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Biomedical subjects

R M Dixon

Publications and source records attributed to R M Dixon.

At least 19 recordsLinked to original sources

Association of canine hypothyroidism with a common major histocompatibility complex DLA class II allele.

Dogs exhibit a range of immune-mediated conditions including a lymphocytic thyroiditis which has many similarities to Hashimoto's thyroiditis in man. We have recently reported an association in Doberman Pinschers between canine hypothyroidism and a rare DLA class II haplotype that contains the DLA-DQA1*00101 allele. We now report a further series of 173 hypothyroid dogs in a range of breeds where a significant association with DLA-DQA1*00101 is shown.

Alleles↗

Long-term survey of laryngoplasty and ventriculocordectomy in an older, mixed-breed population of 200 horses. Part 1: Maintenance of surgical arytenoid abduction and complications of surgery.

REASONS FOR PERFORMING STUDY: Laryngoplasty (LP) is currently the most common surgical treatment for equine laryngeal paralysis, however, there have been no reports quantifying the degree of retention of arytenoid abduction following LP. Additionally, the complications of LP have been poorly documented. OBJECTIVES: To record the degree of arytenoid abduction retention following LP and to accurately document all complications of surgery. METHODS: A study (1986-1998) of 200 horses of mixed breed and workload, median age 6 years (prospective 136 cases and retrospective 64 cases) undergoing LP (using 2 stainless steel wires) and combined ventriculocordectomy was undertaken; 198 owners completed questionnaires, a median of 19 months following surgery. The degree of arytenoid abduction achieved was endoscopically, semi-quantitatively evaluated using a 5-grade system, at 1 day, 7 days, and 6 weeks after surgery. RESULTS: On the day following LP, 62% of horses had good (median grade 2) arytenoid abduction, 10% had excessive (grade 1), and 5% had minimal (grade 4) abduction (overall-median grade 2). Due to progressive loss of abduction, moderate (median grade 3, range 1-5) abduction was present overall at 1 and 6 weeks after LP. Further surgery was required to re-tighten prostheses in 10% of cases with excessive loss of abduction, or to loosen prostheses in 7% of horses which had continuing high levels of LP abduction and significant post operative dysphagia. LP wound problems (mainly seromas and suture abscesses) were reported to last < 2 weeks in 9% of cases, < 4 weeks in 4% and > 4 weeks in 4%. The (partially sutured) laryngotomy wounds discharged post operatively for < 2 weeks in 22% of cases, < 4 weeks in 7% and for > 4 weeks in 2%. Coughing occurred at some stage post operatively in 43% of cases and its presence correlated significantly with the degree of surgical arytenoid abduction. This coughing occurred during eating in 24% of cases and was not associated with eating (or dysphagia) in the other 19% of cases. Chronic (> 6 months duration) coughing occurred in 14% of cases, but appeared to be due to intercurrent pulmonary disease in half of these horses. CONCLUSIONS: Suturing the cricotracheal membrane allows most laryngotomy wounds to heal quickly. Laryngoplasty wound problems were of little long-term consequence when stainless steel wire prostheses were used. POTENTIAL RELEVANCE: A significant loss of LP abduction occurs in most horses in the 6 weeks following surgery and efforts should be made to find ways to prevent such loss. However, excessive LP abduction is associated with post operative dysphagia and coughing.

Animals↗

Urinary cortisol:creatinine ratios in healthy horses and horses with hyperadrenocorticism and non-adrenal disease.

Urinary cortisol and creatinine concentrations, and the cortisol:creatinine ratio were compared between 12 healthy horses (group 1), 13 horses with Cushing's disease (group 2), and eight horses with dysautonomia syndrome (equine grass sickness) (group 3). The mean (sd) urinary cortisol concentrations were 112 (55.7), 250 (357) and 864 (526) nmol/litre in groups 1, 2 and 3, respectively; the mean (sd) urinary creatinine concentrations were 18.9 (7.3), 12.0 (6.7) and 45.2 (26.4) nmol/litre in groups 1, 2 and 3, respectively, and the mean (sd) ratios were 6.1 (2.6), 19.8 (23.8) and 21.3 (14.5) (x 10(-6)) in groups 1, 2 and 3, respectively. The urinary cortisol and creatinine concentrations were significantly greater in group 3 than in groups 1 and 2, but the ratios were not significantly different, although there was a trend (P=0.076) towards higher values in groups 2 and 3. A diagnostic cut-off in the cortisol:creatinine ratio for the confirmation of Cushing's disease of more than 6.9 x 10(-6) was associated with a diagnostic sensitivity and specificity of 92.3 and 75.0 per cent, respectively, when compared with healthy horses. However, when group 3 horses were included, a cut-off of more than 7.4 x 10(-6) was associated with a diagnostic sensitivity and specificity of 84.6 and 54.5 per cent, respectively.

Animals↗

Treatment and therapeutic monitoring of canine hypothyroidism.

Thirty-one dogs with spontaneous hypothyroidism were treated with thyroid hormone replacement therapy (THRT) and monitored for approximately three months. Good clinical and laboratory control was ultimately achieved in all cases with a mean L-thyroxine (T4) dose of 0.026 mg/kg administered once daily. There was a significant increase and decrease in circulating total T4 and canine thyroid stimulating hormone (cTSH) concentrations, respectively, after starting THRT. After commencing treatment, 11 cases subsequently required an increase and three cases required a decrease in dose to achieve optimal clinical control. Median (semi interquartile range [SIR]) circulating six-hour post-pill total T4 (53.6 [27.91 nmol/litre) and cTSH (0.03 [0] microg/litre) concentrations were significantly increased and decreased, respectively, in treated dogs that did not require a dose change; corresponding values in treated dogs in which an increase in dose was required were 29.3 (12.7) nmol/litre and 0.15 (0.62) microg/litre, respectively. However, circulating cTSH measurement was of limited value in assessing therapeutic control because, although increased values were associated with inadequate therapy, reference range cTSH values were common in inadequately treated dogs. Lethargy and mental demeanour were typically the first clinical signs to improve, with significant bodyweight reduction occurring within two weeks of commencing THRT. Routine clinicopathological monitoring was of value in confirming a general metabolic response to THRT, but was of limited value in accurately monitoring cases or tailoring therapy in individual cases.

Animals↗

Daytime liver glycogen accumulation, measured by 13C magnetic resonance spectroscopy, in young children with Type 1 diabetes mellitus.

AIM: To examine daytime liver glycogen accumulation in prepubertal children with Type 1 diabetes mellitus (Type 1 DM) compared with non-diabetic controls. METHODS: Liver glycogen content was ascertained in the fasting (morning) and fed (afternoon) state using 13C magnetic resonance (MR) spectroscopy. Data were analysed from six children with Type 1 DM (median (range) age 8.7 (6.3-12.2) years), who were all on conventional insulin regimens, and six healthy controls (age 8.9 (7-10.2) years). RESULTS: Children with diabetes tended to have lower fasting glycogen values than controls but this did not reach statistical significance (median (range) 154 (70-177) vs. 178 (120-203) mM glycosyl units, Type 1 DM vs. controls respectively; P = 0.06). Glycogen increased in all children with diabetes during the day and concentrations were similar to those in controls by the afternoon (175 (157-299) vs. 172 (136-238) mM glycosyl units; P = 0.7). CONCLUSIONS: The ability of young children with Type 1 DM to replace liver glycogen depleted after an overnight fast was at least as good as that in control subjects, suggesting that impaired glycogen storage is not a contributory factor in nocturnal hypoglycaemia.

Activity Cycles↗

Hypo-osmotic swelling-activated release of organic osmolytes in brain slices: implications for brain oedema in vivo.

A decrease in the intracellular levels of osmotically active species has invariably been seen after swelling of mammalian brain tissue preparations. The exact identity of the species, and the manner of their decrease, remain to be described. We investigated the swelling-activated decrease of organic osmolytes in rat cortical brain slices using (1)H- and (31)P-magnetic resonance spectroscopy. We found that acute hypo-osmotic shock causes decreases in the levels of a range of intracellular amino acids and amino acid derivatives, N-acetyl-aspartate, creatine, GABA, glutamate, hypotaurine, and also in the levels of the methylamines glycerol-phosphorylcholine, phosphorylcholine and choline. Incubation of cortical slices with the anion channel blockers niflumic acid and tamoxifen caused inhibition of organic osmolyte efflux, suggesting that such osmolyte efflux occurs through anion channels. Intracellular phosphocreatine was also seen to decrease during acute hypo-osmotic superfusion, although intracellular ATP remained constant. In addition, the acidification of an intracellular compartment was observed during hypo-osmotic superfusion. Our results suggest a link between brain energy reserve and brain osmoregulation.

Adenosine Triphosphate↗

Effect of biofeedback-assisted relaxation training on foot ulcer healing.

A prospective, randomized study was conducted to determine the effect of biofeedback-assisted relaxation training on foot ulcer healing. For patients with chronic nonhealing foot ulcers, medical care was combined with a standardized biofeedback-assisted relaxation training program in the experimental group. The intervention was designed to increase peripheral perfusion, thereby promoting healing. A total of 32 patients with chronic nonhealing ulcers participated in the study. In the experimental group, 14 out of 16 ulcers (87.5%) healed, as compared with 7 out of 16 ulcers (43.8%) in the control group.

Adult↗

N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington's disease mice.

Huntington's disease (HD) is an autosomal dominant condition involving progressive neurodegeneration, primarily the corpus striatum and cerebral cortex. We have used in vivo magnetic resonance spectroscopy (MRS) to assess specific neuronal markers in transgenic mice (R6/1 line) expressing exon I of the human huntingtin gene with an expanded CAG repeat. Levels of N-acetylaspartate (NAA), an indicator of healthy neuronal function, were significantly reduced (26%) in the corpus striatum of HD mice relative to wild-type littermates at 5 months of age. However, levels of cholines and creatine-phosphocreatine were not altered in the HD mice. Expression of dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32), was assessed by immunohistochemistry in the striatum of HD mice and found to be downregulated by 5 months and, even more dramatically, at 11 months of age. In contrast, expression of calbindin was not significantly decreased in HD mice. Our results suggest that the observed decreases in DARPP-32 and NAA may contribute to aberrant receptor signalling and neuronal dysfunction in HD.

Animals↗

Induction of antigen-specific CD8+ T cells, T helper cells, and protective levels of antibody in humans by particle-mediated administration of a hepatitis B virus DNA vaccine.

A DNA vaccine against the hepatitis B virus (HBV) was evaluated for safety and induction of immune responses in 12 healthy, hepatitis-naïve human volunteers using the needle-free PowderJect system to deliver gold particles coated with DNA directly into cells of the skin. Three groups of four volunteers received three administrations of DNA encoding the surface antigen of HBV at one of the three dose levels (1, 2, or 4 microg). The vaccine was safe and well tolerated, causing only transient and mild to moderate responses at the site of administration. HBV-specific antibody and both CD4+ and CD8+ T cell responses were measured before and after each immunization. All the volunteers developed protective antibody responses of at least 10 mIU/ml. In volunteers who were positive for the HLA class I A2 allele, the vaccine also induced antigen-specific CD8+ T cells that bound HLA-A2/HBsAg(335-343) tetramers, secreted IFN-gamma, and lysed target cells presenting a hepatitis B surface antigen (HBsAg) CTL epitope. Enumeration of HBsAg-specific T cells producing cytokine indicated preferential induction of a Type 1 T helper cell response. These results provide the first demonstration of a DNA vaccine inducing protective antibody titers and both humoral and cell-mediated immune responses in humans.

Adult↗

Intravenous administration of levothyroxine for treatment of suspected myxedema coma complicated by severe hypothermia in a dog.

A 7-year-old male English Coonhound with suspected myxedema coma complicated by severe hypothermia and metabolic abnormalities was treated with a combination of active external and core rewarming techniques, i.v. and oral administration of levothyroxine, supplemental oxygen, and administration of fluids (0.9% NaCl solution). Myxedema coma develops as a consequence of severe hypothyroidism and is characterized by a hypometabolic, stuporous state. Myxedema coma is associated with a high mortality rate, and most reported cases have involved Doberman Pinschers. Intravenous administration of levothyroxine can be used successfully in combination with oral administration to restore normal metabolic function and assist in warming and thermoregulation, although dosages should be conservative to avoid adverse cardiovascular effects.

Administration, Oral↗

Phase II study of the oxygen saturation curve left shifting agent BW12C in combination with the hypoxia activated drug mitomycin C in advanced colorectal cancer.

BW12C (5-[2-formyl-3-hydroxypenoxyl] pentanoic acid) stabilizes oxyhaemoglobin, causing a reversible left-shift of the oxygen saturation curve (OSC) and tissue hypoxia. The activity of mitomycin C (MMC) is enhanced by hypoxia. In this phase II study, 17 patients with metastatic colorectal cancer resistant to 5-fluorouracil (5-FU) received BW12C and MMC. BW12C was given as a bolus loading dose of 45 mg kg(-1) over 1 h, followed by a maintenance infusion of 4 mg kg(-1) h(-1) for 5 h. MMC 6 mg m(-2) was administered over 15 min immediately after the BW12C bolus. The 15 evaluable patients had progressive disease after a median of 2 (range 1-4) cycles of chemotherapy. Haemoglobin electrophoresis 3 and 5 h after the BW12C bolus dose showed a fast moving band consistent with the BW12C-oxyhaemoglobin complex, accounting for approximately 50% of total haemoglobin. The predominant toxicities--nausea/vomiting and vein pain--were mild and did not exceed CTC grade 2. Liver 31P magnetic resonance spectroscopy of patients with hepatic metastases showed no changes consistent with tissue hypoxia. The principle of combining a hypoxically activated drug with an agent that increases tissue hypoxia is clinically feasible, producing an effect equivalent to reducing tumour oxygen delivery by at least 50%. However, BW12C in combination with MMC for 5-FU-resistant colorectal cancer is not an effective regimen. This could be related to drug resistance rather than a failure to enhance cytotoxicity.

Adult↗

The Black Sea Tele-Diab System: development-implementation-clinical evaluation.

This paper describes the application of the GEHR (Good European Health Record) architecture to develop a system to enable the storage and exchange of EHCRs (Electronic Health Care Record) of patients with diabetes, in the Black Sea area. The objectives of the Black Sea Tele Diab System (BSTD) were to develop and evaluate the use of a fully-computerised healthcare record system in a clinical setting, to promote the use of electronic data exchange of healthcare information and to provide a framework for the epidemiological study and monitoring of diabetes care.

Diabetes Mellitus↗

Tolerability and immune responses in humans to a PowderJect DNA vaccine for hepatitis B.

We are developing a DNA vaccine toward hepatitis-B virus (HBV) using PowderJect's proprietary needle-free technology to deliver DNA-coated gold particles directly into cells of the skin. Preclinical studies in animals showed that (i) microgram doses of the DNA vaccine were sufficient to immunize pigs and non-human primates to antibody levels comparable to those obtained with a commercial recombinant subunit vaccine; (ii) the DNA vaccine was effective in mouse strains that respond poorly to protein subunit vaccines; (iii) the vaccine induces robust cytotoxic T-cell responses, and (iv) the vaccine is non-toxic and well tolerated. Based on these findings, this DNA vaccine was evaluated for safety, tolerability, and the induction of immune responses in phase 1 clinical studies in healthy, hepatitis-naïve human volunteers. Preliminary results indicate that the vaccine is safe and well tolerated, and elicits both humoral and cellular immune responses in man.

Animals↗

Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial.

CONTEXT: The protein hormone leptin is important to the homeostatic regulation of body weight. Treatment with exogenous leptin may affect weight loss. OBJECTIVE: To determine the relationship between increasing doses of exogenous leptin administration and weight loss in both lean and obese adults. DESIGN: A randomized, double-blind, placebo-controlled, multicenter, escalating dose cohort trial conducted from April 1997 to October 1998. SETTING: Four university nutrition and obesity clinics and 2 contract clinical research clinics. PARTICIPANTS: Fifty-four lean (body mass index, 20.0-27.5 kg/m2; mean [SD] body weight, 72.0 [9.7] kg) and 73 obese (body mass index, 27.6-36.0 kg/m2; mean [SD] body weight, 89.8 [11.4] kg) predominantly white (80%) men (n = 67) and women (n = 60) with mean (SD) age of 39 (10.3) years. INTERVENTIONS: Recombinant methionyl human leptin self-administered by daily morning subcutaneous injection (0 [placebo], 0.01, 0.03, 0.10, or 0.30 mg/kg). In part A, lean and obese subjects were treated for 4 weeks; in part B, obese subjects were treated for an additional 20 weeks. Lean subjects consumed a eucaloric diet to maintain body weight at the current value, and obese subjects were prescribed a diet that reduced their daily energy intake by 2100 kJ/d (500-kcal/d) from the amount needed to maintain a stable weight. MAIN OUTCOME MEASURES: Body weight, body fat, and incidence of adverse events. RESULTS: Weight loss from baseline increased with increasing dose of leptin among all subjects at 4 weeks (P = .02) and among obese subjects at 24 weeks (P = .01) of treatment. Mean (SD) weight changes at 4 weeks ranged from -0.4 (2.0) kg for placebo (n = 36) to -1.9 kg (1.6) kg for the 0.1 mg/kg dose (n = 29). Mean (SD) weight changes at 24 weeks ranged from -0.7 (5.4) kg for the 0.01 mg/kg dose (n = 6) to -7.1 (8.5) kg for the 0.30 mg/kg dose (n = 8). Fat mass declined from baseline as dose increased among all subjects at 4 weeks (P = .002) and among obese subjects at 24 weeks of treatment (P = .004); more than 95% of weight loss was fat loss in the 2 highest dose cohorts at 24 weeks. Baseline serum leptin concentrations were not related to weight loss at week 4 (P = .88) or at week 24 (P = .76). No clinically significant adverse effects were observed on major organ systems. Mild-to-moderate reactions at the injection site were the most commonly reported adverse effects. CONCLUSIONS: A dose-response relationship with weight and fat loss was observed with subcutaneous recombinant leptin injections in both lean and obese subjects. Based on this study, administration of exogenous leptin appears to induce weight loss in some obese subjects with elevated endogenous serum leptin concentrations. Additional research into the potential role for leptin and related hormones in the treatment of human obesity is warranted.

Adult↗

Epidemiological, clinical, haematological and biochemical characteristics of canine hypothyroidism.

Hypothyroidism was diagnosed in 50 dogs and excluded in 86 dogs suspected of hypothyroidism, on the basis of the results of bovine thyrotropin response tests. Breed, pedigree, sex or neutering status did not significantly influence the likelihood of the dogs being hypothyroid. The hypothyroid dogs were significantly older than the non-hypothyroid dogs referred to the University of Glasgow during the same period. However, when dogs under two years of age were excluded from the statistical analyses there was no significant difference in age between the two groups. The most common clinical characteristics associated with hypothyroidism were metabolic signs (84 per cent of cases), particularly lethargy (76 per cent), obesity or weight gain (44 per cent), and exercise intolerance (24 per cent); and dermatological abnormalities (80 per cent), including alopecia (56 per cent), poor coat quality (30 per cent) and hyperpigmentation (20 per cent). When compared with the laboratory reference limits the most common biochemical and haematological abnormalities were increased concentrations of triglycerides (88 per cent), cholesterol (78 per cent), glucose (49 per cent), and fructosamine (43 per cent), and increased activities of creatine kinase (35 per cent), and decreased concentrations of inorganic phosphate (63 per cent), and a low red blood cell count (40 per cent). When compared with reference limits derived from the euthyroid dogs the most common abnormalities were increased concentrations of gamma-glutamyltransferase (21 per cent), cholesterol (18 per cent), and aspartate aminotransferase (15 per cent) and a decreased red blood cell count (29 per cent), and decreased neutrophils (18 per cent) and decreased activity of creatine kinase (15 per cent). Assessment of cholesterol, creatine kinase, aspartate aminotransferase, gamma-glutamyltransferase, and red blood cell and neutrophil counts may be particularly useful in distinguishing hypothyroid dogs from euthyroid animals with similar clinical signs.

Animals↗

Separate quantification of doubly and singly 13C-labeled metabolites by HSQC-filtered J spectroscopy.

NMR detection of multiply labeled compounds in biological samples is often used to follow metabolic pathways. Detection of protons bound to 13C atoms offers a more sensitive approach than direct 13C detection, but generally results in the loss of carbon-carbon coupling information. We have modified an HSQC sequence to refocus the carbon chemical shifts in order to obtain a proton-correlated 13C homonuclear J spectrum, which allows us to measure singly and doubly labeled compounds in the same spectrum.

Affinity Labels↗

Canine serum thyroglobulin autoantibodies in health, hypothyroidism and non-thyroidal illness.

Thyroglobulin autoantibody (TGAA) was measured in serum from dogs with hypothyroidism (n = 42), non-thyroidal illness (NTI) (n = 77) and clinically healthy dogs (n = 70) using a commercially available enzyme immunoassay kit. Precision studies were consistent with good intra-assay and inter-assay repeatability. TGAA positive results occurred in 15 of the 42 (36 per cent) hypothyroid and four healthy dogs of the remaining 147 animals resulting in a lower incidence of false positive results than obtained with previous TGAA assays. The presence of TGAA was not influenced by age, sex, neutering or pedigree status. Of the four apparently healthy TGAA -positive dogs, two had additional clinicopathological evidence of hypothyroidism. TGAA was positive in 43 per cent of hypothyroid dogs with unexpectedly normal serum c TSH concentrations and was particularly useful in the classification of these cases.

Animals↗