Alterations in plasma non-esterified fatty acid (NEFA) kinetics and relationship with insulin resistance in polycystic ovary syndrome.

STUDY QUESTION: Are non-esterified fatty acid (NEFA) kinetics altered in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Women with PCOS, particularly obese subjects, have dysregulated plasma NEFA kinetics in response to changes in plasma insulin and glucose levels, which are associated with insulin resistance (IR) independently of the fasting plasma NEFA levels. WHAT IS KNOWN ALREADY: Elevated plasma NEFA levels are associated with IR in many disorders, although the homeostasis of NEFA kinetics and its relationship to IR in women with PCOS is unknown. STUDY DESIGN, SIZE, DURATION: We prospectively compared insulin sensitivity and NEFA kinetics in 29 PCOS and 29 healthy controls women matched for BMI. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted in a tertiary institution. Plasma NEFA, glucose and insulin levels were assessed during a modified frequently sampled intravenous glucose tolerance test (mFSIVGTT). Minimal models were used to assess insulin sensitivity (Si) and NEFA kinetics (i.e. model-derived initial plasma NEFA level [NEFA0], phi constant [Φ], reflecting glucose-mediated inhibition of lipolysis and measures of maximum rate of lipolysis [SFFA] and NEFA uptake from plasma [KFFA]). MAIN RESULTS AND THE ROLE OF CHANCE: The study provides new evidence that women with PCOS have defective NEFA kinetics characterized by: (i) lower basal plasma NEFA levels, measured directly and modeled (NEFA0), and (ii) a greater glucose-mediated inhibition of lipolysis in the remote or interstitial space (reflected by a lower affinity constant [Φ]). There were no differences, however, in the maximal rates of adipose tissue lipolysis (SFFA) and the rate at which NEFA leaves the plasma pool (KFFA). The differences observed in NEFA kinetics were exacerbated, and almost exclusively observed, in the obese PCOS subjects. LIMITATIONS, REASONS FOR CAUTION: Our study did not study NEFA subtypes. It was also cross-sectional and based on women affected by PCOS as defined by the 1990 National Institutes of Health (NIH) criteria (i.e. Phenotypes A and B) and identified in the clinical setting. Consequently, extrapolation of the present data to other phenotypes of PCOS should be made with caution. Furthermore, our data is exploratory and therefore requires validation with a larger sample size. WIDER IMPLICATIONS OF THE FINDINGS: Dysfunction in NEFA kinetics may be a marker of metabolic dysfunction in nondiabetic obese women with PCOS and may be more important than simply assessing circulating NEFA levels at a single point in time for understanding the mechanism(s) underlying the IR of PCOS. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by NIH grants R01-DK073632 and R01-HD29364 to R.A.; a Career Development Award from MD Medical Group, Moscow, RF, to D.L. and Augusta University funds to Y.-H.C. RA serves as consultant to Ansh Labs, Medtronics, Spruce Biosciences and Latitude Capital. U.E., Z.A., D.L., R.M., Y.-H.C., R.C.B. and Y.D.I.C. have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Evaluation of the analgesic and pharmacokinetic properties of transdermally administered fentanyl in goats.

OBJECTIVE: Evaluate the analgesic properties and pharmacokinetics of transdermal fentanyl patches (TFPs) in goats. DESIGN: Prospective, randomized study. SETTING: Preclinical Testing Facility at a University Teaching Hospital. ANIMALS: Thirty-four adult female Boer-cross goats. INTERVENTIONS: Goats underwent surgery as part of a concurrent orthopedic research study. Twelve hours prior to surgery, each goat received a TFP (target dosage of 2.5 µg/kg/h), or a placebo patch with analgesia provided by buprenorphine (0.01 mg/kg, IM, q 6 h). Patches were removed after 72 hours. Blood was sampled at specified intervals, up to 84 hours following TFP placement. Plasma concentrations of fentanyl (FEN) were determined using liquid chromatography-mass spectrometry. Postoperative pain assessments were performed by two independent blinded observers. MEASUREMENTS AND MAIN RESULTS: TFPs were applied at a mean (± standard deviation, SD) dose of 2.54 ± 0.36 µg/kg/h. No adverse events occurred. Pain scores between TFP and BUP groups were not significantly different at any time point. Mean plasma FEN concentration (± SD) 2 hours following patch application was 1.06 ± 0.85 ng/mL, and remained above 0.5 ng/mL for 40 hours. Maximum mean plasma FEN concentration (Cmax ) was 1.84 (ranging from 0.81 to 3.35) ng/mL with average time to maximum concentration (Tmax ) of 12 hours after patch application. CONCLUSIONS: TFP resulted in consistent FEN absorption and plasma concentrations within the human and ovine therapeutic ranges. Pain scores for goats administered TFP were not different than those administered buprenorphine. Ease of administration, duration of analgesia, and decreased dosing frequency make TFPs an attractive option for pain management in goats.

Prostate cancer diagnosis using epigenetic biomarkers, 3D high-content imaging and probabilistic cell-by-cell classifiers.

BACKGROUND: Prostate cancer (PCa) management can benefit from novel concepts/biomarkers for reducing the current 20-30% chance of false-negative diagnosis with standard histopathology of biopsied tissue. METHOD: We explored the potential of selected epigenetic markers in combination with validated histopathological markers, 3D high-content imaging, cell-by-cell analysis, and probabilistic classification in generating novel detailed maps of biomarker heterogeneity in patient tissues, and PCa diagnosis. We used consecutive biopsies/radical prostatectomies from five patients for building a database of ∼140,000 analyzed cells across all tissue compartments and for model development; and from five patients and the two well-characterized HPrEpiC primary and LNCaP cancer cell types for model validation. RESULTS: Principal component analysis presented highest covariability for the four biomarkers 4',6-diamidino-2-phenylindole, 5-methylcytosine, 5-hydroxymethylcytosine, and alpha-methylacyl-CoA racemase in the epithelial tissue compartment. The panel also showed best performance in discriminating between normal and cancer-like cells in prostate tissues with a sensitivity and specificity of 85%, correctly classified 87% of HPrEpiC as healthy and 99% of LNCaP cells as cancer-like, identified a majority of aberrant cells within histopathologically benign tissues at baseline diagnosis of patients that were later diagnosed with adenocarcinoma. Using k-nearest neighbor classifier with cells from an initial patient biopsy, the biomarkers were able to predict cancer stage and grade of prostatic tissue that occurred at later prostatectomy with 79% accuracy. CONCLUSION: Our approach showed favorable diagnostic values to identify the portion and pathological category of aberrant cells in a small subset of sampled tissue cells, correlating with the degree of malignancy beyond baseline.

In vitro comparison of 3 techniques of prosthesis attachment to the muscular process of the equine arytenoid cartilage.

OBJECTIVE: To determine the degree and ease of arytenoid abduction achieved with abaxial placement of a FASTak II suture anchor compared to 2 suture patterns with different directions of insertion-caudomedial to craniolateral and medial to lateral. STUDY DESIGN: Ex vivo experimental. STUDY POPULATION: Cadaveric larynges from 10 Standardbred racehorses. METHODS: Each larynx was sequentially instrumented with all 3 arytenoid suture attachment in random order: (1) abaxial placement of a FASTak II suture, (2) caudomedial to craniolateral suture, and (3) medial to lateral suture placement. Each construct was abducted at 5N increments from 0 to 25N and the left to right quotient angle ratio (LRQ) measured from digital pictures acquired at each sequential increment. RESULTS: Arytenoid abduction (higher LRQ) was greater with FASTak II construct than either of the suture patterns. The largest difference occurred at 5N. Approximately 50% less force was required to achieve an LRQ of 1.0 with the FASTak II anchor compared to the suture patterns. No difference was detected between the 2 suture constructs throughout the study. CONCLUSION: Use of the FASTak II suture anchor improved arytenoid abduction compared to 2 suture patterns and minimized the suture loads required to achieve maximum arytenoid abduction. CLINICAL RELEVANCE: Use of the FASTak II anchor may decrease the suture load required to achieve arytenoid abduction in clinical cases. This may reduce the load placed on the laryngoplasty, thereby, minimizing postoperative loss of abduction.

The learning curve for veterinary surgery residents performing hemilaminectomy surgeries in dogs.

OBJECTIVE To describe the learning curve for veterinary surgery residents performing hemilaminectomy surgeries in dogs. DESIGN Retrospective case review and learning curve evaluation. SAMPLE 13 individuals who completed a 3-year surgery residency program at a university teaching hospital and who had no prior experience performing hemilaminectomies. PROCEDURES The 13 residents performed hemilaminectomies on 399 dogs between July 2006 and July 2013. Medical records were reviewed, and operative time was recorded. Data were examined with a linear mixed-effects model to quantify fixed and random effects, a curve-fitting technique to find the best-fit curve, and a segmented 2-phase linear model to describe the domains and learning rates for 2 phases of learning. RESULTS The linear mixed-effects model indicated that increasing patient body weight and increasing surgical complexity (graded on the basis of number and contiguity of hemilaminectomy sites) were associated with longer operative times and that increasing exposure number was associated with shorter operative times. The monoexponential and biexponential parametric curves were of similar quality in modeling the data. The segmented 2-phase linear model showed an early phase of learning during which operative time decreased rapidly and a late phase when operative time decreased more gradually. CONCLUSIONS AND CLINICAL RELEVANCE The learning curve for the residents suggested that for early exposures, instruction in the form of direct supervision provided substantial benefit. By the tenth exposure, the benefit of instruction diminished and ongoing improvement was primarily a result of refinement. If validated by further study, this understanding of a 2-phase learning curve may inform the design of training programs in veterinary surgery.

Predictor variables for and complications associated with Streptococcus equi subsp equi infection in horses.

OBJECTIVE: To evaluate predictor variables for and complications associated with Streptococcus equi subsp equi infection (strangles) in horses. DESIGN: Retrospective case-control study. ANIMALS: 108 horses with strangles (cases) and 215 horses without strangles (controls). PROCEDURES: Medical records from January 2005 through July 2012 were reviewed. Cases were defined as horses with clinical signs of strangles (pyrexia, retropharyngeal lymphadenopathy, and mucopurulent nasal discharge) that were associated with a confirmed strangles outbreak or had positive results for S equi on PCR assay or bacteriologic culture. Controls were defined as horses with pyrexia that did not meet the other criteria for cases. Data compared between cases and controls included signalment, clinical signs, diagnostic test results, and disease complications and outcome. Logistic regression was used to identify variables associated with strangles and its complications. RESULTS: Clinical signs of strangles were not evident in 12 of 25 cases classified as S equi carriers (infected > 40 days). Predictor variables associated with strangles included mucopurulent nasal discharge and external abscesses in the pharyngeal region. Strangles was more likely to be diagnosed in the spring than in the summer. Cases with anemia were more likely to develop purpura hemorrhagica than were cases without anemia. No risk factors were identified for the development of guttural pouch empyema or metastatic abscesses. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that not all horses infected with S equi develop clinical signs of strangles. We recommend that guttural pouch endoscopy and lavage with PCR assay of lavage fluid samples be performed to identify S equi carrier horses.

A unit-based intervention aimed at improving patient adherence to pharmacological thromboprophylaxis.

BACKGROUND: Pharmacological thromboprophylaxis is necessary among many hospitalised patients to prevent venous thromboembolism (VTE). However, a significant number of clinician-ordered doses are not administered with many doses refused by patients. We aimed to assess the impact and sustainability of a multifaceted intervention to improve medication adherence to pharmacological thromboprophylaxis. The intervention included a standardised nursing response to patient refusal, daily assessment of VTE prophylaxis usage and regular feedback on refusal rates. METHODS: We conducted a quasi-experimental study of patients admitted between January 2010 and November 2012 to one of six hospital intervention units (three medical and three oncology units) or five control units. The primary outcome was the proportion of VTE prophylaxis doses missed for any reason. RESULTS: A total of 20,208 admissions occurred at the six hospital units during the study period. In the pre-post analysis, the rate of missed and refused doses decreased significantly after the intervention (24.7% to 14.7% and 18.3% to 9.4%, respectively; p value <0.01 for both comparisons). In multiple regression models with interrupted time series analysis, the intervention was associated with an immediate and sustained decrease in missed (adjusted OR 0.64; 95% CI 0.55 to 0.74 and 0.98; 95%CI 0.97 to 0.99) and refused doses (adjusted OR per month 0.58; 95% CI 0.48 to 0.71 and 0.97; 95%CI 0.96 to 0.98). No immediate or sustained reduction in missed or refused doses was observed in the control units. CONCLUSIONS: Implementation of a multifaceted intervention resulted in an immediate and sustained decrease in the proportion of missed and refused doses of pharmacological thromboprophylaxis. Efforts aimed at increasing patient adherence are a promising approach to improve rates of VTE thromboprophylaxis administration.

Evaluation of the learning curve for a board-certified veterinary surgeon performing laparoendoscopic single-site ovariectomy in dogs.

OBJECTIVE: To define the learning curve and evaluate the outcome for a board-certified veterinary surgeon performing laparoendoscopic single-site (LESS) ovariectomy in dogs. DESIGN: Retrospective case review and learning curve evaluation with a skill acquisition model. Animals-27 client-owned dogs. Procedures-Between April 2011 and December 2012, 27 dogs underwent elective LESS ovariectomy performed by a single experienced board-certified laparoscopic surgeon by means of the same technique. Medical records for these patients were reviewed to determine whether a learning curve could be detected. A commercially available multitrocar port was inserted through a 15- to 20-mm incision at the umbilicus, and LESS ovariectomy was performed with articulating graspers, a bipolar vessel-sealing device, and a 30° telescope. Surgical performance of the surgeon was quantified with an exponential skill acquisition model, and how skill was gained with repetition of the same novel surgical procedure was examined. RESULTS: Median patient body weight was 20 kg (44 lb; range, 3.5 to 41 kg [7.7 to 90.2 lb]). Median surgical time was 35 minutes (range, 20 to 80 minutes). Median patient age was 314 days (range, 176 to 2,913 days). The skill acquisition model revealed that a comparable surgeon could reach 90% of optimal surgery performance after approximately 8 procedures (8.6, 95% confidence interval, 0.5 to 16.6 procedures). According to the model, with each surgery, surgical time would be expected to decrease by 27% (95% confidence interval, 2% to 52%). Complications were limited to minor hemorrhage due to a splenic laceration and a postoperative incisional infection. Follow-up information was available for all 27 cases. All owners were satisfied and indicated that they would pursue LESS ovariectomy again. CONCLUSIONS AND CLINICAL RELEVANCE: The learning curve for LESS ovariectomy was short and definable. Short-term outcome was excellent. Results of this study suggested that an experienced laparoscopic surgeon may anticipate achieving proficiency with this technique after performing approximately 8 procedures.

Stent-assisted balloon-induced intimal disruption and relamination in aortic dissection repair: the STABILISE concept.

OBJECTIVES: The study objective was to describe the Stent-Assisted Balloon-Induced Intimal Disruption and Relamination in Aortic Dissection Repair technique for aortic dissection repair using proximal descending aortic endografting with distal aortic relamination through bare-metal stent and balloon-induced intimal disruption with immediate intimal reapposition. METHODS: Between April 2007 and September 2011, 11 selected patients (10 male; median age, 50 years) underwent proximal descending aortic endografting plus stent-assisted balloon-induced intimal disruption of the thoracoabdominal aorta to treat complicated aortic dissection (7 type A, 4 acute type B). Patients with type A dissection underwent open surgical intervention plus adjunctive retrograde endovascular repair. Serial computed tomography angiography was used to assess aortic remodeling. RESULTS: There were no intraprocedural complications. Thirty-day incidence of death, stroke, and paralysis/visceral ischemia was 9% (n = 1), 0%, and 0%, respectively. Median follow-up was 18 months (range, 4-54 months). Two patients (18%) required secondary endovascular reintervention. No late adverse events or aortic-related deaths occurred. Complete false lumen obliteration occurred in 90% (n = 10) of patients, with stable maximal diameters in the thoracic (P = .6) and abdominal aortas (celiac trunk: P = .34; renal; P = .6; infrarenal: P = .7) at latest follow-up. CONCLUSIONS: The Stent-Assisted Balloon-Induced Intimal Disruption and Relamination in Aortic Dissection Repair approach is a feasible endovascular technique that shows promise to achieve complete repair of the dissected aorta by inducing complete false lumen obliteration. The restoration of uniluminal flow in the thoracoabdominal aorta has the potential to improve long-term outcomes. Prospective, multicenter investigations are required to implement this strategy more broadly.

Evaluation of racing performance after colic surgery in Thoroughbreds: 85 cases (1996-2010).

OBJECTIVE: To determine racing performance after surgery for colic in Thoroughbreds. DESIGN: Retrospective cohort study. ANIMALS: 85 racing Thoroughbreds that survived to discharge following colic surgery and 170 race-matched reference horses. PROCEDURES: Earnings, starts, and earnings per start were compared between horses that underwent surgery and reference horses, the proportions of horses that returned to racing were analyzed, and career longevity was determined. RESULTS: Among 85 racing Thoroughbreds that underwent colic surgery, 31 (36%) had primarily small intestinal lesions, of which 11 underwent resection; 54 (64%) had large intestinal lesions, of which 2 underwent resection. Fifty-nine of 85 (69%) horses that underwent colic surgery returned to racing after a 6-month recovery period versus 125 of 170 (73%) reference horses (OR, 0.81). In the 36-month postoperative period, reference horses earned a mean of $7,866 more, had a mean of 0.26 more starts, and had mean earnings per start of $29 more than horses that underwent surgery. Horses that underwent surgery did not have different career lengths than reference horses. CONCLUSIONS AND CLINICAL RELEVANCE: Horses that underwent colic surgery did not have a significant reduction in measures of performance or career length, compared with a reference cohort.

Hybrid proximal surgery plus adjunctive retrograde endovascular repair in acute DeBakey type I dissection: superior outcomes to conventional surgical repair.

OBJECTIVE: The present study compared the outcomes between conventional surgery and the hybrid approach of proximal surgery with adjunctive retrograde descending aortic endografting plus distal bare metal stenting in acute DeBakey type I dissection. METHODS: From 2003 to 2011, 61 patients underwent surgical management for acute type A aortic dissection at our institution. Of these, 37 were DeBakey type I dissections: 18 patients (group 1) received conventional surgical repair alone, and 19 (group 2) underwent conventional hybrid surgery with adjunctive retrograde descending aortic stent grafting plus distal bare metal stenting. RESULTS: The patients' baseline characteristics were comparable, including the incidence of preoperative malperfusion syndromes (P = .23). The intraoperative and postoperative characteristics were similar, except 4 (22%) patients in group 1 (vs 0 in group 2) had ongoing malperfusion postoperatively (P = .04). Overall, hospital mortality was 11% (n = 2) for group 1 versus 5% (n = 1) for group 2. At a mean follow-up of 50 months, 4 (25%) subjects in group 1 required secondary thoracoabdominal aortic reintervention versus none in group 2 (P = .03). CONCLUSIONS: The use of adjunctive retrograde descending aortic endografting plus distal bare metal stenting during acute DeBakey type 1 dissection repair is a feasible method to enhance thoracoabdominal remodeling. This hybrid strategy improves perioperative outcomes and decreases late distal aortic complications compared with conventional surgical repair for acute DeBakey type I dissection. A prospective, multicenter study is warranted to definitively assess this promising new treatment paradigm.

Intraoperative antinociception and postoperative analgesia following epidural anesthesia versus femoral and sciatic nerve blockade in dogs undergoing stifle joint surgery.

OBJECTIVE: To compare analgesic efficacy of preoperative epidural anesthesia with efficacy of femoral and sciatic nerve blockade in dogs undergoing hind limb orthopedic surgery. DESIGN: Prospective randomized blinded clinical study. ANIMALS: 22 dogs requiring stifle joint surgery. PROCEDURES: Dogs were premedicated with acepromazine and morphine, and anesthesia was induced with diazepam and propofol and maintained with sevoflurane in oxygen. Prior to surgery, a combination of 1.0% lidocaine solution with 0.25% bupivacaine solution was administered either into the lumbosacral epidural space (11 dogs) or perineurally along the femoral and sciatic nerves (11). Intraoperative nociception was assumed if heart rate or systolic blood pressure increased by > 10% from baseline, in which case fentanyl (2 µg/kg [0.9 µg/lb], IV) was administered as rescue analgesia. Following recovery from anesthesia, signs of postoperative pain were assessed every 30 minutes for 360 minutes from the time of local anesthetic administration via the modified Glasgow pain scale. Patients with scores > 5 (scale, 0 to 20) received hydromorphone (0.1 mg/kg [0.05 mg/lb], IV) as rescue analgesia and were then withdrawn from further pain scoring. RESULTS: Treatment groups did not differ significantly in the number fentanyl boluses administered for intraoperative rescue analgesia. Time to administration of first postoperative rescue analgesia was comparable between groups. Furthermore, there was no significant difference between groups in baseline pain scores, nor were there significant differences at any other point during the postoperative period. CONCLUSIONS AND CLINICAL RELEVANCE: Femoral and sciatic nerve blocks provided intraoperative antinociception and postoperative analgesia similar to epidural anesthesia in dogs undergoing stifle joint surgery.

In vitro mechanical testing of an alternate laryngoplasty system (ALPS) for horses.

OBJECTIVE: Mechanical evaluation of a novel alternate laryngoplasty system (ALPS). STUDY DESIGN: Experimental. ANIMAL POPULATION: Cadaveric horse larynges (n = 10). METHODS: Arytenoid and cricoid cartilages were embedded for testing. A novel laryngoplasty system consisting of a metallic anchor, 2 stands of #2 suture material, and a metallic button were evaluated. A traditional laryngoplasty using a single strand of #5 Ethibond was evaluated in parallel. Constructs were evaluated in cyclic testing oscillating from 30 to 50 N for 3600 cycles. Constructs subsequently underwent a single cycle to failure. Distraction during cyclic testing was recorded. Load at failure and stiffness were calculated from single-cycle failure testing. RESULTS: There was no difference in mean arytenoid single-cycle load-to-failure for the Ethibond (206.9 ± 13.1 N) constructs compared with ALPS (220.6 ±17.1 N) constructs (P = .486). In the cricoid under single-cycle testing, the ALPS (236.0 ± 23.4 N) constructs were significantly stronger than the Ethibond (161.5 ± 12.2 N) constructs (P = .013). The combined distraction was significantly greater for Ethibond (6.29 ± 1.24 mm) constructs compared to the ALPS (3.43 ± 0.28 mm) constructs (P = .033). CONCLUSIONS: The ALPS construct was stiffer and at least as strong as the traditional laryngoplasty construct in single cycle failure in both the arytenoid and cricoid cartilages. Combined distraction was significantly reduced using the ALPS compared to the traditional laryngoplasty in vitro under cyclic testing.

Combined proximal stent grafting plus distal bare metal stenting for management of aortic dissection: Superior to standard endovascular repair?

OBJECTIVES: The present study compared the outcomes between combined proximal descending aortic endografting plus distal bare metal stenting and conventional proximal descending aortic stent-graft repair in patients with type A and type B aortic dissection. METHODS: From January 2003 to December 2010, 63 patients underwent endovascular treatment for acute (type A, 24; type B, 21) and chronic (type B, 18) aortic dissection. Of these, 40 patients underwent proximal descending aortic endografting plus distal bare metal stenting (group 1), and 23 underwent proximal descending stent-graft repair alone (group 2). All patients with type A dissection underwent open surgical intervention plus adjunctive retrograde endovascular repair. RESULTS: The patients were comparable for baseline characteristics and treatment indicators, but more group 1 patients were active smokers (P = .03). The intraoperative characteristics were also similar, although 4 patients, all in group 2, developed malperfusion syndrome postoperatively (P = .02). The overall hospital mortality was 6%. At a mean follow-up of 49 months, 9 group 2 patients (43%) required unplanned secondary intervention compared with 4 in group 1 (11%; P = .007). Reintervention for thoracoabdominal aortic aneurysm or visceral ischemia was performed in 4 patients (19%) from group 2 (P = .03). Late aortic-related deaths occurred in 1 (5 %) and 2 (5%) patients in groups 1 and 2, respectively. CONCLUSIONS: Combined proximal descending aortic endografting plus distal bare metal stenting for aortic dissection provides favorable short-term outcomes and decreases late distal aortic complications compared with conventional endovascular repair. These results support a more widespread application of this approach. A prospective, randomized trial is needed before definite conclusions can be made.

Pancreatic ß-cell dysfunction in polycystic ovary syndrome: the role of metformin.

OBJECTIVE: To determine whether the administration of 6 months of daily metformin treatment in women with polycystic ovary syndrome (PCOS) would significantly improve pancreatic ß-cell function as measured by an increase in the disposition index. METHODS: We enrolled women with PCOS from a private practice and from the Mount Sinai Hospital Endocrinology Clinic. All patients underwent frequently sampled intravenous glucose tolerance tests both on and off 500 to 1000 mg of twice daily metformin. Values of insulin sensitivity, glucose effectiveness, acute insulin response to glucose, and disposition index were calculated for each test. The product of acute insulin response to glucose and insulin sensitivity yielded the disposition index and estimated the degree of ß-cell compensation for insulin resistance. RESULTS: We enrolled 14 women. We observed no significant changes in insulin sensitivity, glucose effectiveness, or acute insulin response to glucose, disposition index, or distributed glucose at time 0 before or after metformin treatment. Patients with PCOS treated with metformin remained statistically on the same hyperbolic curve, which is consistent with previously reported results of the effect of metformin on ß-cell function. In contrast, the proportional change in disposition index correlated significantly with the proportional change in insulin sensitivity. Patients whose insulin sensitivity decreased after treatment showed a proportional decrease in disposition index, while patients whose insulin sensitivity increased showed a proportional increase in disposition index. CONCLUSIONS: Our findings suggest that acute insulin response to glucose does not proportionately change to match change in insulin sensitivity. Thus, there may be a ß-cell defect in women with PCOS.

High incidence of insulin resistance and dysglycemia amongst nondiabetic cardiac surgical patients.

BACKGROUND: Undiagnosed glycometabolic dysfunction is prominent amongst nondiabetic cardiac surgical patients, whereas perioperative dysglycemia is associated with adverse outcomes. This study assessed whether the preoperative level of insulin resistance predicts the degree of perioperative dysglycemia in nondiabetic, normoglycemic cardiac surgical patients. METHODS: Twenty-two nondiabetic patients awaiting cardiac operations were assessed for metabolic parameters and whole-body insulin resistance (mean glucose infusion [GINF] rate) using the hyperinsulinemic-euglycemic clamp. Intraoperative and postoperative glucose levels and treatment requirements were analyzed. Linear regression analysis was used to find predictors of baseline, peak intraoperative, and mean postoperative fasting blood glucose (FBG). RESULTS: The mean GINF recorded in nondiabetic, normoglycemic patients was 3.5 ± 1.4 mg/kg/min. The mean peak intraoperative and mean postoperative FBG concentrations were 154.9 ± 34.2 mg/dL (range, 108.1 to 227.0 mg/dL) and 120.7 ± 16.2 mg/dL (range, 100.9 to 154.9 mg/dL), respectively. The GINF correlated inversely with mean peak intraoperative (r = -0.7, p = 0.02) and mean postoperative FBG (r = -0.8, p = 0.01). The GINF did not correlate with preoperative FBG levels (r = 0.3, p = 0.4). Preoperative FBG did not correlate with peak intraoperative (r = 0.4, p = 0.5) or mean postoperative FBG (r = 0.5, p = 0.3). CONCLUSIONS: Nondiabetic, normoglycemic cardiac surgical patients are highly insulin resistant using the hyperinsulinemic-euglycemic clamp. Preoperative insulin resistance, not FBG, is significantly associated with the development of perioperative dysglycemia. Insulin resistance screening may be useful to identify insulin resistance preoperatively and predict the degree of perioperative dysglycemia in cardiac surgical patients but should be performed with a more appropriate and reproducible test.

Selenocompounds in juvenile white sturgeon: estimating absorption, disposition, and elimination of selenium using Bayesian hierarchical modeling.

The biological function of selenium (Se) is determined by its form and concentration. Selenium is an essential micronutrient for all vertebrates, however, at environmental levels, it is a potent toxin. In the San Francisco Bay-Delta, Se pollution threatens top predatory fish, including white sturgeon. A multi-compartmental Bayesian hierarchical model was developed to estimate the fractional rates of absorption, disposition, and elimination of selenocompounds, in white sturgeon, from tissue measurements obtained in a previous study (Huang et al., 2012). This modeling methodology allows for a population based approach to estimate kinetic physiological parameters in white sturgeon. Briefly, thirty juvenile white sturgeon (five per treatment) were orally intubated with a control (no selenium) or a single dose of Se (500 µg Se/kg body weight) in the form of one inorganic (Selenite) or four organic selenocompounds: selenocystine (SeCys), l-selenomethionine (SeMet), Se-methylseleno-l-cysteine (MSeCys), or selenoyeast (SeYeast). Blood and urine Se were measured at intervals throughout the 48h post intubation period and eight tissues were sampled at 48 h. The model is composed of four state variables, conceptually the gut (Q1), blood (Q2), and tissue (Q3); and urine (Q0), all in units of µg Se. Six kinetics parameters were estimated: the fractional rates [1/h] of absorption, tissue disposition, tissue release, and urinary elimination (k12, k23, k32, and k20), the proportion of the absorbed dose eliminated through the urine (f20), and the distribution blood volume (V; percent body weight, BW). The parameter k12 was higher in sturgeon given the organic Se forms, in the descending order of MSeCys > SeMet > SeCys > Selenite > SeYeast. The parameters k23 and k32 followed similar patterns, and f20 was lowest in fish given MSeCys. Selenium form did not affect k20 or V. The parameter differences observed can be attributed to the different mechanisms of transmucosal transport, metabolic reduction, and storage of the Se forms, which, in general, appear to be similar to that in mammals. We have demonstrated that the Bayesian approach is a powerful tool for integrating quantitative information from a study with sparse blood and urinary measurements and tissue concentrations from a single time point, while providing a full characterization of parameter variability. The model permits the quantitative mechanistic interpretation and predictions of Se absorption, disposition, and elimination processes. Furthermore, the model represents a first step towards population based physiological toxicokinetic modeling of Se in white sturgeon.

Attempted medical management of suspected ascending colon displacement in horses.

OBJECTIVE: To determine the success of medical management of suspected displacement of the ascending (large) colon in horses. STUDY DESIGN: Retrospective case series. ANIMALS: Horses (n = 127) with suspected large colon displacement. METHODS: Medical records (January 1998-September 2008) of horses admitted for colic were reviewed. Suspected large colon displacement was diagnosed from clinical examination and in some cases, subsequent surgical examination. Medically managed horses were exercised and administered intravenous fluids and analgesia. Horses with suspected left dorsal displacement (LDD) of the large colon were also administered phenylephrine. RESULTS: Medical management had a high success rate for treatment of suspected right dorsal displacement (RDD) (64%) and LDD (76%) of the large colon; 4 horses died (1) or were euthanatized (3) and 36 horses had surgery. Of 127 horses treated medically or surgically for a colon displacement, 94% survived to hospital discharge. CONCLUSIONS: Horses with suspected RDD or LDD of the large colon may respond to medical management including exercise.

Effect of general anesthesia on plasma cardiac troponin I concentrations in healthy horses.

OBJECTIVE: To evaluate the effect of general anesthesia on plasma cTnI concentrations in horses. ANIMALS, MATERIALS AND METHODS: Thirty-two horses undergoing general anesthesia and either elective surgery or MRI without surgery were prospectively studied. Twenty-nine horses (22 surgical, 7 imaging) completed the study. Plasma cTnI concentrations were determined prior to anesthesia and at 6, 12 and 24 h following discontinuation of the inhalant anesthetic. RESULTS: All horses had cTnI values within the reference range at all time points. Six horses (21%) developed detectable cTnI 6 or 12 h following anesthesia. Risk factors for detectable cTnI include increasing age and dorsal recumbency. Horses with detectable cTnI had significantly lower mean and diastolic arterial blood pressures than those without detectable cTnI. CONCLUSION: Uncomplicated general anesthesia with or without surgery does not result in cardiac troponin I elevations above the reference range in the first 24 h postoperatively.

α-Melanocyte--stimulating hormone and adrenocorticotropin concentrations in response to thyrotropin-releasing hormone and comparison with adrenocorticotropin concentration after domperidone administration in healthy horses and horses with pituitary pars intermedia dysfunction.

OBJECTIVE: To compare endogenous ACTH and α-melanocyte-stimulating hormone (α-MSH) concentrations after administration of thyrotropin-releasing hormone (TRH) and to compare ACTH concentrations after TRH administration with those following domperidone administration in healthy horses and horses with pituitary pars intermedia dysfunction (PPID). DESIGN: Prospective case series. ANIMALS: 69 clinically normal horses and 47 horses with or suspected to have PPID. PROCEDURES: ACTH concentrations were measured during 108 TRH stimulation tests in 88 horses, and α-MSH concentrations were measured during 56 TRH stimulation tests in 50 horses. In 28 of these horses, ACTH concentrations after domperidone administration were measured and test results were compared. The pituitary gland was histologically examined in all horses that were euthanatized. RESULTS: ACTH and α-MSH concentrations increased in all horses after TRH administration, with a greater and more prolonged increase in horses with PPID. Percentage increase was significantly greater for α-MSH concentration than for ACTH concentration. The change in ACTH concentration after domperidone administration was less consistent in differentiating clinically normal horses from those with PPID than was the response to TRH. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that ACTH concentration in response to TRH administration was useful for the diagnosis of PPID in horses and appeared more accurate than response to domperidone administration. Use of an α-MSH concentration ≥ 30 or 50 pmol/L did not appear superior to use of an ACTH concentration ≥ 36 pg/mL for the diagnosis of PPID, either before or 30 minutes after TRH administration.