/- 0.055 microm2/microm/day after transplantation (p0.0002) and activation frequency from 0.24 +/- 0.21/year-1 to 0.81 +/- 0. 67/year-1 (p0.0001). No significant change was observed in wall width, but there was a trend toward an increase in indices of resorption cavity size. There was a small increase in osteoid seam width postoperatively (p0.02) and decrease in mineralization lag time (p0.001). No significant changes in indices of cancellous bone structure were observed in the postoperative biopsies. These results demonstrate a highly significant and quantitatively large increase in bone turnover in the first 3 months after liver transplantation. Although no significant disruption of cancellous bone structure was demonstrated during the time course of the study, the observed changes in bone remodeling predispose to trabecular penetration and may thus result in long-term adverse effects on bone strength.

The responses in heart rate, plasma lactate and rectal temperature of standardbred trotters to draught loaded interval exercise on a treadmill and a race track were studied. The horses were exercised with incrementally increasing trotting speeds for two-minute intervals with draught loads of 10, 20 and 30 kilopond (kp) in three different tests. Each trotting interval was followed by two-minute periods at a walk without a draught load. Measurements of heart rate and plasma lactate were made at the end of each interval and the rectal temperature was taken at the end of the exercise. The heart rate and plasma lactate levels were significantly lower on the treadmill than on the track in the tests with 10 kp, but no significant differences were found between the treadmill and track exercise tests with the heavier draught resistances. No differences were observed in rectal temperature between treadmill and track conditions. From these findings it was concluded that the workload was significantly greater on the race track compared to the treadmill when the draught resistance was low (10 kp). Although the workload increased on both the race track and the treadmill as draught resistance increased, at the heavier draught resistances track exercise was no longer more demanding than exercise on the treadmill.

In this study, 4 Standardbred geldings were exercised at 20 and 35 degrees C. The exercise test (ET) consisted of 2 exercise bouts separated by 2 h of rest in their boxes. Blood samples were taken before, during and after the second exercise bout and muscle (m. gluteus medius) biopsies were taken before the first exercise bout and after an intensive trot over 2600 m in the second exercise bout. The blood samples were analysed for plasma potassium and total plasma protein concentration (TPP) and the muscle fibres were analysed for elemental composition by x-ray microanalysis. The intracellular content was as follows: sodium (Na) = 40 +/- 7; magnesium (Mg) = 32 +/- 4; phosphorus (P) = 282 +/- 15; sulphur (S) = 222 +/- 13; chloride (Cl) = 119 +/- 31; potassium (K) = 304 +/- 21 and calcium (Ca) = 8 +/- 2 mmol/kg dry weight under resting conditions. Intracellular potassium content increased after exercise compared to resting values. There was a good correlation between exercise intensity, plasma potassium concentration and shifts in plasma volume, indicated by alterations in TPP. This probably reflects the very fast shift of potassium and fluid between muscle and plasma. Plasma potassium concentrations decreased below resting values post exercise. The higher dehydration degree and potassium sweat loss after exercise at 35 degrees C was not reflected in lower muscular potassium content, but by a lower plasma potassium/total plasma protein ratio after exercise, indicating less circulating potassium.

Five Standardbred trotters performed treadmill exercise with incrementally increasing trotting velocities for 2 min intervals in three different tests until fatigue. Each test was performed with draught loads of either 10, 20 or 30 kilopond (kp). Each trotting interval was followed by 2 min periods at a walk without draught load. Recordings were made of heart rate (HR), respiratory rate (RR), plasma lactate (PLA) and stride frequency (SF) at the end of each trotting interval. The HR increased to average values of 191 +/- 10,203 +/- 10 and 214 +/- 7 bpm and PLA increased to 3.8 +/- 0.7, 7.3 +/- 3.8 and 10.8 +/- 6.4 mmol/l at 9 m/s in the three tests, respectively. The HR response to exercise was significantly higher with increasing draught loads, and PLA was significantly higher with 30 kp compared to 10 kp draught resistance. The lowest respiratory rate was seen in the test with 30 kp loading. Peak oxygen uptake (VO2peak) was measured in a separate test on a sloped treadmill with increasing velocities without draught load and averaged 70.4 +/- 9.11/min. Muscle biopsies were taken from the gluteus muscle. Individual variations were seen in VO2peak, muscle fibre composition and HR and PLA responses to exercise. In conclusion, at a certain velocity a small increase in draught resistance from 10 to 30 kp significantly increases both the HR and PLA responses. At comparable work intensities the horses differed in circulatory and metabolic responses to exercise.

Novel dideoxy pyrimidine nucleosides possessing a 4′-carboxyl function are synthesized and recognized to be inhibitors of HBV and / or HCV replication.