The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice.

The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9 µg/mL (n = 3) at 0.25 h post-dose with an AUCinf of 3.67 µg h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31 µg/mL at 0.25 h post-dose with an AUCinf of 4.94 ± 2.93 µg h/mL and a half-life of 0.52 ± 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53 µg/mL were seen 0.25 h post-dose with a mean AUCinf of 2.10 ± 0.49 µg h/mL and a half-life of 0.51 ± 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may represent a model for assessing the biotransformation of such compounds in humans.

Alcohol dependence in the Naval Service.

Alcohol misuse is a significant occupational health issue in the United Kingdom Armed Forces. Dependence associated with alcohol misuse represents the severe end of the clinical and occupational consequences of sustained alcohol misuse. This article aims to explore the diagnosis, management and occupational considerations of alcohol dependence in the Naval Service environment.

Red Alert: diagnosis and management of the acute red eye.

The acute red eye represents a broad spectrum of disease encompassing benign self-limiting conditions to potentially vision-threatening ophthalmic or system disease. This article will review clinical principles essential for the diagnosis and treatment of red eye relevant to all Armed Forces primary care and emergency medicine practitioners.

The pharmacokinetics and metabolism of lumiracoxib in chimeric humanized and murinized FRG mice.

The pharmacokinetics and metabolism of lumiracoxib were studied, after administration of single 10mg/kg oral doses to chimeric liver-humanized and murinized FRG mice. In the chimeric humanized mice, lumiracoxib reached peak observed concentrations in the blood of 1.10±0.08µg/mL at 0.25-0.5h post-dose with an AUCinf of 1.74±0.52µgh/mL and an effective half-life for the drug of 1.42±0.72h (n=3). In the case of the murinized animals peak observed concentrations in the blood were determined as 1.15±0.08µg/mL at 0.25h post-dose with an AUCinf of 1.94±0.22µgh/mL and an effective half-life of 1.28±0.02h (n=3). Analysis of blood indicated only the presence of unchanged lumiracoxib. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles obtained in humanized mice were different compared to murinized animals with e.g., a higher proportion of the dose detected in the form of acyl glucuronide metabolites and much reduced amounts of taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57bl/6J mice and humans, revealed a greater though not complete match between chimeric humanized mice and humans, such that the liver-humanized FRG model may represent a useful approach to assessing the biotransformation of such compounds in humans.

Ultrasonographic assessment of the rate of solid-phase gastric emptying in dogs.

Twelve healthy dogs were used in an ultrasonographic assessment of the effect of the composition of a solid meal on the rate of gastric emptying. The dogs were fasted for nine hours before they were fed either a standard or a high energy density test meal, in a cross-over study design. The gastric antrum was visualised with a 6.5 MHz microconvex transducer, and the area inside the elliptical shape defined by the craniocaudal and ventrodorsal diameters of the stomach was measured. Antral images were acquired at regular intervals for six hours after the ingestion of the test meal. Three indices to describe the rate of gastric emptying were computed: the gastric half-emptying time (t1/2), the time to 50 per cent maximal antral area (t50%), and the time of maximal antral area (tmax). The values of t50% and t1/2 calculated for the high energy density meals were significantly longer than for the standard meals, but there was no significant difference between the tmax values.

Current concepts in the management of infections in bones and joints.

Significant changes have taken place in the epidemiology, microbiology and antibiotic therapy of bone and joint infections. Gram-negative bacilli have become an increasingly common cause, particularly in immunocompromised patients; anaerobes have been implicated in osteomyelitis associated with metallic foreign bodies; and there is increasing use of oral antibiotic regimens following an initial period of parenteral treatment. Gram-negative bacilli and anaerobes are found in polymicrobial non-haematogenous osteomyelitis (e.g. post-traumatic, post-surgical), but Staphylococcus aureus remains the most common cause of acute haematogenous osteomyelitis, with streptococci and Haemophilus influenzae responsible for most of the remainder. A precise microbiological diagnosis is essential. Diagnosis is based on Gram stain and culture of bone biopsies or aspirated pus, or on blood cultures. Specimens should be obtained before starting therapy. Any suspected primary foci of infection should be cultured. Parenteral antibiotics are given as soon as specimens are obtained, and continued for at least 3 weeks. The common causative organisms in septic arthritis are the same as in osteomyelitis, with the addition of Neisseria gonorrhoeae in young, sexually active adults. As in osteomyelitis, a precise microbiological diagnosis is of paramount importance, ideally by joint aspiration for cell count, Gram stain, biochemical analysis and culture, or by blood cultures. Optimum therapy is with antibiotics, repeated therapeutic aspirations, and resting the joint. Parenteral antibiotics should be started as soon as specimens are obtained and continued for 4 to 6 weeks. Gonococcal arthritis, however, can be treated successfully with 1 week of antibiotics. When treatment of either osteomyelitis or septic arthritis is continued with oral antibiotics, serum antibiotic concentrations or serum bactericidal levels are mandatory to ensure adequate absorption.

The effects of propranolol on hepatic encephalopathy in patients with cirrhosis and portal hypertension.

Beta adrenoreceptor blocking drugs have been used for the prevention of haemorrhage from oesophageal varices. However, it is possible that these agents, by virtue of their effects on hepatic blood flow, may impair liver function and precipitate hepatic encephalopathy. We have therefore studied the effect of the beta blocking drug propranolol on hepatic encephalopathy in patients with cirrhosis and portal hypertension. Twenty patients were randomly assigned to receive 4 weeks treatment with propranolol or an identical-looking placebo, the former given in a dose sufficient to reduce resting pulse rate by greater than or equal to 25%. Before and after treatment patients were assessed for the severity of liver disease and the presence of encephalopathy. EEG mean cycle frequency and fasting arterial ammonia concentrations were also measured, and in order to detect latent hepatic encephalopathy, each patient underwent a battery of psychometric tests. Patients were blinded as to their treatment, as were those assessing their responses. Neither propranolol nor placebo had any significant effect on the parameters measured. On propranolol median EEG mean cycle frequency fell from 9.08 ct s-1 (range 8.63-11.0 ct s-1) to 8.73 ct s-1 (range 8.27-11.44 ct s-1), and median fasting arterial ammonia concentration fell from 66 mumol litre-1 (range 40-329 mumol litre-1) to 49 mumol litre-1 (range 37-188 mumol litre-1). Psychometric test values, while initially abnormal and suggestive of latent hepatic encephalopathy in the majority of patients, did not change significantly during the study.

The clinical application of a urine albumin:creatinine ratio point-of-care device.

INTRODUCTION: Microalbuminuria is an accepted predictive marker for the early detection of renal disease and the identification of patients at high risk of developing complications of diabetes and hypertension. The Bayer Clinitek 50 is a urine chemistry point-of-care analyser for the semi-quantitative measurement of albumin and creatinine and calculation of albumin:creatinine ratio (ACR). METHOD: Urine samples were obtained from 252 consecutive patients attending a city center diabetic clinic, and from 40 patients on admission to the ICU. Albumin and creatinine measurements were carried out using the Clinitek 50 and by the central laboratory. RESULTS: The Clinitek 50 results agreed with the central laboratory results in 89% of the diabetic patient samples and 80% of the ICU patient samples. Excluding samples defined as normal by the Clinitek 50 (ACR<3.4 mg/mmol) would have resulted in an 80% reduction in samples sent to the lab for further quantification. The average length of stay in the group of ICU patients with normal ACR was significantly less than for those patients with an abnormal ACR (p<0.005). CONCLUSIONS: The Clinitek 50 provides useful, immediate clinical information regarding the microalbuminuria status for use in the diabetic clinic setting or as a potential immediate risk management tool in intensive care.

Group G streptococcal septicaemia: report of six cases.

The increased isolation of Group G streptococci from blood cultures in our laboratory is reported and the association between Group G streptococcal septicaemia and underlying malignancy is confirmed.

Determination of corpora lutea numbers in Booroola--Texel ewes using transrectal ultrasound.

Ovulation rates in Booroola--Texel ewes are currently determined by laparoscopic examination of the ovaries during the luteal phase allowing for carrier status of the ewe to be diagnosed. However, this is an invasive procedure and the aim of this work was to determine whether or not transrectal ultrasound would be an acceptable and accurate alternative to laparoscopy for this purpose in ewes. Transrectal ultrasound was performed using a 5.0 MHz transducer in 18 ewes restrained in the standing position. They were then euthanized and laparoscopy was performed, following which the reproductive tracts were recovered. An additional 22 ewes were subjected to scanning in dorsal recumbency, using a 7.5 MHz transducer, at various stages of the luteal phase before being euthanized and the reproductive tracts recovered. The ovarian structures identified using each method were then compared. The results demonstrated that laparoscopy is an accurate method of determining ovulation rates in ewes. Transrectal ultrasound examination appeared to be an acceptable and non-invasive procedure. The use of a 7.5 MHz transducer with the ewes in dorsal recumbency produced the best results and clearest images of the ovaries, which allowed for the determination of the number of corpora lutea (CL) and the presence of other structures. Accuracy improved with experience in the technique, the stage of the luteal phase at which the examination was performed, the number of CL present in the ovary and the age of the ewe. Further work is needed to confirm this finding due to the small numbers of animals in the present study. This ultrasound technique, however, has the potential to provide an alternative to laparoscopy for the determination of numbers of CL in ewes.

Comparison of ultrasonography, radiography and a single computed tomography slice for the identification of fluid within the canine tympanic bulla.

Fluid accumulation within the tympanic bulla (TB) is an important diagnostic indicator in clinical cases of canine otitis media although its identification can be a challenge using currently available imaging techniques. The aim of this study was to compare ultrasound with radiography and a single computed tomography (CT) slice for the identification of fluid within the TB of canine cadavers. A random number of TB in 66 cadavers were filled with ultrasound gel. Rostrocaudal open mouth (RCdoM) radiographs and CT images were interpreted by 2 blinded radiologists and ultrasound examinations were performed by 2 blinded sonographers. The heads were then frozen and sectioned to confirm the contents of each TB. Although CT remained the most accurate method, comparable results were obtained by one of the sonographers and even the inexperienced sonographer produced results superior to radiography. Ultrasound has several advantages over the other imaging techniques and this study suggests that it may have an application in the investigation of canine otitis media although further work in live animals would be required to confirm this.

Ultrasound imaging of the canine tympanic bulla.

A procedure for imaging the canine tympanic bulla, external ear canal and adjacent structures using currently available ultrasound equipment was established. Lateral and ventral transducer positions were identified for this purpose and a 6.5 MHz curvilinear transducer was considered to be optimal. The sonographic appearance of these structures in cadavers and live dogs unaffected by ear disease is documented. Fluid was introduced into the tympanic bullae of the cadavers and its presence could be identified through the bony wall of the bulla. The ability of ultrasound to differentiate between gas and fluid within the bulla has important clinical implications as this is a common occurrence in dogs with middle ear disease. Ultrasound has several advantages over other imaging modalities and the examination procedure was well tolerated by unsedated dogs.

A review of methods for assessment of the rate of gastric emptying in the dog and cat: 1898-2002.

Gastric emptying is the process by which food is delivered to the small intestine at a rate and in a form that optimizes intestinal absorption of nutrients. The rate of gastric emptying is subject to alteration by physiological, pharmacological, and pathological conditions. Gastric emptying of solids is of greater clinical significance because disordered gastric emptying rarely is detectable in the liquid phase. Imaging techniques have the disadvantage of requiring restraint of the animal and access to expensive equipment. Radiographic methods require administration of test meals that are not similar to food. Scintigraphy is the gold standard method for assessment of gastric emptying but requires administration of a radioisotope. Magnetic resonance imaging has not yet been applied for assessment of gastric emptying in small animals. Ultrasonography is a potentially useful, but subjective, method for assessment of gastric emptying in dogs. Gastric tracer methods require insertion of gastric or intestinal cannulae and are rarely applied outside of the research laboratory. The paracetamol absorption test has been applied for assessment of liquid phase gastric emptying in the dog, but requires IV cannulation. The gastric emptying breath test is a noninvasive method for assessment of gastric emptying that has been applied in dogs and cats. This method can be carried out away from the veterinary hospital, but the effects of physiological and pathological abnormalities on the test are not known. Advances in technology will facilitate the development of reliable methods for assessment of gastric emptying in small animals.

Streptococcus suis bacteraemia.

Streptococcus suis is a zoonotic pathogen which causes meningitis, arthritis and septicaemia in pigs, and rarely meningitis or septicaemia in humans. This organism has recently been isolated from pigs in New Zealand, where it appears to be widely distributed in pig herds. This case is the first report of human infection in New Zealand.

Idiopathic hepatic veno-occlusive disease causing Budd-Chiari-like syndrome in a cat.

Budd-Chiari-like syndrome (BCLS) is a rare clinical entity characterised by portal hypertension and ascites. This report describes a case of BCLS in a cat due to obstruction at the level of the hepatic veins. The diagnosis was based on the clinical findings and a histopathological assessment of the liver demonstrating perivenular fibrosis around the central and sublobular veins. Although these lesions are similar to those observed in man with BCLS, the aetiology in this case remains unknown.

Invasive mediastinal staging of non-small-cell lung cancer: a clinical practice guideline.

INTRODUCTION: In non-small-cell lung cancer (nsclc), invasive mediastinal staging is typically used to guide treatment decision-making. Here, we present clinical practice guideline recommendations for invasive mediastinal staging in nsclc patients who have been staged T1-4, N0-3, with no distant metastases. METHODS: Draft recommendations were formulated based on the best available evidence gathered by a systematic review and a consensus of expert opinion. The draft recommendations underwent an internal review by clinical and methodology experts, and an external review by clinical practitioners through a survey assessing the clinical relevance and overall quality of the guideline. Feedback from the internal and external reviews was integrated into the clinical practice guideline. RESULTS: In general, most clinical experts agreed with the guideline, approving it for methodologic rigour. More than 80% of the surveyed practitioners gave it a high quality rating. The expert reviewers also provided written comments, with some of the suggested changes being incorporated into the final version of the guideline. CONCLUSIONS: In the clinical practice guideline, invasive mediastinal staging of nsclc is recommended in all cases except those involving patients with normal-sized lymph nodes, negative combine positron-emission tomography and computed tomography, and peripheral clinical stage 1A tumour. When performing mediastinoscopy, 5 nodal stations (2R/L, 4R/L, and 7) should routinely be examined.