Pyroglutamic acidosis caused by the combination of two common medicines prescribed in everyday practice.

We present the case of a 71-year-old female treated for infective endocarditis with flucloxacillin and paracetamol. Her clinical course became complicated by a blood-gas demonstrating a raised anion gap metabolic acidosis. The patient was diagnosed with pyroglutamic metabolic acidosis. This is a rare interaction between high dose flucloxacillin and paracetamol, and is an important complication to recognize.

Subchondral bone structure and synovial fluid metabolism are altered in injured and contralateral limbs 7 days after non-invasive joint injury in skeletally-mature C57BL/6 mice.

OBJECTIVE: Post-traumatic osteoarthritis (PTOA) commonly develops after ACL injury, but early changes to the joint soon after injury are insufficiently understood. The objectives of this study were (1) evaluate the response of subchondral bone tissue modulus to joint injury and (2) identify which bone structural, material, and metabolic outcomes are local (i.e., injured joint only) or systemic (i.e., injured and contralateral-to-injured). DESIGN: Female C57Bl∖6N mice (19 weeks at injury) underwent tibial compression overload to simulate ACL injury (n = 8) or a small pre-load (n = 8). Synovial fluid was harvested at euthanasia 7 days later for metabolomic profiling. Bone outcomes included epiphyseal and SCB microarchitecture, SCB nanoindentation modulus, SCB formation rate, and osteoclast number density. RESULTS: Injury decreased epiphyseal bone volume fraction ([-5.29, -1.38%], P = 0.0016) and decreased SCB thickness for injured vs sham-injured limbs ([2.2, 31.4 µm], P = 0.017)). Epiphyseal bone loss commonly occurred for contralateral-to-injured limbs. There was not sufficient evidence to conclude that SCB modulus changes with injury. Metabolomic analyses revealed dysregulated synovial fluid metabolism with joint injury but that many metabolic pathways are shared between injured and contralateral-to-injured limbs. CONCLUSION: This study demonstrates rapid changes to bone structure and synovial fluid metabolism after injury with the potential for influencing the progression to PTOA. These changes are often evidenced in the contralateral-to-injured limb, indicating that systemic musculoskeletal responses to joint injury should not be overlooked.

Quinolone-induced Biceps Tendon Rupture.

Presentation A 76-year-old man presented with acute left upper limb pain and subsequent large ecchymosis. Diagnosis An ultrasound study was performed which showed partial left biceps tendon rupture. Treatment He was managed conservatively with Orthopaedic input. The patient was given analgesia and reassured. Discussion Tendon rupture is an unusual but serious complication of quinolone exposure. This case highlights that this should be included in the differential for acute limb pain in patients who have been prescribed these drugs.

Imaging and Staging of Endometrial Cancer.

Endometrial carcinoma is the most common female pelvic malignancy in the United States. Although endometrial cancer is staged according to the International Federation of Gynecology and Obstetrics surgical system, early and accurate diagnostic assessment of disease status of gynecologic malignancies is important for optimal treatment planning and outcome prediction. Preoperative imaging may assist in evaluation of local extent and detection of distant metastatic disease guiding the optimal course of treatment. Several imaging techniques such as transvaginal ultrasound, computed tomography, and magnetic resonance imaging have been used as tools for preoperative staging of endometrial cancer. Positron emission tomography/computed tomography and more recently, positron emission tomography/magnetic resonance imaging have also been used in the management of endometrial cancer. Cross-sectional imaging, especially MRI, may detect gross myometrial invasion or extension of tumor to the cervical stroma which can alter management. Imaging studies can also evaluate the presence of lymph nodal involvement, and detect local and distant metastatic disease at diagnosis. Additionally, imaging also plays a role in the monitoring of treatment and surveillance of the patients for detection of early recurrent disease. In this article, we will review the imaging and staging of endometrial cancer.

Uterine Carcinosarcomas.

Uterine carcinosarcoma (UCS) is a rare and aggressive variant of endometrial cancer, distinguished by its containment of both epithelial and sarcomatous elements. This article reviews the epidemiology, pathologic classification and staging of UCS, along with the typical findings seen on different imaging modalities. Prognosis and therapies will also be discussed.

Immunohistochemical differentiation of reactive from malignant mesothelium as a diagnostic aid in canine pericardial disease.

OBJECTIVES: To develop a provisional immunohistochemistry panel for distinguishing reactive pericardium, atypical mesothelial proliferation and mesothelioma in dogs. MATERIALS AND METHODS: Archived pericardial biopsies were subject to haematoxylin and eosin staining, immunohistochemistry for cytokeratin, vimentin, insulin-like growth factor II mRNA-binding protein 3, glucose transporter 1 and desmin. Samples were scored for intensity and number of cells stained. RESULTS: Ten biopsies of reactive mesothelium, 17 of atypical mesothelial proliferation, 26 of mesothelioma and five of normal pericardium were identified on the basis of haematoxylin and eosin staining. Cytokeratin and vimentin were expressed in all biopsies, confirming mesothelial origin. Normal pericardial samples had the lowest scores for insulin-like growth factor II mRNA-binding protein 3, glucose transporter 1 and desmin. Mesothelioma and atypical proliferative samples were similar to each other, with higher scores for insulin-like growth factor II mRNA-binding protein 3 and glucose transporter 1 than the reactive samples. Desmin staining was variable. Insulin-like growth factor II mRNA-binding protein 3 was the best to distinguish between disease groups. CLINICAL SIGNIFICANCE: An immunohistochemistry panel of cytokeratin, vimentin, insulin-like growth factor II mRNA-binding protein 3 and glucose transporter 1 could provide superior information compared with haematoxylin and eosin staining alone in the diagnosis of cases of mesothelial proliferation in canine pericardium, but further validation is warranted.

Epidemiology of basal cell carcinoma: a 10-year comparative study.

Basal cell carcinoma (BCC) is a slow-growing and locally aggressive skin cancer. Despite its high incidence, good quality epidemiological data are sparse. We therefore organised a retrospective study of two separate years' incidence of BCC in one county within the United Kingdom (Dorset) with an interval of 10 years between them. There were 2455 patients in 2006, and 3797 in 2016, who had a new diagnosis with corresponding crude incidences of 459.99 and 491.92/100,000 person-years. The male:female ratio was 1:071 for both years. The head and neck was the most common site, with the cheek, nose, and forehead being the most common subsites. This is a substantial increase in the incidence of BCC, and is much higher than previous reported rates for the UK. More stringent local and national registries are required to monitor the increasing numbers of BCC and help health care systems to plan preventive strategies and provide the most effective treatment.

Contamination of multidose butorphanol vials in small animal general practices.

OBJECTIVES: To assess and quantify medetomidine contamination of butorphanol multidose vials in small animal general practices and determine if practice policies and procedures regarding drug handling, as determined by questionnaire, impact upon contamination level. METHODS: Samples of butorphanol were withdrawn from in-use vials in participating practices in June and July 2013. Samples were analysed using high-performance liquid chromatography and mass spectrometry. RESULTS: Forty-one samples were obtained from 31 practices. Contamination was detected in 29 samples from 10 mL vials. The mean (αsd) contamination was 0 · 275 (α0 · 393) µg/mL; maximum contamination in any vial was 2 · 034 µg/mL. There was no correlation between volume of the vial used and the level of contamination. None of the survey factors predicted contamination levels of the vials. CLINICAL SIGNIFICANCE: Contamination of butorphanol multidose vials with medetomidine was common but the level of contamination was insufficient to cause detrimental effects in dogs if butorphanol were to be administered alone. The potential for sporadic higher levels of contamination must be taken into account, especially when using 50 mL vials when sedating critically ill cases, because there is a risk of clinical side effects.

Primary vaginal cancer: role of MRI in diagnosis, staging and treatment.

Primary carcinoma of the vagina is rare, accounting for 1-3% of all gynaecological malignancies. MRI has an increasing role in diagnosis, staging, treatment and assessment of complications in gynaecologic malignancy. In this review, we illustrate the utility of MRI in patients with primary vaginal cancer and highlight key aspects of staging, treatment, recurrence and complications.

Potentiation of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica following its co-administration with the metabolic inhibitor, ketoconazole.

An in vivo study in the laboratory rat model has been carried out to monitor morphological changes in adult Fasciola hepatica over a 4-day period resulting from co-treatment with triclabendazole (TCBZ) and ketoconazole (KTZ), a cytochrome P450 inhibitor. Rats were infected with the triclabendazole-resistant Oberon isolate of F. hepatica, dosed orally with triclabendazole at a dosage of 10mg/kg live weight and ketoconazole at a dosage of 10mg/kg live weight. Flukes were recovered at 24, 48, 72 and 96 h post-treatment (p.t.) and changes to fluke ultrastructure were assessed using transmission electron microscopy (TEM). Results showed an increase in the severity of changes to the fluke ultrastructure with time p.t. Swelling of the basal infolds and the associated mucopolysaccharide masses became more severe with time. Golgi complexes, if present, were greatly reduced in size and number by 96 h p.t., and sub-tegumental flooding was seen from the 72 h time-period onwards. Some sloughing of the tegumental covering over the spines was observed at 96 h p.t. The results demonstrated that the Oberon isolate is more sensitive to TCBZ action in the presence of KTZ than to TCBZ alone, reinforcing the idea that altered drug metabolism is involved in the resistance mechanism. Moreover, they support the concept that TCBZ+inhibitor combinations (aimed at altering drug pharmacokinetics and potentiating the action of TCBZ) could be used in the treatment of TCBZ-R populations of F. hepatica.

Erratum to: inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica.

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The cytochrome P450 (CYP 450) enzyme pathway was inhibited using ketoconazole (KTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP 450 system was inhibited by a 2-h pre-incubation in ketoconazole (40 µM), then incubated for a further 22 h in NCTC medium containing either KTZ, KTZ + nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM), KTZ + NADPH + TCBZ (15 µg/ml), or KTZ + NADPH + triclabendazole sulphoxide (TCBZ.SO; 15 µg/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than TCBZ-resistant isolate. However, co-incubation with KTZ + TCBZ, but more particularly KTZ + TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own: for example, there was severe swelling of the basal infolds and their associated mucopolysaccharide masses, accompanied by an accumulation of secretory bodies just below the apex. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis, production, and transport of secretory bodies were badly disrupted. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZ-resistant flukes and this process may play a role in the development of drug resistance.

Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica.

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The cytochrome P450 (CYP 450) enzyme pathway was inhibited using ketoconazole (KTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP 450 system was inhibited by a 2-h pre-incubation in ketoconazole (40 µM), then incubated for a further 22 h in NCTC medium containing either KTZ, KTZ + nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM), KTZ + NADPH + TCBZ (15 µg/ml), or KTZ + NADPH + triclabendazole sulphoxide (TCBZ.SO; 15 µg/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than TCBZ-resistant isolate. However, co-incubation with KTZ + TCBZ, but more particularly KTZ + TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own: in the syncytium, for example, there was severe swelling of the basal infolds and their associated mucopolysaccharide masses, accompanied by an accumulation of secretory bodies just below the apex. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis, production, and transport of secretory bodies were badly disrupted. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZ-resistant flukes and this process may play a role in the development of drug resistance.

Enhancement of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica by co-treatment with ketoconazole.

An in vivo study in the laboratory rat model was carried out to monitor morphological changes in adult Fasciola hepatica over a 4-day period resulting from combination treatment of triclabendazole (TCBZ) and the metabolic inhibitor, ketoconazole (KTZ). Rats were infected with the TCBZ-resistant Oberon isolate of F. hepatica and divided into 3 groups at 12 weeks post-infection. The first group was dosed orally with TCBZ at a dosage of 10mg/kg and KTZ at a dosage of 10mg/kg. Flukes were recovered at 24, 48, 72 and 96 h post-treatment (p.t.). A second group of rats was treated with TCBZ alone (10mg/kg) and sacrificed at 96 h p.t. The third group acted as untreated controls. Surface changes were monitored by scanning electron microscopy (SEM). In flukes from the TCBZ+KTZ-treated group, the results showed a progressive and time-dependent increase in the level of disruption to the tegumental syncytium. Swelling, furrowing, blebbing and sloughing of the syncytium increased with time p.t. Another feature seen was a thick layer of tegumental shedding in some fluke samples at different times p.t. By comparison, flukes treated with TCBZ alone remained unaffected. The results demonstrated that the Oberon isolate is only sensitive to drug action in the presence of ketoconazole, indicating that combining triclabendazole with a metabolic inhibitor could be used to preserve the effectiveness of the drug against TCBZ-resistant populations of F. hepatica.

Piperonyl butoxide enhances triclabendazole action against triclabendazole-resistant Fasciola hepatica.

A study has been carried out to determine whether the action of triclabendazole (TCBZ) against the liver fluke, Fasciola hepatica is altered by inhibition of the cytochrome P450 (CYP 450)-mediated drug metabolism pathway. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible fluke isolates were used for these experiments, the basic design of which is given in the paper by Devine et al. (2010a). Piperonyl butoxide (PB) was the CYP P450 inhibitor used. Morphological changes resulting from drug treatment and following metabolic inhibition were assessed by means of transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than TCBZ-resistant isolate. However, co-incubation with PB+TCBZ, but more particularly PB+TCBZ.SO, led to greater changes to the TCBZ-resistant isolate than with each drug on its own, with blebbing of the apical plasma membrane, severe swelling of the basal infolds and their associated mucopolysaccharide masses in the syncytium and flooding in the internal tissues. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis and production of secretory bodies were badly disrupted. The mitochondria were swollen throughout the tegumental system and the somatic muscle blocks were disrupted. With the TCBZ-susceptible Cullompton isolate, there was a limited increase in drug action following co-incubation with PB. The results provide evidence that the condition of a TCBZ-resistant fluke can be altered by inhibition of drug metabolism. Moreover, they support the concept that altered drug metabolism contributes to the mechanism of resistance to TCBZ.

Congestive heart failure in two pet rabbits.

This case report describes congestive heart failure with pleural effusion in two middle-aged, pet house rabbits. Both had a history of acute onset dyspnoea, weakness and weight loss. Bi-atrial enlargement was seen on echocardiography in both rabbits. One rabbit had atrial fibrillation and ventricular premature complexes identified on electrocardiography. There was a radiographically evident pleural effusion in both rabbits and thoracocentesis was undertaken in one rabbit. These findings were confirmed on post-mortem examination. The aetiology for the underlying heart disease was not found, but the potential types of cardiomyopathies are discussed.

Tenderness enhancement of beef from Bos indicus and Bos taurus cattle following electrical stimulation.

High voltage electrical stimulation (1130 V peak, 14.28 bidirectional half sinusoidal pulses/s) or low voltage stimulation (45 V peak, 36 alternating square wave pulses/s) was used on cattle: (1) low voltage stimulation applied for 10 or 40 s with fast and slow chilling or high voltage stimulation for 60 s with normal chilling, applied to 100% Bos taurus cattle, (2) low voltage stimulation (40 s) and high voltage stimulation (60 s) with normal chilling applied to mixed Bos indicus and B.taurus cattle, (3) high voltage stimulation (54 s) with normal chilling applied to B. taurus and B. indicus cattle of 0-100% B. indicus composition, and (4) high voltage stimulation (60 s) applied to 100% B. taurus and 100% B. indicus cattle. All stimulation parameters enhanced the tenderness of steaks from M. longissimus thoracis et lumborum (LTL) aged at 1°C up to 28 days compared with non stimulated LTL. Short low voltage stimulation of 10s was marginally more effective than no stimulation and longer durations of 40s were very effective and high voltage stimulation was most effective. The shear force values for non stimulated B. indicus LTL are much greater than for B. taurus, but following high voltage stimulation LTL of B. indicus were similar to B. taurus and all had lower shear force values than from non stimulated carcasses. Thus adequate electrical stimulation removes any toughness of LTL related to B. indicus genetic composition.

Modelling muscle energy-metabolism in anaerobic muscle.

A mathematical model of anaerobic muscle energy-metabolism was developed to predict pH and the concentrations of nine muscle metabolites over time. Phosphorous-31 Nuclear Magnetic Resonance was used to measure time-course data for some phosphate metabolites and pH in anoxic M. semitendinosus taken from three slaughtered sheep. Muscles were held at 35 degrees C during the experiment. Measurement commenced 25 min post mortem and concluded before rigor mortis. The model was fitted to these data within experimental error, by simultaneously varying model parameter values and initial substrate concentrations. The model was used to simulate the period from death until metabolic activity ceased, in order to predict the different stages of metabolic response to anoxia. The model suggested that alkalinisation would occur in all three muscles in the first few minutes after the onset of anoxia, followed by a steady decline in pH. For two of the muscles this decline continued until rigor, with final pH values of 5.60 and 6.07. For the other muscle, pH reached a low of 5.60 near rigor but then increased to a final value of 5.73. A rise in pH after rigor has been observed but not previously explained in the literature. The modelling results suggest it was caused by the alkalising effect of adenosine monophosphate deamination being greater at low pH than the acidifying effect of inosine monophosphate dephosphorylation.