Biomedical subjects
Publications and source records attributed to J Beech.
Monthly intravenous pegylated liposomal doxorubicin (PLD) 50 mg m(-2), although well tolerated, showed almost no activity in this phase II study of 16 patients with advanced hepatocellular carcinoma with a response rate of 0%, stable disease 19%, median time to progression of 2.4 months, 1-year survival of 25% and median survival of 6.5 months.
This single-centre phase I trial was designed to determine the maximum tolerated dose of irinotecan and the recommended dose to use in combination with a fixed dose of 5-fluorouracil (5-FU) administered as a protracted venous infusion, for the first-line treatment of metastatic colorectal cancer (CRC). Tolerability and efficacy were secondary end points. In all, 22 patients, median age 57 years, were treated with escalating, weekly doses of irinotecan (50, 75, 100 and 85 mg m(-2)) in combination with 250 mg m(-2) 5-FU administered as a continuous infusion. All patients had measurable disease. The combination was well tolerated up to an irinotecan dose of 75 mg m(-2). However, three out of five patients at the 100 mg m(-2) irinotecan dose level had their dose reduced due to multiple grade 2 toxicities, and eventually one patient stopped treatment due to grade 3 diarrhoea and multiple grade 2 toxicities. Subsequent patients were recruited at an irinotecan dose level of 85 mg m(-2). The overall response rate was 55%, comprising one complete and 11 partial responses (PRs). Six patients also achieved sustained stable disease (SD), giving a clinical benefit (complete response/PR/SD) response of 82%. The median duration of response was 238 days (8.5 months) and median time to progression was 224 days (8.0 months). Two patients who achieved PRs underwent partial hepatectomies. Thus, irinotecan (85 mg m(-2)) combined with a continuous infusion of 5-FU (250 mg m(-2)) is an active and well-tolerated regimen for the treatment of metastatic CRC. It represents an effective treatment for patients who require close supervision and support, throughout their initial exposure to chemotherapy for this disease, and this dose combination was recommended for an ongoing phase II study.
Tear production was evaluated in 39 horses and 29 ponies using Schirmer tear test strips to determine whether diurnal or weekly fluctuations occur, whether location of strip placement has an effect, if values are the same for both eyes in an animal and whether sex, age, stabling vs. pasture and winter vs. summer had an effect. There was no test in which the raw score was less than 10 mm, although there were many occasions where tear wetting exceeded 35 mm. Analysis of the raw (continuous) scores by linear regression provided no evidence that signalment, housing or season or location of strip placement affected results. The distribution of tear test scores for a 'population' of eyes did not differ when the right eye was compared with the left eye or when the same eye was compared at different times on the same day. Individual test wetting values for opposing eyes measured at the same time, and also wetting values for the same eye measured at different times on the same day sometimes differed substantially. In winter maximum tear wetting exceeded 35 mm more frequently in the STT I than in the STT II even in housed horses and ponies, but there was no consistent significant difference. There appears to be wide variability in the STT I in normal horses and ponies.
Inflammatory stimuli result in the production of cutaneous eicosanoids, which are known to contribute to the process of tumor promotion. Cyclooxygenase (COX), the rate-limiting enzyme for the production of prostaglandins (PG) from arachidonic acid, exists in at least two isoforms, COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and plays various physiological roles, whereas increased COX-2 expression is known to occur in several types of epithelial neoplasms. Enhanced PG synthesis is a potential contributing factor in UVB-induced nonmelanoma skin cancers (NMSC). Increased COX-2 staining occurs in murine skin neoplasms after chronic exposure to carcinogenic doses of UVB. In this study, immunohistochemical and Western blot analyses were employed to assess longitudinally COX-2 expression in a standard mouse UVB complete carcinogenesis protocol and in human basal cell carcinomas (BCC) and squamous cell carcinomas (SCC). During UVB irradiation of mice, COX-2 expression consistently increased in the hyperplastic skin, the benign papillomas and the SCC. COX-2 expression was also increased in human actinic keratoses, SCC and BCC as well as in murine SCC and BCC. The pattern of COX-2 expression was quite variable, occurring in a patchy distribution in some lesions with staining confined mainly to suprabasal cell layers. In general, COX-2 expression progressively became more extensive in benign papillomas and well-differentiated murine SCC. The staining was predominantly cytoplasmic and perinuclear in some focal areas in tissue stroma around both murine and human tumors. Western blot analysis confirmed negative COX-2 expression in normal skin, whereas acute UVB exposure resulted in increased enzyme expression, which continued to increase in developing papillomas and SCC. Because of the evidence indicating a pathogenic role for eicosanoids in murine and human skin neoplasms, we performed studies to assess the anti-inflammatory and anticarcinogenic effects of green tea extracts, which are potent antioxidants. Acute exposure of the human skin to UVB (minimum erythema dose x 4) caused a transient enhancement of the COX-2 expression, which reverted to baseline within hours; however, in murine skin the expression persisted for several days. Pretreatment with the topically applied green tea extract (1 mg/cm2) largely abrogated the acute COX-2 response to UVB in mice or humans. In summary, enhanced COX-2 expression serves as a marker of epidermal UVB exposure for murine and human NMSC. These results suggest that COX-2 inhibitors could have potent anticarcinogenic effects in UVB-induced skin cancer.
Hailey-Hailey disease (HHD, MIM 16960) is inherited in an autosomal dominant manner and characterized by persistent blisters and erosions of the skin. Impaired intercellular adhesion and epidermal blistering also occur in individuals with pemphigus (which is due to autoantibodies directed against desmosomal proteins) and in patients with Darier disease (DD, MIM 124200), which is caused by mutations in a gene encoding a sarco/endoplasmic reticulum (ER)-Golgi calcium pump. We report here the identification of mutations in ATP2C1, encoding the human homologue of an ATP-powered pump that sequesters calcium into the Golgi in yeast, in 21 HHD kindreds. Regulation of cytoplasmic calcium is impaired in cultured keratinocytes from HHD patients, and the normal epidermal calcium gradient is attenuated in vivo in HHD patients. Our findings not only provide an understanding of the molecular basis of HHD, but also underscore the importance of calcium control to the functioning of stratified squamous epithelia.
OBJECTIVE: To determine sensitivity of equine skeletal muscle to tetrodotoxin and compare that with sensitivity of murine and human skeletal muscles. SAMPLE POPULATION: Semimembranosus, vastus lateralis, triceps brachii, and masseter muscle specimens from 22 euthanatized horses, vastus lateralis muscle biopsy specimens from 25 clinically normal humans, and diaphragmatic muscle specimens from 6 mice. PROCEDURE: Electrically elicited twitch responses were measured in muscle specimens incubated in medium alone and with tetrodotoxin (100 nM, 400 nM, 1.6 microM for equine specimens and 100 nM, 200 nM, 400 nM, 800 nM, 1.6 microM for murine and human specimens). Percentages of tetrodotoxin-sensitive and -resistant sodium channels were determined and compared among muscles and species. RESULTS: 2 sodium channels with different sensitivities to tetrodotoxin were identified in equine muscle. One was blocked with 100 nM tetrodotoxin and the other was unaffected by tetrodotoxin at concentrations up to 1.6 microM. The only difference detected among the 4 equine muscles was that masseter muscle specimens had a higher percentage of tetrodotoxin-sensitive channels than triceps brachii muscle specimens. Tetrodotoxin-resistant sodium channels constituted 31 to 66% of the equine muscle twitch response, which was greater than that determined for normal human and murine muscle (< 5%). CONCLUSION AND CLINICAL RELEVANCE: Equine skeletal muscle contains a high percentage of tetrodotoxin-resistant sodium channels. The 4 equine muscles evaluated were more similar to each other than to murine and human muscles. Shifts in expression of sodium channel subtypes may play a role in the manifestation of certain myopathies.
OBJECTIVE: To evaluate results of cytologic examination of specimens obtained by means of tracheal washes (TW) in 42 horses with a history of poor performance. DESIGN: Cross-sectional case series. ANIMALS: 42 horses with a history of poor performance. PROCEDURE: A TW was performed via endoscopy before and after horses exercised on a high-speed treadmill, and specimens were evaluated microscopically and graded. RESULTS: Ten (24%) horses were considered to be clinically normal before and after exercise. Pulmonary hemorrhage was diagnosed in 8 (19%) horses. One horse had evidence of exercise-induced pulmonary hemorrhage (EIPH) before exercise and pulmonary hemorrhage and allergic or inflammatory airway disease (IAD) after exercise. Five (12%) horses had IAD, and 1 had IAD and pulmonary hemorrhage after exercise. Seven (17%) horses had evidence of EIPH and IAD in both specimens. Four (10%) horses with EIPH had an increase in the proportion of hemosiderophages in the specimen obtained after exercise. Specimens obtained before exercise in 6 (14%) horses were not representative of the respiratory tract and could not be compared with specimens obtained after exercise. CLINICAL IMPLICATIONS: Interpretation of TW specimens obtained before and after exercise differed for only 5 of 36 (14%) horses. Specimens obtained after exercise were more likely to reveal airway disease. All specimens obtained after exercise adequately represented the respiratory tract, whereas 6 specimens obtained before exercise did not. Specimens obtained after exercise contained more airway secretions and had less cytologic evidence of pharyngeal contamination. Therefore, we recommend that TW samples be obtained after exercise in horses.
The identification of mutations in Hedgehog (HH) pathway genes in some basal cell carcinomas (BCC) and the detection of HH pathway dysregulation in almost all BCC confirms the importance of this developmental regulatory pathway in human BCC tumorigenesis. Moreover, the occurrence of UVB signature mutations in key HH pathway genes in BCC provides the first genetic evidence that UV radiation (UVR) may be the principal mutagen involved in BCC tumorigenesis. We review herein current advances in the understanding of the role of the HH pathway in BCC tumorigenesis including transgenic and knock-out animal models of HH pathway dysregulation. Furthermore, we summarize abnormalities in other tumor suppressors and oncogenes including ras and p53 and evidence for interactions between these regulatory genes and the HH pathway.
We have assessed the possibility of artefacts that can arise in attempting to perform simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) using a small prototype MR compatible PET scanner (McPET). In these experiments, we examine MR images for any major artefacts or loss in image quality due to inhomogeneities in the magnetic field, radiofrequency interference or susceptibility effects caused by operation of the PET system inside the MR scanner. In addition, possible artefacts in the PET images caused by the static and time-varying magnetic fields or radiofrequency interference from the MR system were investigated. Biological tissue and a T2-weighted spin echo sequence were used to examine susceptibility artefacts due to components of the McPET scanner (scintillator, optical fibres) situated in the MR field of view. A range of commonly used MR pulse sequences was studied while acquiring PET data to look for possible artefacts in either the PET or MR images. Other than a small loss in signal-to-noise using gradient echo sequences, there was no significant interaction between the two imaging systems. Simultaneous PET and MR imaging of simple phantoms was also carried out in different MR systems with field strengths ranging from 0.2 to 4.7 T. The results of these studies demonstrate that it is possible to acquire PET and MR images simultaneously, without any significant artefacts or loss in image quality, using our prototype MR compatible PET scanner.
In equine hyperkalemic periodic paralysis (HyperPP), there is evidence suggesting that the primary defect in the sodium channel is associated with a secondary alteration in triacylglycerol-associated fatty acid metabolism (TAFAM) in skeletal muscle. Furthermore, TAFAM may be involved in the therapeutic action of phenytoin. The effects of phenytoin treatment on the transcript levels of three key proteins in TAFAM, hormone sensitive lipase (HSL), carnitine palmitoyltransferase (CPT), and fatty acid binding protein (FABP), were examined. These transcripts were quantitated by competitive reverse transcription polymerase chain reaction in undifferentiated and differentiated primary cultures of equine skeletal muscle from control, heterozygous HyperPP, and homozygous-affected HyperPP horses. There was a 10-fold lower level of HSL transcript in both undifferentiated and differentiated cultures from homozygous-affected horses than from horses of the other genotypes. Phenytoin selectively increased the HSL transcript in homozygous-affected differentiated cultures to levels similar to those of the other genotypes. The levels of CPT and FABP transcripts were unaffected by genotype, differentiation, and phenytoin treatment. These results suggest that the primary defect in HyperPP may secondarily decrease HSL transcript levels and that the therapeutic action of phenytoin may include regulation of mRNA transcripts in skeletal muscle.
This article reports on a longitudinal study of reading progress in a group of five-year-old deaf children and a group of hearing controls. All children were prereaders at the beginning of the study and the IQ of the two groups were matched. The deaf children varied considerably on a number of measures, including implicit phonological awareness, oral ability, and familiarity with British Sign Language and fingerspelling. Overall, the deaf children made significantly less reading progress than their hearing peers over the first year of schooling, and they also scored significantly lower on the test of rime and onset awareness. However, considerable variation in the reading progress of the deaf children was positively correlated with oral skills, rime/onset awareness, and language comprehension. Language comprehension, itself, was positively correlated with signing and fingerspelling. The deaf children were assessed again one year later, when learning to read continued to be very delayed, and the pattern of correlation was essentially the same. The implications of these findings for the education of deaf children are discussed.
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OBJECTIVE: To determine the effect of exercise on arterial blood gas tensions and upper airway and cardiac function in clinically normal Quarter Horses and horses heterozygous and homozygous for hyperkalemic periodic paralysis (HYPP). ANIMALS AND PROCEDURE: 5 clinically normal Quarter Horses, and 5 heterozygous and 2 homozygous HYPP-affected horses were examined before, during, and after exercise on a high-speed treadmill. Arterial blood gas tensions, ECG, and echocardiogram were obtained prior to exercise. Upper airway endoscopy, collection of arterial blood samples, and continuous electrocardiography were performed during a high-intensity stepwise exercise test. An ECG was obtained within 1-minute after completion of the final step. RESULTS: None of the horses homozygous or heterozygous for HYPP had signs of weakness or muscle fasciculations before, during, or after exercise. Horses homozygous for HYPP had intermittent laryngospasm, dynamic pharyngeal collapse, and appreciable hypoxemia, hypercapnia, and ventricular premature contractions during exercise. Heterozygous and clinically normal horses did not have any abnormalities. Potassium concentration increased significantly above the baseline reference range during exercise in all groups of horses. CONCLUSIONS: Horses homozygous for HYPP had laryngospasm and dynamic pharyngeal collapse associated with exercise, most likely secondary to increase in potassium concentration. Upper airway dysfunction is the most likely cause of hypoxemia and hypercapnia. Cardiac arrhythmias were most likely caused by a combination of hypoxemia and hyperkalemia.
This article presents a brief description of what is known about the cause and pathogenesis of chronic intermittent rhabdomyolysis in horses. Clinically applicable diagnostic tests and published results in affected horses, prophylaxis, and treatment of the acute case are discussed.
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BACKGROUND: The abundance of a specific sodium channel subunit (SkM2) appeared to be altered in vitro in cell cultures from persons susceptible to malignant hyperthermia. This study sought to determine whether these findings are artifacts of cell culture or whether they may be relevant to malignant hyperthermia. METHODS: Regulation of transcript levels of SkM2, a specific sodium channel alpha-subunit, was determined by mRNA analysis. Functional SkM2 protein was estimated in biopsy sections of vastus lateralis muscle by inhibiting the directly elicited muscle twitch by tetrodotoxin, which can differentiate at least three sodium currents in skeletal muscle. RESULTS: The transcript levels of SkM2 were depressed by 115-fold in six of seven persons susceptible to malignant hyperthermia; and the functional expression of the SkM2 protein, based on the tetrodotoxin sensitivity of the directly elicited twitch, was decreased by at least fourfold in muscle from persons susceptible to malignant hyperthermia compared with persons who were not susceptible. CONCLUSIONS: As in previous studies in cell culture, altered mRNA and/or the functional expression of a specific subunit of the sodium channel (SkM2) was found in biopsy sections of muscle from all 12 persons examined who were susceptible to malignant hyperthermia but in none of the 16 nonsusceptible participants. Human malignant hyperthermia is a heterogeneous disorder, and the down-regulation of SkM2 may be involved in the final common pathway through which mutations in any one of several proteins, including the ryanodine receptor, could render a person susceptible.
An 8-month-old female Vietnamese pot-bellied pig was examined because of a 48-hour history of anorexia and signs of depression. Hypothermia, dehydration, pronounced respiratory effort, and muffled heart sounds were detected. Abdominal ultrasonography revealed ascites and hepatic congestion. Echocardiography revealed pericardial effusion and fibrinous pericarditis. Ultrasound-guided pericardiocentesis was diagnostic and therapeutic. Cytologic examination of pericardial and peritoneal fluid revealed degenerated neutrophils and intra-and extracellular gram-positive cocci. On microbial culture of pericardial and peritoneal fluid specimens, moderate growth of a beta-hemolytic Streptococcus sp of group G was observed. After initial treatment corrected hypothermia and dehydration, the pig was treated with sulfadiazine/sulfamerazine/sulfamethazine and oxytetracycline for 30 days. Echocardiographic examination 3 months after the initial examination revealed resolution of the pericardial effusion and fibrinous pericarditis.
Horses with hyperkalaemic periodic paralysis were challenged with an oral dose of potassium chloride, and the prophylactic efficacy of phenytoin, acetazolamide and hydrochlorothiazide was evaluated, with at least three weeks separating the trials of each drug. After the administration of potassium chloride without prophylactic medication the horses' clinical signs ranged from generalised fine muscle fasciculations to gross tremors, and weakness with occassional prolapse of the nictitating membrane; plasma potassium concentration increased significantly (P < 0.01) from 4.0 +/- 0.2 to 6.0 +/- 1.01 mmol litre-1. After treatment with acetazolamide the administration of potassium chloride resulted in a significant (P < 0.02) increase in plasma potassium from 3.7 +/- 0.3 to 4.5 +/- 0.4 mmol litre-1 and two of five horses showed clinical signs unless the dosage was increased from 2.2 to 4.4 mg kg-1 twice daily. Three of the four horses treated with hydrochlorothiazide showed clinical signs but their plasma potassium did not rise significantly (3.6 +/- 0.3 to 4.6 +/- 1.0 mmol litre-1). None of the five horses treated with phenytoin showed clinical signs despite a significant increase in plasma potassium from 3.8 +/- 0.6 to 5.3 +/- 1.1 mmol litre-1 (P < 0.05). In general the clinical signs were not correlated consistently with the plasma levels of potassium, and phenytoin appeared to prevent the clinical signs in spite of the hyperkalaemia.