bluuebunny/crossref_metadata_2025 huggingface dataset:
The Transforming Growth Factor-β Pathway Is a Common Target of Drugs That Prevent Experimental Diabetic Retinopathy
Authors: Gerhardinger Chiara , Dagher Zeina , Sebastiani Paola , Park Yong Seek , Lorenzi Mara
Published: April 2009

OBJECTIVE

Prevention of diabetic retinopathy would benefit from availability of drugs that preempt the effects of hyperglycemia on retinal vessels. We aimed to identify candidate drug targets by investigating the molecular effects of drugs that prevent retinal capillary demise in the diabetic rat.

RESEARCH DESIGN AND METHODS

We examined the gene expression profile of retinal vessels isolated from rats with 6 months of streptozotocin-induced diabetes and compared it with that of control rats. We then tested whether the aldose reductase inhibitor sorbinil and aspirin, which have different mechanisms of action, prevented common molecular abnormalities induced by diabetes. The Affymetrix GeneChip Rat Genome 230 2.0 array was complemented by real-time RT-PCR, immunoblotting, and immunohistochemistry.

RESULTS

The retinal vessels of diabetic rats showed differential expression of 20 genes of the transforming growth factor (TGF)-β pathway, in addition to genes involved in oxidative stress, inflammation, vascular remodeling, and apoptosis. The complete loop of TGF-β signaling, including Smad2 phosphorylation, was enhanced in the retinal vessels, but not in the neural retina. Sorbinil normalized the expression of 71% of the genes related to oxidative stress and 62% of those related to inflammation. Aspirin had minimal or no effect on these two categories. The two drugs were instead concordant in reducing the upregulation of genes of the TGF-β pathway (55% for sorbinil and 40% for aspirin) and apoptosis (74 and 42%, respectively).

CONCLUSIONS

Oxidative and inflammatory stress is the distinct signature that the polyol pathway leaves on retinal vessels. TGF-β and apoptosis are, however, the ultimate targets to prevent the capillary demise in diabetic retinopathy.
Enhanced Glucose Tolerance by SK4 Channel Inhibition in Pancreatic β-Cells
Authors: Düfer Martina , Gier Belinda , Wolpers Daniela , Krippeit-Drews Peter , Ruth Peter , Drews Gisela
Published: April 2009

OBJECTIVE

Ca2+-regulated K+ channels are involved in numerous Ca2+-dependent signaling pathways. In this study, we investigated whether the Ca2+-activated K+ channel of intermediate conductance SK4 (KCa3.1, IK1) plays a physiological role in pancreatic β-cell function.

RESEARCH DESIGN AND METHODS

Glucose tolerance and insulin sensitivity were determined in wild-type (WT) or SK4 knockout (SK4-KO) mice. Electrophysiological experiments were performed with the patch-clamp technique. The cytosolic Ca2+ concentration ([Ca2+]c) was determined by fura-2 fluorescence. Insulin release was assessed by radioimmunoassay, and SK4 protein was detected by Western blot analysis.

RESULTS

SK4-KO mice showed improved glucose tolerance, whereas insulin sensitivity was not altered. The animals were not hypoglycemic. Isolated SK4-KO β-cells stimulated with 15 mmol/l glucose had an increased Ca2+ action potential frequency, and single-action potentials were broadened. These alterations were coupled to increased [Ca2+]c. In addition, glucose responsiveness of membrane potential, [Ca2+]c, and insulin secretion were shifted to lower glucose concentrations. SK4 protein was expressed in WT islets. An increase in K+ currents and concomitant membrane hyperpolarization could be evoked in WT β-cells by the SK4 channel opener DCEBIO (100 μmol/l). Accordingly, the SK4 channel blocker TRAM-34 (1 μmol/l) partly inhibited KCa currents and induced electrical activity at a threshold glucose concentration. In stimulated WT β-cells, TRAM-34 further increased [Ca2+]c and broadened action potentials similar to those seen in SK4-KO β-cells. SK4 channels were found to substantially contribute to Kslow (slowly activating K+ current).

CONCLUSIONS

SK4 channels are involved in β-cell stimulus-secretion coupling. Deficiency of SK4 current induces elevated β-cell responsiveness and coincides with improved glucose tolerance in vivo. Therefore, pharmacologic modulation of these channels might provide an interesting approach for the development of novel insulinotropic drugs.
Confirmation of Multiple Risk Loci and Genetic Impacts by a Genome-Wide Association Study of Type 2 Diabetes in the Japanese Population
Authors: Takeuchi Fumihiko , Serizawa Masakuni , Yamamoto Ken , Fujisawa Tomomi , Nakashima Eitaro , Ohnaka Keizo , Ikegami Hiroshi , Sugiyama Takao , Katsuya Tomohiro , Miyagishi Makoto , Nakashima Naoki , Nawata Hajime , Nakamura Jiro , Kono Suminori , Takayanagi Ryoichi , Kato Norihiro
Published: April 2009

OBJECTIVE

To identify novel type 2 diabetes gene variants and confirm previously identified ones, a three-staged genome-wide association study was performed in the Japanese population.

RESEARCH DESIGN AND METHODS

In the stage 1 scan, we genotyped 519 case and 503 control subjects with 482,625 single nucleotide polymorphism (SNP) markers; in the stage 2 panel comprising 1,110 case subjects and 1,014 control subjects, we assessed 1,456 SNPs (P < 0.0025, stage 1); additionally to direct genotyping, 964 healthy control subjects formed the in silico control panel. Along with genome-wide exploration, we aimed to replicate the disease association of 17 SNPs from 16 candidate loci previously identified in Europeans. The associated and/or replicated loci (23 SNPs; P < 7 × 10–5 for genome-wide exploration and P < 0.05 for replication) were examined in the stage 3 panel comprising 4,000 case subjects and 12,569 population-based samples, from which 4,889 nondiabetic control subjects were preselected. The 12,569 subjects were used for overall risk assessment in the general population.

RESULTS

Four loci—1 novel with suggestive evidence (PEPD on 19q13, P = 1.4 × 10–5) and three previously reported—were identified; the association of CDKAL1, CDKN2A/CDKN2B, and KCNQ1 were confirmed (P < 10–19). Moreover, significant associations were replicated in five other candidate loci: TCF7L2, IGF2BP2, SLC30A8, HHEX, and KCNJ11. There was substantial overlap of type 2 diabetes susceptibility genes between the two populations, whereas effect size and explained variance tended to be higher in the Japanese population.

CONCLUSIONS

The strength of association was more prominent in the Japanese population than in Europeans for more than half of the confirmed type 2 diabetes loci.
The Presence and Severity of Chronic Kidney Disease Predicts All-Cause Mortality in Type 1 Diabetes
Authors: Groop Per-Henrik , Thomas Merlin C. , Moran John L. , Wadèn Johan , Thorn Lena M. , Mäkinen Ville-Petteri , Rosengård-Bärlund Milla , Saraheimo Markku , Hietala Kustaa , Heikkilä Outi , Forsblom Carol
Published: April 2009

OBJECTIVES

This study aimed to identify clinical features associated with premature mortality in a large contemporary cohort of adults with type 1 diabetes.

RESEARCH DESIGN AND METHODS

The Finnish Diabetic Nephropathy (FinnDiane) study is a national multicenter prospective follow-up study of 4,201 adults with type 1 diabetes from 21 university and central hospitals, 33 district hospitals, and 26 primary health care centers across Finland.

RESULTS

During a median 7 years of follow-up, there were 291 deaths (7%), 3.6-fold (95% CI 3.2–4.0) more than that observed in the age- and sex-matched general population. Excess mortality was only observed in individuals with chronic kidney disease. Individuals with normoalbuminuria showed no excess mortality beyond the general population (standardized mortality ratio [SMR] 0.8, 95% CI 0.5–1.1), independent of the duration of diabetes. The presence of microalbuminuria, macroalbuminuria, and end-stage kidney disease was associated with 2.8, 9.2, and 18.3 times higher SMR, respectively. The increase in mortality across each stage of albuminuria was equivalent to the risk conferred by preexisting macrovascular disease. In addition, the glomerular filtration rate was independently associated with mortality, such that individuals with impaired kidney function, as well as those demonstrating hyperfiltration, had an increased risk of death.

CONCLUSIONS

An independent graded association was observed between the presence and severity of kidney disease and mortality in a large contemporary cohort of individuals with type 1 diabetes. These findings highlight the clinical and public health importance of chronic kidney disease and its prevention in the management of type 1 diabetes.
Diabetes-Specific HLA-DR–Restricted Proinflammatory T-Cell Response to Wheat Polypeptides in Tissue Transglutaminase Antibody–Negative Patients With Type 1 Diabetes
Authors: Mojibian Majid , Chakir Habiba , Lefebvre David E. , Crookshank Jennifer A. , Sonier Brigitte , Keely Erin , Scott Fraser W.
Published: April 2009

OBJECTIVE

There is evidence of gut barrier and immune system dysfunction in some patients with type 1 diabetes, possibly linked with exposure to dietary wheat polypeptides (WP). However, questions arise regarding the frequency of abnormal immune responses to wheat and their nature, and it remains unclear whether such responses are diabetes specific.

RESEARCH DESIGN AND METHODS

In type 1 diabetic patients and healthy control subjects, the immune response of peripheral CD3+ T-cells to WPs, ovalbumin, gliadin, α-gliadin 33-mer peptide, tetanus toxoid, and phytohemagglutinin was measured using a carboxyfluorescein diacetate succinimidyl ester (CFSE) proliferation assay. T–helper cell type 1 (Th1), Th2, and Th17 cytokines were analyzed in WP-stimulated peripheral blood mononuclear cell (PBMNC) supernatants, and HLA was analyzed by PCR.

RESULTS

Of 42 patients, 20 displayed increased CD3+ T-cell proliferation to WPs and were classified as responders; proliferative responses to other dietary antigens were less pronounced. WP-stimulated PBMNCs from patients showed a mixed proinflammatory cytokine response with large amounts of IFN-γ, IL-17A, and increased TNF. HLA-DQ2, the major celiac disease risk gene, was not significantly different. Nearly all responders carried the diabetes risk gene HLA-DR4. Anti-DR antibodies blocked the WP response and inhibited secretion of Th1 and Th17 cytokines. High amounts of WP-stimulated IL-6 were not blocked.

CONCLUSIONS

T-cell reactivity to WPs was frequently present in type 1 diabetic patients and associated with HLA-DR4 but not HLA-DQ2. The presence of an HLA-DR–restricted Th1 and Th17 response to WPs in a subset of patients indicates a diabetes-related inflammatory state in the gut immune tissues associated with defective oral tolerance and possibly gut barrier dysfunction.
Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21
Authors: Mai Knut , Andres Janin , Biedasek Katrin , Weicht Jessica , Bobbert Thomas , Sabath Markus , Meinus Sabine , Reinecke Franziska , Möhlig Matthias , Weickert Martin O. , Clemenz Markus , Pfeiffer Andreas F.H. , Kintscher Ulrich , Spuler Simone , Spranger Joachim
Published: April 2009

OBJECTIVE

Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator–activator receptor (PPAR) α–dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARα, might modify FGF-21 levels.

RESEARCH DESIGN AND METHODS

The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARγ activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks.

RESULTS

Oleate and linoleate increased FGF-21 expression and secretion in a PPARα-dependent fashion, as demonstrated by small-interfering RNA–induced PPARα knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect.

CONCLUSIONS

The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity.
Macrophages and Adipocytes in Human Obesity
Authors: Capel Frédéric , Klimčáková Eva , Viguerie Nathalie , Roussel Balbine , Vítková Michaela , Kováčiková Michaela , Polák Jan , Kováčová Zuzana , Galitzky Jean , Maoret Jean-José , Hanáček Jiří , Pers Tune H. , Bouloumié Anne , Štich Vladimir , Langin Dominique
Published: April 2009

OBJECTIVE

We investigated the regulation of adipose tissue gene expression during different phases of a dietary weight loss program and its relation with insulin sensitivity.

RESEARCH DESIGN AND METHODS

Twenty-two obese women followed a dietary intervention program composed of an energy restriction phase with a 4-week very-low-calorie diet and a weight stabilization period composed of a 2-month low-calorie diet followed by 3–4 months of a weight maintenance diet. At each time point, a euglycemic-hyperinsulinemic clamp and subcutaneous adipose tissue biopsies were performed. Adipose tissue gene expression profiling was performed using a DNA microarray in a subgroup of eight women. RT–quantitative PCR was used for determination of mRNA levels of 31 adipose tissue macrophage markers (n = 22).

RESULTS

Body weight, fat mass, and C-reactive protein level decreased and glucose disposal rate increased during the dietary intervention program. Transcriptome profiling revealed two main patterns of variations. The first involved 464 mostly adipocyte genes involved in metabolism that were downregulated during energy restriction, upregulated during weight stabilization, and unchanged during the dietary intervention. The second comprised 511 mainly macrophage genes involved in inflammatory pathways that were not changed or upregulated during energy restriction and downregulated during weight stabilization and dietary intervention. Accordingly, macrophage markers were upregulated during energy restriction and downregulated during weight stabilization and dietary intervention. The increase in glucose disposal rates in each dietary phase was associated with variation in expression of sets of 80–110 genes that differed among energy restriction, weight stabilization, and dietary intervention.

CONCLUSIONS

Adipose tissue macrophages and adipocytes show distinct patterns of gene regulation and association with insulin sensitivity during the various phases of a dietary weight loss program.
Additive Interaction Between the Renin-Angiotensin System and Lipid Metabolism for Cancer in Type 2 Diabetes
Authors: Yang Xilin , Zhao Hailu , Sui Yi , Ma Ronald C.W. , So Wing Yee , Ko Gary T.C. , Kong Alice P.S. , Ozaki Risa , Yeung Chun Yip , Xu Gang , Tong Peter C.Y. , Chan Juliana C.N.
Published: April 2009

OBJECTIVE

Clinical and experimental studies suggest cross-talk between lipid metabolism and the renin-angiotensin system (RAS) in atherogenesis. The aim of this study was to explore interactions between these two systems in mediating cancer risk in type 2 diabetes.

RESEARCH DESIGN AND METHODS

A prospective cohort of 4,160 Chinese patients with type 2 diabetes, free of cancer at enrollment, were analyzed using Cox models. Interaction of RAS inhibitors (angiotensin I–converting enzyme inhibitors or angiotensin II receptor blockers) and statins was estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S). RERI > 0, AP > 0, or S > 1 indicates additive interaction between the two classes of drugs. Molecular mechanisms underlying these interactions were explored using a uninephrectomy (UNX) rat model with renal carcinogenesis.

RESULTS

During 21,992 person-years of follow-up, 190 patients developed cancer. Use of RAS inhibitors and statins in isolation or combination during follow-up was associated with reduced risk of cancer after adjustment for covariates. The multivariable RERI and AP for the additive interaction between these drug classes for cancer were significant (0.53 [95% CI 0.20–0.87] and 2.65 [0.38–4.91], respectively). In the UNX rat model, inhibition of the RAS prevented renal cell carcinoma by normalizing hydroxymethylglutaryl-CoA reductase (HMGCR) expression and the insulin-like growth factor-1 (IGF-1) signaling pathway.

CONCLUSIONS

Combined use of RAS inhibitors and statins may act synergistically to reduce cancer risk, possibly via HMGCR and IGF-1 signaling pathways in high-risk conditions such as type 2 diabetes.
Deletion of PKCε Selectively Enhances the Amplifying Pathways of Glucose-Stimulated Insulin Secretion via Increased Lipolysis in Mouse β-Cells
Authors: Cantley James , Burchfield James G. , Pearson Gemma L. , Schmitz-Peiffer Carsten , Leitges Michael , Biden Trevor J.
Published: April 2009

OBJECTIVE

Insufficient insulin secretion is a hallmark of type 2 diabetes, and exposure of β-cells to elevated lipid levels (lipotoxicity) contributes to secretory dysfunction. Functional ablation of protein kinase C ε (PKCε) has been shown to improve glucose homeostasis in models of type 2 diabetes and, in particular, to enhance glucose-stimulated insulin secretion (GSIS) after lipid exposure. Therefore, we investigated the lipid-dependent mechanisms responsible for the enhanced GSIS after inactivation of PKCε.

RESEARCH DESIGN AND METHODS

We cultured islets isolated from PKCε knockout (PKCεKO) mice in palmitate prior to measuring GSIS, Ca2+ responses, palmitate esterification products, lipolysis, lipase activity, and gene expression.

RESULTS

The enhanced GSIS could not be explained by increased expression of another PKC isoform or by alterations in glucose-stimulated Ca2+ influx. Instead, an upregulation of the amplifying pathways of GSIS in lipid-cultured PKCεKO β-cells was revealed under conditions in which functional ATP-sensitive K+ channels were bypassed. Furthermore, we showed increased esterification of palmitate into triglyceride pools and an enhanced rate of lipolysis and triglyceride lipase activity in PKCεKO islets. Acute treatment with the lipase inhibitor orlistat blocked the enhancement of GSIS in lipid-cultured PKCεKO islets, suggesting that a lipolytic product mediates the enhancement of glucose-amplified insulin secretion after PKCε deletion.

CONCLUSIONS

Our findings demonstrate a mechanistic link between lipolysis and the amplifying pathways of GSIS in murine β-cells, and they suggest an interaction between PKCε and lipolysis. These results further highlight the therapeutic potential of PKCε inhibition to enhance GSIS from the β-cell under conditions of lipid excess.
High Incidence of Metabolically Active Brown Adipose Tissue in Healthy Adult Humans
Authors: Saito Masayuki , Okamatsu-Ogura Yuko , Matsushita Mami , Watanabe Kumiko , Yoneshiro Takeshi , Nio-Kobayashi Junko , Iwanaga Toshihiko , Miyagawa Masao , Kameya Toshimitsu , Nakada Kunihiro , Kawai Yuko , Tsujisaki Masayuki
Published: April 2009

OBJECTIVE

The significant roles of brown adipose tissue (BAT) in the regulation of energy expenditure and adiposity are established in small rodents but have been controversial in humans. The objective is to examine the prevalence of metabolically active BAT in healthy adult humans and to clarify the effects of cold exposure and adiposity.

RESEARCH DESIGN AND METHODS

In vivo 2-[18F]fluoro-2-deoxyglucose (FDG) uptake into adipose tissue was measured in 56 healthy volunteers (31 male and 25 female subjects) aged 23–65 years by positron emission tomography (PET) combined with X-ray computed tomography (CT).

RESULTS

When exposed to cold (19°C) for 2 h, 17 of 32 younger subjects (aged 23–35 years) and 2 of 24 elderly subjects (aged 38–65 years) showed a substantial FDG uptake into adipose tissue of the supraclavicular and paraspinal regions, whereas they showed no detectable uptake when kept warm (27°C). Histological examinations confirmed the presence of brown adipocytes in these regions. The cold-activated FDG uptake was increased in winter compared with summer (P < 0.001) and was inversely related to BMI (P < 0.001) and total (P < 0.01) and visceral (P < 0.001) fat areas estimated from CT image at the umbilical level.

CONCLUSIONS

Our findings, being against the conventional view, indicate the high incidence of metabolically active BAT in adult humans and suggest a role in the control of body temperature and adiposity.
Type 2 Diabetes Prevention in the Real World
Authors: Absetz Pilvikki , Oldenburg Brian , Hankonen Nelli , Valve Raisa , Heinonen Heikki , Nissinen Aulikki , Fogelholm Mikael , Talja Martti , Uutela Antti
Published: April 2009

OBJECTIVE

We study the effectiveness of the GOAL Lifestyle Implementation Trial at the 36-month follow-up.

RESEARCH DESIGN AND METHODS

Participants (n = 352, type 2 diabetes risk score FINDRISC = 16.2 ± 3.3, BMI 32.6 ± 5.0 kg/m2) received six lifestyle counseling sessions over 8 months. Measurements were at baseline, 12 months (88.6%), and 36 months (77.0%).

RESULTS

Statistically significant risk reduction at 12 months was maintained at 36 months in weight (−1.0 ± 5.6 kg), BMI (−0.5 ± 2.1 kg/m2), and serum total cholesterol (−0.4 ± 1.1 mmol/l).

CONCLUSIONS

Maintenance of risk reduction in this “real world” trial proves the intervention's potential for significant public health impact.
Body Iron Stores and Glucose Intolerance in Premenopausal Women
Authors: Martínez-García M. Ángeles , Luque-Ramírez Manuel , San-Millán José L. , Escobar-Morreale Héctor F.
Published: April 2009

OBJECTIVE

Increased serum ferritin levels and iron stores may be involved in the development of abnormal glucose tolerance in women presenting with obesity and/or polycystic ovary syndrome (PCOS). We aimed to study the determinants of serum ferritin levels in premenopausal women among indexes of insulin resistance, adiposity, hyperandrogenism, and genotypes pertaining to inflammation, oxidative stress, and iron metabolism.

RESEARCH DESIGN AND METHODS

A total of 257 premenopausal women, classified depending on the presence or absence of PCOS, obesity, and/or abnormal glucose tolerance, underwent a complete metabolic evaluation, serum ferritin, haptoglobin, and C-reactive protein (CRP) measurements, and genotyping for proinflammatory and prooxidant variants and mutations in the HFE gene.

RESULTS

Serum ferritin concentrations were increased in women presenting with PCOS and/or abnormal glucose tolerance, independent of obesity. A stepwise multivariate linear regression analysis (R2 = 0.18, P < 0.0001) retained menstrual dysfunction (β = 0.14, P = 0.035), free testosterone (β = 0.14, P = 0.052), insulin sensitivity index (β = −0.12, P = 0.012), the His63Asp variant in HFE (β = 0.16, P = 0.008), and abnormal glucose tolerance (β = 0.15, P = 0.015) as significant predictors of the logarithm of ferritin levels, whereas CRP, haptoglobin, waist-to-hip ratio, or variants in the TNFα, TNFRSF1B, IL6, IL6ST, IL6Rα, PON1, and HFE Cys282Tyr mutation exerted no influence.

CONCLUSIONS

Androgen excess (partly because of hyperandrogenemia and partly because of menstrual dysfunction), insulin resistance, abnormal glucose tolerance, and the HFE His63Asp variant correlate with ferritin levels in premenopausal women.
Diabetes Numeracy
Authors: Osborn Chandra Y. , Cavanaugh Kerri , Wallston Kenneth A. , White Richard O. , Rothman Russell L.
Published: April 2009

OBJECTIVE

Understanding the reasons and eliminating the pervasive health disparities in diabetes is a major research, clinical, and health policy goal. We examined whether health literacy, general numeracy, and diabetes-related numeracy explain the association between African American race and poor glycemic control (A1C) in patients with diabetes.

RESEARCH DESIGN AND METHODS

Adults with type 2 diabetes (n = 383) were enrolled in a cross-sectional study at primary care and diabetes clinics at three medical centers. Data collected included the following: self-reported race, health literacy, general numeracy, diabetes-related numeracy, A1C, and sociodemographic factors. A series of structural equation models were estimated to explore the interrelations between variables and test for mediation.

RESULTS

In model 1, younger age (r = −0.21, P < 0.001), insulin use (r = 0.27, P < 0.001), greater years with diabetes (r = 0.16, P < 0.01), and African American race (r = 0.12, P < 0.01) were all associated with poorer glycemic control. In model 2, diabetes-related numeracy emerged as a strong predictor of A1C (r = −0.46, P < 0.001), reducing the association between African American and poor glycemic control to nonsignificance (r = 0.10, NS). In model 3, African American race and older age were associated with lower diabetes-related numeracy; younger age, insulin use, more years with diabetes, and lower diabetes-related numeracy were associated with poor glycemic control.

CONCLUSIONS

Diabetes-related numeracy reduced the explanatory power of African American race, such that low diabetes-related numeracy, not African American race, was significantly related to poor glycemic control. Interventions that address numeracy could help to reduce racial disparities in diabetes.
Stability of common biochemistry analytes in equine blood stored at room temperature
Authors: RENDLE D. I. , HELLER J. , HUGHES K. J. , INNOCENT G. T. , DURHAM A. E.
Published: April 2009

Reasons for performing study: Time delays between collection of blood samples and biochemical analysis of equine blood are unavoidably common in equine practice. The effect that delays may have on the accuracy of results of blood biochemical analyses is not well established.

Hypothesis: Delays in processing of blood of up to 72h results in alterations in measured levels of common biochemical analytes that are of potential clinical relevance. Separation of serum prior to storage is protective against the effects of time delays.

Methods: Samples of clotted blood, separated serum and oxalate fluoride plasma from 20 horses were stored and analysed at 0, 24, 48 and 72 h. Graphical exploration of each analyte was undertaken. General linear models with fixed effects were fitted for the whole blood data. The mean bias and 95% limits of agreement were calculated, using bootstrapped data, to assess agreement between pairs of samples analysed at 0 h and other time points. Bland‐Altman plots were used to explore general trends in the data. Pairedttests were used to compare the results from whole blood and separated serum.

Results: Delays in processing equine blood resulted in significant increases in measured concentrations of aspartate aminotransferase, creatine kinase, lactate dehydrogenase, total bile acids and magnesium. A significant decrease in concentration was identified for glucose (serum and oxalate fluoride preserved plasma). Separation of serum immediately following clot formation resulted in nonsignificant increases in accuracy for some analytes.

Conclusions and practical significance: Delays in processing of blood samples may result in biochemical changes of clinical relevance in individual cases; however, in the majority of cases, where delays are only a few days and a number of analytes are assessed concurrently, delays are unlikely to have an effect on the interpretation of results. Separation of serum following clot formation is of limited benefit. Clinical samples in which a delay in processing has occurred may be interpreted with reference to the data presented.
The effect of rising and sitting trot on back movements and head‐neck position of the horse
Authors: de COCQ P. , PRINSEN H. , SPRINGER N. C. N. , van WEEREN P. R. , SCHREUDER M. , MULLER M. , van LEEUWEN J. L.
Published: April 2009

Reason for performing study: During trot, the rider can either rise from the saddle during every stride or remain seated. Rising trot is used frequently because it is widely assumed that it decreases the loading of the equine back. This has, however, not been demonstrated in an objective study.

Objective: To determine the effects of rising and sitting trot on the movements of the horse.

Hypothesis: Sitting trot has more extending effect on the horse's back than rising trot and also results in a higher head and neck position.

Methods: Twelve horses and one rider were used. Kinematic data were captured at trot during over ground locomotion under 3 conditions: unloaded, rising trot and sitting trot. Back movements were calculated using a previously described method with a correction for trunk position. Head‐neck position was expressed as extension and flexion of C1, C3 and C6, and vertical displacement of C1 and the bit.

Results: Sitting trot had an overall extending effect on the back of horses when compared to the unloaded situation. In rising trot: the maximal flexion of the back was similar to the unloaded situation, while the maximal extension was similar to sitting trot; lateral bending of the back was larger than during the unloaded situation and sitting trot; and the horses held their heads lower than in the other conditions. The angle of C6 was more flexed in rising than in sitting trot.

Conclusions and clinical relevance: The back movement during rising trot showed characteristics of both sitting trot and the unloaded condition. As the same maximal extension of the back is reached during rising and sitting trot, there is no reason to believe that rising trot was less challenging for the back.
Pharmacokinetics of detomidine administered to horses at rest and after maximal exercise
Authors: HUBBELL J. A. E. , SAMS R. A. , SCHMALL L. M. , ROBERTSON J. T. , HINCHCLIFF DrK. W. , MUIR W. W.
Published: April 2009

Reason for performing study: Increased doses of detomidine are required to produce sedation in horses after maximal exercise compared to calm or resting horses.

Objectives: To determine if the pharmacokinetics of detomidine in Thoroughbred horses are different when the drug is given during recuperation from a brief period of maximal exercise compared to administration at rest.

Methods: Six Thoroughbred horses were preconditioned by exercising them on a treadmill. Each horse ran a simulated race at a treadmill speed that caused it to exercise at 120% of its maximal oxygen consumption. One minute after the end of exercise, horses were treated with detomidine. Each horse was treated with the same dose of detomidine on a second occasion a minimum of 14 days later while standing in a stocks. Samples of heparinised blood were obtained at various time points on both occasions. Plasma detomidine concentrations were determined by liquid chromatographymass spectrometry. The plasma concentration vs. time data were analysed by nonlinear regression analysis.

Results: Median back‐extrapolated time zero plasma concentration was significantly lower and median plasma half‐life and median mean residence time were significantly longer when detomidine was administered after exercise compared to administration at rest. Median volume of distribution was significantly higher after exercise but median plasma clearance was not different between the 2 administrations.

Conclusions and potential relevance: Detomidine i.v. is more widely distributed when administered to horses immediately after exercise compared to administration at rest resulting in lower peak plasma concentrations and a slower rate of elimination. The dose requirement to produce an equivalent effect may be higher in horses after exercise than in resting horses and less frequent subsequent doses may be required to produce a sustained effect.
Short‐term outcome of equine emergency admissions at a university referral hospital
Authors: SOUTHWOOD L. L. , DOLENTE B. A. , LINDBORG S. , RUSSELL G. , BOSTON R.
Published: April 2009

Reasons for performing study: Obtaining data on emergency admission survival rates is important to provide clients with an estimate of prognosis and to identify areas in which improvements in case management can be achieved.

Objective: To determine the short‐term outcome of equine emergency admissions to a university referral hospital during a 12 month period.

Methods: Short‐term outcome was defined as survival to discharge or died/euthanasia during hospitalisation. The overall death (euthanasia) rate was calculated; and rate for horses with different categories of: age; admission month, day and time; presenting complaint (PC); duration of clinical signs prior to presentation; clinical pathology abnormalities; and therapy/therapeutic‐related procedures performed was recorded.

Results: There were 918 admissions. The overall death rate was 24%. Foals (34%) and geriatric (40%) subjects had a death rate that was higher than that for mature horses (21%, referent). The death rate was highest in March (37%). Horses with a PC categorised as neurological (46%) or neonatal (41%) had the highest and as ophthalmological (5%) or trauma/skin (13%) the lowest death rates. There was no difference in death rate between different admission days or times or the duration of clinical signs prior to presentation. The death rates for horses with abnormal peritoneal fluid (71%), coagulopathy (63%), acid‐base abnormalities (52%), hypoproteinaemia (47%), dehydration (43%), hypoxia/hypercapnia (48%), leucopenia (44%), electrolyte abnormalities (39%), hyperlactataemia (39%) or azotaemia (35%) were high. The death rate for horses treated with intranasal oxygen (57%), plasma (34%) or polymixin B (35%) was high and for horses undergoing laceration repair/joint (0%) or synovial cavity lavage (4%) was low.

Conclusions: Age and critical illness were important contributing factors to a higher death rate.Potential relevance: Improving the understanding of disease processes in and developing treatment strategies for neonatal and geriatric patients as well as critically ill patients is required.
Two‐ and three‐dimensional computed tomographic anatomy of the enamel, infundibulae and pulp of 126 equine cheek teeth. Part 2: Findings in teeth with macroscopic occlusal or computed tomographic lesions
Authors: WINDLEY Z. , WELLER R. , TREMAINE W. H. , PERKINS J. D.
Published: April 2009

Reasons for performing study: Dental disease often presents a diagnostic challenge in the horse. Computed tomography (CT) is increasingly used in the evaluation of head related disease in the horse, but the CT appearance of the most common dental diseases of horses has not yet been fully described.

Objective: To describe the CT appearance of the peripheral enamel, pulp, infundibular enamel and cement in equine cheek teeth with macroscopic occlusal or CT lesions.

Methods: In this study, 126 cadaveric cheek teeth with eruption ages of between 0.5 and 19 years were evaluated for lesions of their infundibulae, pulp and enamel using occlusal surface morphology, 2‐ (2D) and 3‐dimensional (3D) CT and anatomical sectioning. Variations in teeth with no macroscopic lesions have been described in a previous study. The infundibular lesions were categorised further into one of 6 classifications.

Results: Infundibular lesions were identified on CT in 90% (115/128) of infundibulae. Of these, 65% (83/128) had infundibular lesions on occlusal surface examination. The extent of infundibular lesions observed varied with age group. All infundibulae over 6 years post eruption had detectable lesions. Peripheral enamel hypoplasia and enamel prolapses, were observed in 10% (12/126) and 1.6% (2/126) of teeth, respectively. The CT appearance of teeth with pulp infections was seen to vary with differing pathologies.

Conclusions and potential relevance: The high prevalence of infundibular lesions should encourage consideration of their clinical significance, in addition to the role of infundibulae in dental disease of the horse. Two‐dimensional and 3D CT proved to be highly valuable imaging modalities for dental disease, enabling lesions within the enamel, infundibulae and pulp of equine cheek teeth to be easily detected. The results of this study will facilitate the use of 2D and 3D CT as clinical diagnostic tools for dental disease and aid in the selection of the most appropriate treatment protocol.
Ultrasonographic assessment of the superficial digital flexor tendons of National Hunt racehorses in training over two racing seasons
Authors: AVELLA C. S. , ELY E. R. , VERHEYEN K. L. P. , PRICE J. S. , WOOD J. L. N. , SMITH R. K. W.
Published: April 2009

Reasons for performing study: It is important to ascertain the prevalence of superficial digital flexor tendon (SDFT) injuries and to improve methods of predicting injury in National Hunt (NH) racehorses.

Objectives: To establish: 1) the prevalence of SDFT tendinopathy in NH horses; 2) whether routine ultrasonography can be used to predict SDFT injuries; 3) whether previous tendinopathy predisposes to reinjury; 4) a normal range for the SDFT cross‐sectional area (CSA); and 5) the effects of gender, age, background (ex‐flat or exstore), limb, training and rest periods on SDFT CSA.

Methods: Routine ultrasound assessment of the palmar metacarpal soft tissues of 263 NH racehorses was performed on up to 6 occasions over 2 NH racing seasons.

Results: The prevalence of SDFT pathology detected using ultrasonography was 24% (n = 148), with a nonsignificant variation between yards of 10–40%. No changes in SDFT CSA or ultrasonographic appearance were detected prior to injury. Older horses had a significantly higher prevalence of SDFT pathology compared to younger horses, and horses with tendinopathy were more likely to suffer an acute injury compared to horses with no evidence of pathology. A reference range for normal CSA measurements was established as 77–139 mm2at level 4, from 142 horses with no ultrasonographic evidence of SDFT pathology. The CSA of normal horses did not vary significantly with age, limb or over 2 racing seasons, but did with sex and background.

Conclusions: The study confirms that SDFT tendinopathy is common in NH horses, with substantial variation between training yards. Ultrasonography at 3 month intervals did not seem to predict acute SDFT injuries.

Potential relevance: Variation in the prevalence of tendinopathy between yards suggests that training methods may influence injury rate. It was not possible to predict injury using routine ultrasonography and therefore other methods must be identified. A normal reference range for SDFT CSA is provided.
Initial investigation of mortality rates and prognostic indicators in horses with colic in Israel: A retrospective study
Authors: SUTTON G. A. , ERTZMAN‐GINSBURG R. , STEINMAN A. , MILGRAM J.
Published: April 2009

Reasons for performing study: Initial assessment of the mortality rates and prognostic indicators in horses with colic presented to a referral hospital in Israel.

Objectives: To determine mortality rates and to identify potential prognostic indicators in horses undergoing treatment for colic.

Methods: The medical records of 208 colic cases were reviewed and mortality rates calculated including 95% confidence intervals. Mortality rates in surgical cases were calculated separately for strangulating and nonstrangulating lesions as well as for lesions of the large and small intestines. Potential prognostic indicators were identified and evaluated by Student'sttest or X2test, where appropriate. Those found to be significant (P<0.05) were evaluated in 2 logistic regression models; one including all horses with colic and one for surgical cases only.

Results: The overall mortality rate was 51/208 (25%); 5/72 (7%) in medically treated cases, 46/136 (34%) in surgical cases, 30/50 (60%) in strangulating lesions and 15/85 (18%) in nonstrangulating lesions, 17/27 (63%) in cases involving small intestinal lesions and 28/108 (26%) in cases with large intestinal lesions. Clinical parameters found to be significantly associated with death by univariate analysis were medical/surgical treatment, location of lesion, severity of lesion, mucous membrane colour (MM), capillary refill time (CRT) and heart rate. Using a multivariate logistic regression model, including all cases, medical/surgical treatment, CRT and MM were found to be prognostic indicators and when using the surgical cases alone, only CRT and lesion severity remained related to mortality.

Conclusions: Mortality rates were similar or better than those previously reported in most cases, however, studies from the USA and the UK published better success rates for small intestinal surgeries. Cultural attitudes toward euthanasia may be associated with mortality rates.

Potential relevance: These results assist clinicians in providing an immediate prognosis based on clinical findings at presentation and contribute to an international database that may aid future research in improving treatment of colic.
Influence of the position of the foot on MRI signal in the deep digital flexor tendon and collateral ligaments of the distal interphalangeal joint in the standing horse
Authors: SPRIET M. , ZWINGENBERGER A.
Published: April 2009

Reasons for performing study: Hyperintense signal is sometimes observed in ligaments and tendons of the equine foot on standing magnetic resonance examination without associated changes in size and shape. In such cases, the presence of a true lesion or an artifact should be considered. A change in position of a ligament or tendon relative to the magnetic field can induce increased signal intensity due to the magic angle effect.

Objectives: To assess if positional rotation of the foot in the solar plane could be responsible for artifactual changes in signal intensity in the collateral ligaments of the distal interphalangeal joint and in the deep digital flexor tendon.

Methods: Six isolated equine feet were imaged with a standing equine magnetic resonance system in 9 different positions with different degrees of rotation in the solar plane.

Results: Rotation of the limb induced a linear hyperintense signal on all feet at the palmar aspect of one of the lobes of the deep digital flexor tendon and at the dorsal aspect of the other lobe. Changes in signal intensity in the collateral ligaments of the distal interphalangeal joint occurred with rotation of the limb only in those feet where mediolateral hoof imbalance was present.

Conclusions: The position and conformation of the foot influence the signal intensity in the deep digital flexor tendon and in the collateral ligaments of the distal interphalangeal joint.

Potential relevance: The significance of increased signal intensity in the deep digital flexor tendon and in the collateral ligaments of the distal interphalangeal joint should be interpreted with regard to the position and the conformation of the foot.
Neurectomy of the deep branch of the lateral plantar nerve can cause neurogenic atrophy of the muscle fibres in the proximal part of the suspensory ligament(M. interosseous III)
Authors: PAUWELS F. E. , SCHUMACHER J. , MAYHEW I. G. , van SICKLE D. C.
Published: April 2009

Neurectomy of the deep branch of the right lateral plantar nerve was performed on a single healthy mature horse. Six weeks after surgery, the horse was subjected to euthanasia and both hind suspensory ligaments harvested. The cross sectional area of the muscular part of the proximal part of the suspensory ligament was measured and assessed for morphological abnormalities in a blinded fashion. There was a clear difference in cross sectional area of the muscular part between treated and control ligament and there was profound neurogenic atrophy of the muscular fibres in the treated ligament.
Ophthalmic antimicrobial therapy in the horse
Authors: Matthews A. G.
Published: April 2009

Effective antimicrobial therapy of infectious ocular disease in the horse may be difficult to achieve. This paper reviews the routes of delivery, the pharmacokinetics and the bioavailability of the various antimicrobial agents used in the treatment of ocular infection in the horse. The modes of action and the criteria for selection of the common antibacterial, antimycotic and antiviral drugs used are described.
Effects of different forms of exercise on post inhibitory rebound and unwanted behaviour in stabled horses
Authors: FREIRE R. , BUCKLEY P. , COOPER J. J.
Published: April 2009

Reasons for performing study: It is unknown if different locomotor activities are equally effective at meeting the stabled horse's need for exercise and if they attenuate unwanted behaviour.

Hypothesis: Alternative forms of exercise influence the intensity of locomotor activities during a period of turn‐out (the so‐called rebound effect) and the occurrence of unwanted or undesirable activities during standard handling situations.

Method: Twenty‐four horses kept in stables were randomly assigned to one of 4 exercise regimes (walker, treadmill, turn‐out and riding) for 4 consecutive days. Because these forms of exercise provide additional environmental stimulation, beyond that provided by exercise, each horse served as its own control in 4 corresponding (no exercise) control treatments presented in a balanced order. Unwanted behaviour was tested by taking horses to weighing scales and loading and unloading them onto a 4‐horse float by an experienced handler and the rebound effect was tested by releasing them into a large arena for a period of 15 min at the end of the exercise and control treatments.

Results: Locomotor activities made up a large part of behaviour in the large arena following control treatments and all exercise regimes were sufficient to reduce the intensity of walking (P<0.05), trotting (P<0.01) and cantering (P<0.001) on release into a large arena. Exercise regime reduced the number of bucks (P<0.01) and rolling (P<0.05) during rebound tests suggesting that turn‐out was having a stronger effect than the other 3 exercise regimes. Exercise regimes significantly reduced the amount of unwanted behaviour and the number of commands given by the handler during weighing (P<0.05) but had no effect on these behaviours during loading onto a float.

Conclusion: Providing stabled horses with one hour/day of exercise on a walker, treadmill, turn‐out or by being ridden are all effective at allowing expression of locomotor activities in stabled horses.

Potential relevance: Providing stabled horses with regular exercise is likely to provide positive effects on horse welfare, training ability and handler safety.
Resection cystoplasty of a squamous cell carcinoma in a mare
Authors: Serena A. , Naranjo C. , Koch C. , Darien B. J.
Published: April 2009

A 22‐year‐old Arabian mare was examined for evaluation of haematuria of 2 months' duration. Complete blood cell count and chemistry revealed anaemia of chronic disease (i.e. normocytic, normochromic) and hypoproteinaemia. Cystoscopy revealed a haemorrhagic mass protruding into the lumen of the urinary bladder in the apical region. The mass was surgically removed by partial cystectomy performed through a caudal ventral midline laparotomy. Histological examination of the mass confirmed the diagnosis of squamous cell carcinoma. Tumours of the equine urinary bladder are rare, and when a partial cystectomy is indicated, a caudal ventral midline laparotomy may provide adequate surgical exposure even in adult horses.