Activating internal tandem duplication (ITD) insertions in the juxtamembrane domain of the FLT3 tyrosine kinase are found in about one fourth of patients with acute myeloid leukemia and have been ...shown to be an independent negative prognostic factor for survival. We show that sorafenib (BAY 43-9006, Nexavar) potently inhibits FLT3 enzymatic and signaling activities. In HEK293 cells stably transfected with FLT3-WT or FLT3-ITD, sorafenib blocked basal and ligand dependent FLT3-mediated tyrosine autophosphorylation as well as extracellular signal-regulated kinase1/2 and Stat5 phosphorylation. In leukemia cell lines MV4-11 and EOL-1, sorafenib treatment resulted in decreased cell proliferation and inhibition of FLT3 signaling. The growth of the FLT3-independent RS4-11 cell line was only weakly inhibited by sorafenib. Cell cycle arrest and induction of apoptosis were observed upon treatment with sorafenib in MV4-11 and EOL-1 cells. The antitumor efficacy of sorafenib was evaluated against the MV4-11 leukemia grown subcutaneously in NCr nu/nu mice. Doses of 3 and 10 mg/kg administered orally for 14 days resulted in six and nine out of 10 animals with complete responses, respectively. The demonstration that sorafenib exhibits potent target inhibition and efficacy in FLT3-driven models suggests that this compound may have a therapeutic benefit for patients with FLT3-driven leukemias.
In four composting experiments, survival of avian influenza (AI) and Newcastle disease (ND) viruses was assessed by virus isolation in embryonated chicken eggs (ECEs) and by real-time reverse ...transcriptase–polymerase chain reaction. Specimens contained in nylon mesh bags consisted of 20-g samples of chicken manure, used litter, or feed that had been inoculated with allantoic fluid containing an AI virus (H6N2, Expt. 1) or an ND vaccine virus (Expt. 2). Other specimens consisted of 20-g samples of infected ECEs that had been homogenized and mixed with corn silage. As a control, allantoic fluid diluted in phosphate-buffered saline was contained in sealed vials. Except for the feed, in which the AI virus was inactivated soon after the specimen was inoculated, on day 0 the specimens buried in compost or placed outside at ambient temperatures contained at least 5.0 log10 of virus and 7.7 log10 of viral RNA. By day 7, temperatures in compost ranged from 50 C to 65 C, and viruses had been killed in all specimens in bags. In comparison, viruses in sealed vials remained viable to day 10. Viral RNA in mesh-bag specimens had been degraded to nondetectable levels by day 10, but it was still detected in sealed vials on day 21. In specimens that were held at ambient temperatures (13 C–28 C), the viruses in mesh-bag specimens were inactivated by day 21, but their RNA was still detected. In comparison, the viruses in sealed vials survived to day 21. In Expts. 3 and 4, viruses were inactivated in carcass specimens and in whole ECEs during composting. In an in vitro experiment, the time required for a 1-log10 reduction of viruses was significantly shorter (P < 0.05) in water extracts from compost than in phosphate buffers at temperatures of 25 C to 45 C. This study provided evidence that microbial activity during composting contributed to the rapid killing of AI and ND viruses and to the degradation of their viral RNA.
Objectives
Surgical drainage is the traditional mainstay of treatment of paediatric deep neck space infection (DNSI), but recently non‐operative management in selected cases has been advocated. We ...sought to identify any characteristics predictive of requirement for surgical intervention.
Design
Retrospective cohort study using receiver operating characteristics analyses.
Setting
Tertiary referral paediatric hospital.
Participants
Children (≤16 years) with a radiologically confirmed diagnosis of retro‐ or parapharyngeal abscess over a ten‐year period.
Main outcome measures
Predictive value of clinical and radiological variables in determining the requirement for surgical intervention. Length of hospital stay (LoS) was also examined.
Results
Ninety‐three children were studied, 15 (16.1%) of whom underwent immediate surgery, 42 (45.2%) of whom underwent delayed surgery following an initial period of conservative management, and 36 (38.7%) of whom were managed conservatively. Age, WCC and CRP were not predictive of the need for surgical drainage. Radiological abscess diameter, however, was predictive of requirement surgery (AUC = 0.85 95% CI ± 0.09 P = 0.02), with a cut‐off value of 2.5 cm determined assuming equal weight to sensitivity and specificity. All DNSIs were successfully treated with no adverse outcomes, and there was no significant difference in LoS between groups. In those managed surgically, outcome and LoS did not depend on yield of pus.
Conclusions
Selected paediatric DNSIs can be successfully managed conservatively, with abscess diameter >2.5 cm a significant predictor of need for surgical intervention. Any benefit of surgery does not appear to depend on intra‐operative yield of pus.
Abstract Less than 20 years after Herrick described the first case, the cold was proposed as having a role in precipitating pain in sickle cell disease. Numerous publications focus on weather ...changes, in particular exposure to the cold, and their association with vaso-occlusive (painful) episodes. Whereas several theories have been proposed to explain the association, a plausible hypothesis based on our current understanding of the pathophysiology of pain has not been offered. We hypothesize that the pain evoked by these weather changes are allodyinic (pain with stimulus not typically painful) and hyperalgesic (heightened pain with painful stimulus) responses due to the presence of neuropathic pain. This hypothesis represents a paradigm shift in understanding, as well as explaining at least some of the pain experience in sickle cell disease, and should be the impetus to further determine the characteristics of those patients who develop allodynia and hyperalgesia to cold weather. Whereas some researchers have suggested that those with sickle cell disease may have neuropathic pain, including a report from our own ongoing study 1 , it has not been well accepted nor has it been applied in understanding pain associated with sickle cell disease. The conceptual shift and new understanding is important to develop preventive strategies, apply pain therapies new to the sickle cell population, and view pain in sickle cell disease in the context of a chronic disease.
In this paper, we consider a number of practical and theoretical aspects of the Wilkie asset model, many of which apply to any similar model used for simulation over time. We discuss the experience ...of the Wilkie model since 2009. We then discuss the variables that can form the working set, the input set and the output set, all of which may be different. There are different ways of simulating, either in a linear parallel structure or in a branching tree structure. We then discuss the initial conditions required, which may be market conditions at some date, or may be “neutral” initial conditions, which may be defined in different ways. One method of generating initial conditions would be to simulate them randomly, from their own long-term distribution, and we show how to calculate the means, variances and covariances of these. What we call “neutralising parameters” may have a role, and we discuss how these may be found. Finally, we suggest using additional information in the first periods of the simulation to adjust the formulae or parameters for a limited “select period”.
Previous studies have reported that intestinal populations of Clostridium perfringens, the causative agent of necrotic enteritis (NE), are correlated with diets high in glycine. To establish a direct ...causative link, 3 trials were conducted to examine the effect of dietary glycine levels on gut populations of C. perfringens, alpha-toxin production, and NE lesion scores in broiler chickens. In trials 1 and 2, 12 groups of 4 birds were fed 4 different ideal protein-balanced diets formulated to contain 0.75, 1.58, 3.04, or 4.21% glycine from d 14 to 28 of age. In trial 3, 24 groups of 4 birds were given 6 different ideal protein-balanced diets formulated to contain 0.50, 0.75, 1.00, 1.50, 2.00, or 4.00% glycine. All birds were orally challenged with a broth culture of C. perfringens type A on d 1 and between d 14 and 21 of age and killed on d 28. The majority of birds showed clinical signs of NE with 4.16 to 8.33% mortality in the 3 trials. The highest mortality and intestinal lesion scores were observed in chickens receiving 3.04% glycine in trials 1 and 2, and 4.00% glycine in trial 3. Clostridium perfringens populations in the cecum varied quadratically with increasing dietary glycine, with the maximal response seen at 3.30, 3.89, and 3.51% dietary glycine in trials 1, 2, and 3, respectively. Numbers of lactobacilli in cecum declined significantly (P < 0.05) with increasing levels of glycine. The results suggest that dietary glycine level has a significant effect on C. perfringens and lactobacilli populations and may be a predisposing factor for NE in broiler chickens.
Sore throats and tonsillitis represent a considerable health burden as well as a significant source of expenditure for the National Health Service (NHS). As part of the recent NHS savings drive, the ...introduction of 'procedures of low clinical effectiveness' (PoLCE) lists has reinforced a large reduction in the number of tonsillectomies performed. We carried out a cross-sectional study of trends in emergency sore throat admissions in the context of the number of tonsillectomies performed.
Hospital Episode Statistics (HES) data were extracted. Office for National Statistics data were also used.
Between 1991 and 2011, the overall tonsillectomy rate fell by 44%. In the same time, the admission rate for tonsillitis rose by 310% (Pearson's r=-0.67, p=0.01). The peritonsillar abscess admission rate rose by 31% (r=-0.79, p<0.01). Between 1996 and 2011, the overall tonsillectomy rate fell by 41% and the retro and parapharyngeal abscess admission rate rose by 39% (r=-0.55, p=0.026). There was a 14% overall increase in tonsillectomy and sore throat associated bed days. This was despite the large fall in tonsillectomy numbers and the reduction in length of hospital stay.
Efforts to reduce the tonsillectomy rate are correlated with a significant rise in emergency admissions. The rise in the retro and parapharyngeal abscess rate is perhaps most alarming given the very high mortality of these conditions. Bed day data suggest that no net saving has been made despite the new measures.
Objectives
Management of laryngopharyngeal reflux (LPR) typically comprises alginates and proton pump inhibitors (PPIs) alone or in combination, yet evidence to support any particular treatment ...regimen is lacking. We sought to evaluate the efficacy of Gaviscon® Advance alone versus co-prescription with a PPI in treating LPR.
Methods
One hundred consecutive LPR patients with a reflux symptom index (RSI) score > 10 attending our joint voice clinic (JVC) were studied prospectively. All were treated with Gaviscon® Advance four times daily. If patients had been started on a PPI prior to their JVC attendance, this was optimised to a twice-daily dosing regimen and continued. RSI scores were recorded at first attendance and 3 months post-treatment via postal questionnaire. Scores were analysed using
t
tests and Levene’s test for equality of variances.
Results
Follow-up RSI scores were returned by 72 patients, 39 of whom were treated with Gaviscon® Advance only (group A) and 33 with Gaviscon® Advance + PPI (group B). Mean pre-treatment RSI scores were similar between groups group A: 19.2, 95% confidence interval (CI) ± 2.4; group B: 21.3, 95% CI ± 3.2 (
p
= 0.65). No significant differences were observed with respect to 3-month post-treatment RSI scores group A: 9.9, 95% CI ± 2.8; group B: 12.6, 95% CI ± 4.2 (
p
= 0.82) and change in RSI scores group A: 9.3, 95% CI ± 3.0; group B: 8.7, 95% CI ± 2.9
p
= 0.75).
Conclusions
Gaviscon® Advance alone is effective in treating symptoms of LPR, while co-prescription with a high-dose PPI offers no additional benefit.
The development of exceptionally potent inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid), and anandamide ...(an endogenous ligand for cannabinoid receptors) is detailed. The inhibitors may serve as useful tools to clarify the role of endogenous oleamide and anandamide and may prove to be useful therapeutic agents for the treatment of sleep disorders or pain. The combination of several features--an optimal C12-C8 chain length, π -unsaturation introduction at the corresponding arachidonoyl Δ8,9/Δ11,12and oleoyl Δ9,10location, and an α -keto N4oxazolopyridine with incorporation of a second weakly basic nitrogen provided FAAH inhibitors with Kis that drop below 200 pM and are 102-103times more potent than the corresponding trifluoromethyl ketones.
Chronic intestinal pseudo-obstruction (CIPO) may be a primary or secondary phenomenon and is often multifactorial. Treatment is largely directed at improving colonic motility. The use of ...cholinesterase inhibitors such as pyridostigmine has been hypothesized to increase acetylcholine in the bowel, improving symptoms and transit times.
A systematic review of the use of pyridostigmine in CIPO was conducted using scientific and commercial search engines identifying scientific studies enrolling adult human subjects, published from 2000 to 2022 in the English language.
Four studies were identified including two randomized controlled trials (RCT) and two observational studies. The studies had heterogenous inclusion criteria, dosing regimens and reported outcomes. Two studies were identified as being at high risk of bias. All studies reported improved patient outcomes with use of pyridostigmine, and low rates (4.3%) of mild cholinergic side effects. No major side effects were reported.
The use of pyridostigmine in management of CIPO is biologically plausible due to its ability to increase colonic motility, and early studies on its role are uniformly suggestive of benefit with low side-effect profile. Four clinical studies have been conducted to date, with small sample sizes, heterogeneity and high risk of bias. Further high-quality studies are required to enable assessment of pyridostigmine's utility as an effective management strategy in CIPO.
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