The effect of oral metformin on insulin sensitivity in insulin-resistant ponies

Metformin may be an effective therapeutic option for insulin-resistant (I-R) horses/ponies because, in humans, it reportedly enhances insulin sensitivity (SI) of peripheral tissues without stimulating insulin secretion. To determine the effect of metformin on insulin and glucose dynamics in I-R ponies, six ponies were studied in a cross-over design by Minimal Model analysis of a frequently-sampled intravenous glucose tolerance test (FSIGT). Metformin was administered at 15 mg/kg bodyweight (BW), orally, twice-daily, for 21 days to the metformin-treated group. The control group received a placebo. A FSIGT was conducted before and after treatment. The Minimal Model of glucose and insulin dynamics rendered indices describing SI, glucose effectiveness (Sg), acute insulin response to glucose (AIRg) and the disposition index (DI). The body condition score (BCS), BW and cresty neck score (CNS) were also assessed. There was no significant change in SI, Sg, AIRg, DI, BW, BCS or CNS in response to metformin, or over time in the control group. There were no measurable benefits of metformin on SI, consistent with recent work showing that the bioavailability of metformin in horses is poor, and chronic dosing may not achieve therapeutic blood concentrations. Alternatively, metformin may only be effective in obese ponies losing weight or with hyperglycaemia.     

Physiologic assessment of blood glucose homeostasis via combined intravenous glucose and insulin testing in horses

OBJECTIVE: To characterize the physiologic response to i.v. bolus injection of glucose and insulin for development of a combined glucose-insulin test (CGIT) in horses. ANIMALS: 6 healthy mares and 1 mare each with pituitary adenoma and urolithiasis. PROCEDURE: Horses were given a CGIT (glucose, 150 mg/kg; insulin, 0.1 U/kg); results were compared with a singular i.v. glucose tolerance test (GTT; 150 mg/kg) and a singular i.v. insulin sensitivity test (IST; 0.1 U/kg). Healthy horses were also given a CGIT after receiving xylazine and undergoing stress. RESULTS: Physiologically, the CGIT resulted in a 2-phase curve with positive (hyperglycemic) and negative (hypoglycemic) portions; the positive phase came first (250% of baseline at 1 minute). The descending segment declined linearly to baseline by approximately 30 minutes and to a nadir at 58% of baseline by 75 minutes. After a 35-minute valley, a linear ascent to baseline began. Addition of insulin in the CGIT increased glucose utilization by approximately 4.5 times during the positive phase but not during the negative phase. The diseases' effects and experimental inhibition of insulin secretion with xylazine and stress were detectable by use of the 2 phases of the CGIT. Only a single positive phase resulted from the GTT and a single negative phase from the IST CONCLUSIONS AND CLINICAL RELEVANCE: The CGIT resulted in a consistent, well-defined glycemia profile, which can be disrupted experimentally or by a disease process. The CGIT has clinical potential because it provides integrated information and more information than either the singular GTT or IST.     

Comparison of radical scavenging effect, inhibition of microsomal oxygen free radical generation, and serum lipoprotein oxidation of several natural antioxidants

Typical components of the Mediterranean diet, such as olive oil and red wine, contain high concentrations of complex phenols, which have been suggested to have an important antioxidant role. The aim of the present work was to determine the inhibitory potency of compounds such as oleuropein, hydroxytyrosol, and other structurally related compounds, such as gallic acid, toward reactive oxygen species generation and free radical scavenging ability. The potency of these compounds was also examined with respect to protecting in vitro low-density lipoprotein oxidation. These studies indicate that complex phenols, such as hydroxytyrosol, and gallic acid both inhibit free radical generation and act as free radical scavengers. The use of three different approaches to determine antioxidant potency demonstrates that activity in one test does not necessarily correlate with activity in another. It was also demonstrated that the presence of two phenolic groups is not always associated with antioxidant activity.     

Cytologic identification of fungal arthritis in a Labrador Retriever with disseminated Talaromyces helicus infection

An 8‐year‐old, neutered male Labrador Retriever presented with acute forelimb lameness. Clinical signs progressed over one week. On physical examination, right cubital joint effusion and bilateral axillary lymphadenomegaly were noted, and severe internal lymphadenomegaly was observed ultrasonographically. Granulomatous lymphadenitis with intralesional fungi was noted cytologically, and the dog was ultimately diagnosed with disseminated Talaromyces helicus infection via PCR of a pure isolate. Extensive medical therapy was pursued, and months later, an arthrocentesis was performed due to continued lameness and severe cubital joint effusion. The synovial fluid contained increased numbers of neutrophils, macrophages, and multinucleated giant cells. Frequent fungal hyphae were found both intracellularly and extracellularly. These basophilic organisms were 2‐4 µm in width with internal eosinophilic granules, roughly parallel walls, and occasional to frequent septa. Round to oval yeast‐like forms with thin, clear halos were also occasionally identified. Due to the severity of clinical signs, the right thoracic limb was amputated. Histologic examination of the cubital joint revealed marked granulomatous synovitis, fasciitis, panniculitis, and osteomyelitis, all with intralesional fungi. Talaromyces helicus is a very rare cause of disease, reported only in one other dog. Granulomatous lymphadenitis appears to be a feature of this disease, but this report is the first to describe a significant synovial component.     

Inhibition of collagenase breakdown of equine corneas by tetanus antitoxin,equine serum and acetylcysteine

Objective To determine whether tetanus antitoxin, equine serum, and acetylcysteine, which are currently used in the treatment of equine corneal ulcer, inhibit the digestion of equine corneal collagen when exposed to collagenase in vitro. Animals studied Corneas from 40 adult horses. Procedures Sections of equine corneas were incubated with saline, a solution of bacterial collagenase in saline, bacterial collagenase in saline plus equine tetanus antitoxin, bacterial collagenase in saline plus equine serum, or bacterial collagenase in saline plus acetylcysteine. Each one of the collagenase inhibitors was tested at different concentrations. The degree of corneal collagen digestion was determined by concentrations of hydroxyproline released into the incubation media and/or by weight loss of the cornea. Results Corneas exposed to collagenase released a significant (0.05 level) large amount of hydroxyproline (43.1 ± 2.3 µg/mL/100 mg cornea/5 h) and decreased cornea weight by up to 89%. Blood serum (200 µL/mL), purified albumin or globulin fractions of serum, tetanus antitoxin (120 units/mL), and acetylcysteine (20 mg/mL) when used at the highest concentrations blocked collagenase digestive activity by approximately 50%. Dilution of inhibitors decreased corneal protection and linearly increased corneal weight loss. Purified equine serum albumin and globulin fractions were equally effective in protecting corneas. Conclusions This experiment indicates that tetanus antitoxin, serum and acetylcysteine equally protected corneas from collagenase digestion, in vitro. However, a clinical trial is needed to establish relative therapeutic value.     

Relationship Between Landscape Characteristics,History, and Lakewater Acidification in the Adirondack Mountains,New York

Interactions between acidic deposition and watershed characteristics were evaluated for a group of lakes in the Adirondack Mountains, New York. Landscape characteristics were compiled and examined relative to paleolimnological inferences of historical acidification. Results of estimates of acidification using the Model of Acidification of Groundwater in Catchments (MAGIC) and paleolimnological analysis were compared to physical, biological, and landscape change data, including such factors as watershed disturbance, logging, fire, and windthrow, to evaluate if inclusion of additional processes could improve model estimates. Results of bivariate and multivariate analysis confirmed that lakes that have experienced historical acidification tend to be those that receive relatively high amounts of precipitation and have short hydraulic residence times. These variables explained 58% of the diatom-inferred acidification. A combined model of long-term precipitation amount, hydraulic residence time, and recent blowdown accounted for 71% of the historic acidification in the Adirondacks. Lakes that have increased in pH since pre-industrial times tend to be those subject to substantial human disturbance and those that burned during major fires recorded after 1900. The magnitude of the discrepancy between MAGIC model and diatom-inferred hindcasts of acidification was not significantly correlated with any of the landscape change variables, suggesting that additional modifications to the MAGIC model to take into account landscape change are not likely to appreciably improve model performance.     

Inhibition of N-Type Calcium Channels by Fluorophenoxyanilide Derivatives

A set of fluorophenoxyanilides, designed to be simplified analogues of previously reported ω-conotoxin GVIA mimetics, were prepared and tested for N-type calcium channel inhibition in a SH-SY5Y neuroblastoma FLIPR assay. N-type or Ca_v2.2 channel is a validated target for the treatment of refractory chronic pain. Despite being significantly less complex than the originally designed mimetics, up to a seven-fold improvement in activity was observed.