Second-line immunotherapy and functional outcomes in autoimmune encephalitis: A systematic review and individual patient data meta-analysis.

Autoimmune encephalitis (AE) is a neurological disorder caused by autoimmune attack on cerebral proteins. Experts currently recommend staged immunotherapeutic management, with first-line immunotherapy followed by second-line immunotherapy if response to first-line therapy is inadequate. Meta-analysis of the evidence base may provide higher quality evidence to support this recommendation. We undertook a systematic review of observational cohort studies reporting AE patients treated with either second-line immunotherapy or first-line immunotherapy alone, and outcomes reported using the modified Rankin Scale (mRS; search date: April 22, 2020). We performed several one-stage multilevel individual patient data (IPD) meta-analyses to examine the association between second-line immunotherapy and final mRS scores (PROSPERO ID CRD42020181805). IPD were obtained for 356 patients from 25 studies. Most studies were rated as moderate to high risk of bias. Seventy-one patients (71/356, 19%) were treated with second-line immunotherapy. We did not find a statistically significant association between treatment with second-line immunotherapy and final mRS score for the cohort overall (odds ratio [OR] = 1.74, 95% confidence interval [CI] = .98-3.08, p = .057), or subgroups with anti-N-methyl-D-aspartate receptor encephalitis (OR = 1.03, 95% CI = .45-2.38, p = .944) or severe AE (maximum mRS score > 2; OR = 1.673, 95% CI = .93-3.00, p = .085). Treatment with second-line immunotherapy was associated with higher final mRS scores in subgroups with anti-leucine-rich glioma-inactivated 1 AE (OR = 6.70, 95% CI = 1.28-35.1, p = .024) and long-term (at least 12 months) follow-up (OR = 3.94, 95% CI = 1.67-9.27, p = .002). We did not observe an association between treatment with second-line immunotherapy and lower final mRS scores in patients with AE. This result should be interpreted with caution, given the risk of bias, limited adjustment for disease severity, and insensitivity of the mRS in estimating psychiatric and cognitive disability.

Temporal patterns of epileptiform discharges in genetic generalized epilepsies.

OBJECTIVE: We sought to investigate the temporal patterns and sleep-wake cycle-related epileptiform discharges (EDs) in genetic generalized epilepsies (GGEs). METHODS: We studied 24-hour ambulatory electroencephalography (EEG) recordings of patients with GGE, diagnosed and classified according to the International League against Epilepsy criteria. We manually coded the type of discharge, time of occurrence, duration, and arousal state of each ED. We employed mixed effects Poisson regression modeling to study the temporal distribution of epileptiform discharges. Additionally, we used multinomial regression analysis to explore the significance of the relationship between different states of arousal and types of epileptiform discharges. RESULTS: We analyzed 6923 EDs from 105 abnormal 24-hour EEGs. Mixed effects Poisson regression analysis demonstrated significant changes in ED counts across time blocks. This distribution was largely influenced by the state of arousal. Generalized fragments (duration<2s) and focal discharges were more frequent during non-REM sleep while paroxysms (duration≥2s) were more frequent in wakefulness. Overall, 67% of epileptiform discharges occurred in non-REM sleep and only 33% occurred in wakefulness. Twenty-four patients (23%) had ED exclusively in sleep. Epileptiform discharges peaked from 23:00 through 07:00h. SIGNIFICANCE: There is a time-of-day dependency of ED with a significant influence exerted by the state of arousal. Our observations suggest that the generation of epileptiform discharges is not a random process but is the result of complex interactions among biological rhythms such as the sleep-wake cycle and the intrinsic circadian pacemaker. High density of ED in sleep suggests that 24-hour EEG recording with the capture of natural sleep may be more useful than routine EEG to diagnose GGE.

Prerace venous blood gases and acid-base values in Standardbred horses: effects of geography, season, prerace furosemide, gender, age, and trainer using big data analytics.

OBJECTIVE: A retrospective study was conducted to establish the prerace venous acid-base and blood gas values of Standardbred horses at rest using big data analytics. SAMPLES: Venous blood samples (73,382) were collected during seven racing seasons from 3 regional tracks in the Commonwealth of Pennsylvania. Horses were detained 2 hours prior to race time. PROCEDURES: A mixed-effects linear regression model was used for estimating the marginal model adjusted mean (marginal mean) for all major outcomes. The interaction between age and gender, track, and the interaction between month, treatment (furosemide), and year were the major confounders included in the model. Random effects were set on individual animal nested within trainer. Partial pressure of venous carbon dioxide (PVCO2), partial pressure of oxygen (PVO2), and pH were measured, and base excess (BE), total carbon dioxide (TCO2), and bicarbonate (HCO3-) were calculated. RESULTS: Significant (P < .001) geographical differences in track locations were seen. Seasonal reductions in acid-base values started in January with significant (P < .001) decreases from adjacent months seen in June, July, and August followed by a gradual return. There were significant increases (P < .001) in BE and TCO2 and decreases in PVO2 with age. Significant differences (P < .001) in acid-base values were seen when comparing genders. A population of trainers were significantly different (P < .001) from the marginal mean and considered outliers. CLINICAL RELEVANCE: In a population of horses, big data analytics was used to confirm the effects of geography, season, prerace furosemide, gender, age, and trainer influence on blood gases and the acid-base profile.

The Relationship Between Lipoproteins and Insulin Sensitivity in Youth With Obesity and Abnormal Glucose Tolerance.

CONTEXT: Youth with obesity and abnormal glucose tolerance have an increased risk for atherosclerosis but the relative contributions of insulin resistance and hyperglycemia to dyslipidemia and the development of subclinical atherosclerosis are unknown. OBJECTIVE: This work aims to determine the association between insulin resistance, dyslipidemia, and carotid intimal thickness (cIMT) in adolescents with normal and abnormal glucose tolerance. METHODS: An observational cohort study in 155 youth: 44 obese insulin sensitive (OIS; fasting insulin ≤ 20 µM/mL, body mass index [BMI] ≥ 95th percentile), 35 obese insulin resistant (OIR; fasting insulin > 20 µM/mL, BMI ≥ 95th percentile), 34 obese abnormal glucose tolerant (AGT; BMI ≥ 95th percentile), and 42 Lean (BMI 5th-85th percentile). Lipids, lipoprotein particle size and concentration (-P), insulin sensitivity (SI an intravenous glucose test), and CMIT were compared using linear models adjusted for age, race/ethnicity, biological sex, and Tanner stage. Lipid/lipoprotein profile and CMIT were reevaluated in a subset after 2 years. RESULTS: Compared to OIS and Lean, OIR and AGT had elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) but similar total cholesterol and low-density lipoprotein cholesterol (LDL-C). Among OIS, OIR, AGT, lower SI was associated with atherogenic lipids (higher triglycerides, LDL-C, non-HDL-C, and lower HDL-C) and lipoproteins (higher total LDL-P and small HDL-P, and lower large HDL-P). There was a steeper decline in the association of SI with HDL-C and large HDL-P in AGT compared with OIR and OIS. cIMT was comparable across groups and inversely correlated with SI, with no change after 2 years. CONCLUSION: Among youth with obesity, insulin resistance was associated with an atherogenic lipoprotein/lipid profile and cIMT, regardless of glucose tolerance status. Insulin resistance in AGT youth was associated with a shift to smaller HDL-P compared to normoglycemic youth with obesity. Alterations in HDL-P metabolism may be early adverse manifestations of hyperglycemia in youth with obesity.

Sleep-Disordered Breathing and Free Fatty Acid Metabolism.

BACKGROUND: Sleep-disordered breathing (SDB) is independently associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. However, data on whether SDB alters the metabolism of free fatty acids (FFAs) are lacking. RESEARCH QUESTION: The primary objective of the current study was to characterize alterations in FFA metabolism across the spectrum of SDB severity. STUDY DESIGN AND METHODS: The study sample included 118 participants with and without SDB who underwent full-montage polysomnography, the frequently sampled IV glucose tolerance test (FSIGTT), and body composition measurements including determination of percent body fat. Parameters of lipolysis suppression, time to FFA nadir, and FFA rebound after an IV glucose challenge were derived using a mathematical model. Multivariable regression analyses were used to characterize the independent associations between SDB severity and parameters of FFA metabolism. RESULTS: SDB severity, as assessed by the apnea-hypopnea index, was associated with adipocyte insulin resistance, a decrease in the glucose- and insulin-mediated suppression of lipolysis, a longer duration to reach a nadir in FFA levels during the FSIGTT, and a sluggish rebound in FFA levels after suppression. Severity of SDB-related hypoxemia was independently associated with adipocyte insulin resistance and the time to reach the FFA nadir during the FSIGTT. Finally, a higher percentage of stage N3 sleep was positively associated with greater suppression of lipolysis and a faster rebound in the FFA levels during the FSIGTT. INTERPRETATION: Independent of adiposity, SDB is associated with impairments in FFA metabolism, which may contribute to the development of glucose intolerance and type 2 diabetes in SDB.

"Sleep Surge": The impact of sleep onset and offset on epileptiform discharges in idiopathic generalized epilepsies.

OBJECTIVE: To investigate the impact of sleep onset and offset on the rate of epileptiform discharges (ED) in idiopathic generalized epilepsies (IGE). METHODS: We studied the temporal distribution of EDs with mixed-effects Poisson regression modeling in a cohort of patients diagnosed with IGE who underwent 24-hour ambulatory electroencephalography (EEG) recordings. We defined the mean number discharges per hour per subject as the mean ED rate. The association between each hour and the mean ED rate was quantified with incidence rate ratio (IRR) as the metric. We calculated the IRR of each hourly block for the total cohort in relation to sleep onset and offset. Finally, we admitted secondary risk factors into our Poisson regression model and quantified changes in IRR in order to investigate the impact of those variables on the outcome. The secondary risk factors included: epilepsy syndrome, duration of seizure freedom, duration of epilepsy, number of antiepileptic drugs (AED), type of AED, and age. RESULTS: A total of 39 patients with a mean age of 29.1 y (SD = 10.1) were studied. The distribution of ED rate demonstrated a highly significant abrupt increase in the first hour after sleep onset (IRR = 3.96; p < 0.001). On the contrary, the ED rate significantly dropped in the second hour after the sleep offset compared with the last hour block before sleep offset (IRR = 0.39; p < 0.001). None of the secondary risk factors demonstrated any significant impact on this pattern. CONCLUSIONS: Sleep onset is a very significant trigger for the generation of EDs in IGE. SIGNIFICANCE: Our results support the hypothesis that there is a "critical zone of vigilance" in the sleep-wake boundary from which generalized EDs are more likely to emerge.

A compartmental model describing changes in progesterone concentrations during the oestrous cycle.

The objective of this study was to develop a mathematical model that accurately describes the rise and decline in plasma progesterone concentrations, and is able to define parameters describing progesterone appearance and disappearance during the bovine oestrous cycle. Daily plasma progesterone data from 27 cows were used to develop a compartmental model consisting of an appearance function and an appearance modulating function. Model outputs included an apparent appearance or secretion duration, appearance rate and an average disappearance rate (expressed as arbitrary units per day; units/d). Shape-based clustering identified three common shape-based groups (or clusters) of progesterone profiles defined as either 'peaked' profile, with the profile reaching a distinguishable peak, 'structured', with the profile exhibiting a wave-like pattern, or 'flat top', with the profile reaching a plateau. Differences in the model parameters for the three different shapes of progesterone profiles were examined: peaked (n=13), flat top (n=7) and structured (n=7). The mean duration of apparent appearance was 11.49 (SD 0.17 d) for all 27 profiles. The model estimates for total appearance of progesterone (area under the curve; ng/ml per cycle), mean appearance rate and maximum appearance rate were 69.04 ng/ml per cycle (SD 15.2 ng/ml per cycle), 3.19 ng/ml per cycle (sd 0.7 ng/ml per d) and 6.70 ng/ml (SD 1.31 ng/ml), respectively. The average disappearance rate was 1.0 units/d (SD 0.04 units/d). The apparent appearance duration was greatest (P<0.01) in the flat top profiles (12.54, SD 0.41 d) followed by the structured (11.77, SD 0.66 d) and the peaked (10.80, SD 0.30 d) profiles. Total and mean progesterone appearance, maximum progesterone appearance rate, and the progesterone disappearance rates were not different between the profiles. The model successfully simulated all components of the progesterone profile and was able to define specific parameters of different shaped progesterone profiles. A simple model able to estimate parameters describing progesterone appearance and disappearance can be used to explore the relationships between profile shapes and reproductive outcomes.

Methods for the Detection of Seizure Bursts in Epilepsy.

Background: Seizure clusters and "bursts" are of clinical importance. Clusters are reported to be a marker of antiepileptic drug resistance. Additionally, seizure clustering has been found to be associated with increased morbidity and mortality. However, there are no statistical methods described in the literature to delineate bursting phenomenon in epileptic seizures. Methods: We present three automatic burst detection methods referred to as precision constrained grouping (PCG), burst duration constrained grouping (BCG), and interseizure interval constrained grouping (ICG). Concordance correlation coefficients were used to confirm the pairwise agreement between common bursts isolated using these three automatic burst detection procedures. Additionally, three graphical methods were employed to demonstrate seizure bursts: modified scatter plots, staircase plots, and dropline plots. Burst detection procedures are demonstrated on data from continuous intracranial ambulatory EEG monitoring in a patient diagnosed with drug-refractory focal epilepsy. Results: We analyzed 1,569 seizures, from our assigned index patient, captured on ambulatory intracranial EEG monitoring. A total of 31, 32, and 32 seizure bursts were detected by the three quantitative methods (BCG, ICG, and PCG), respectively. The concordance correlation coefficient was ≥0.99 signifying considerably stronger than chance burst detector agreements with one another. Conclusions: Bursting is a quantifiable temporal phenomenon in epilepsy and seizure bursts can be reliably detected using our methodology.

Catheter-directed gastric artery chemical embolization suppresses systemic ghrelin levels in porcine model.

PURPOSE: To prospectively test, in a porcine model, the hypothesis that catheter-directed gastric artery chemical embolization (GACE) can result in suppression of systemic ghrelin levels and affect weight gain. MATERIALS AND METHODS: This study, which had Animal Care and Use Committee approval, was performed in healthy, growing swine (weight range, 40-45 kg; n = 10). GACE was performed in five swine with the infusion of sodium morrhuate (125 mug) selectively into the gastric arteries that supply the fundus. Five control animals underwent a sham procedure with 5 mL of saline. Weight and fasting plasma ghrelin levels were obtained in animals at baseline and in weeks 1-4. Statistical testing for substantial differences in ghrelin blood levels over time and between treated and untreated animals was performed by using a cross-sectional time-series linear model with feasibility generalized least squares. RESULTS: The pattern of the change in ghrelin levels over time was significantly different between control and treated animals (P < .004). In treated animals, ghrelin levels were significantly reduced at week 1 (mean, 664.1 pg/mL +/- 103.1 [standard error of the mean], P < .02), week 2 (mean, 618.1 pg/mL +/- 180.4, P < .001), week 3 (mean, 578.4 pg/mL +/- 214.9, P < .001), and week 4 (mean, 876.6 pg/mL +/- 228.6, P < .03) relative to baseline (mean, 1006.3 pg/mL +/- 190.1). The percentage change in serum ghrelin values in swine treated with GACE decreased from baseline to -34%, -38.6%, -42.5%, and -12.9% during weeks 1-4, respectively. In control swine, percentage change in serum ghrelin was -1.7%, -9.7%, +2.6%, and +18.2% during weeks 1-4, respectively. At the end of 4 weeks, control swine continued to gain weight, with a 15.1% increase from their original weight, while the weight in swine treated with GACE plateaued at an increase of 7.8% from the original weight. CONCLUSION: Catheter-directed GACE can suppress the appetite hormone ghrelin and affect weight gain.

Characteristics of Epileptiform Discharge Duration and Interdischarge Interval in Genetic Generalized Epilepsies.

We sought to investigate (1) the characteristics of epileptiform discharge (ED) duration and interdischarge interval (IDI) and (2) the influence of vigilance state on the ED duration and IDI in genetic generalized epilepsy (GGE). In a cohort of patients diagnosed with GGE, 24-h ambulatory EEG recordings were performed prospectively. We then tabulated durations, IDI, and vigilance state in relation to all EDs captured on EEGs. We used K-means cluster analysis and finite mixture modeling to quantify and characterize the groups of ED duration and IDI. To investigate the influence of sleep, we calculated the mean, median, and SEM in each population from all subjects for sleep state and wakefulness separately, followed by the Kruskal-Wallis test to compare the groups. We analyzed 4,679 EDs and corresponding IDI from 23 abnormal 24-h ambulatory EEGs. Our analysis defined two populations of ED durations and IDI: short and long. In all populations, both ED durations and IDI were significantly longer in wakefulness. Our results highlight different characteristics of ED populations in GGE and the influence by the sleep-wake cycle.

EEG correlates of seizure freedom in genetic generalized epilepsies.

BACKGROUND: We investigated the association between epileptiform EEG abnormalities and the preceding duration of seizure freedom in genetic generalized epilepsies (GGE). METHODS: We analyzed 24-hour ambulatory EEG recordings of patients with GGE diagnosed and classified according to the International League Against Epilepsy criteria. We quantified epileptiform EEG abnormalities into density scores (total duration of epileptiform discharges per hour) and estimated the preceding seizure-free duration at the time of EEG recording based on the last self-reported seizure. We then employed regression analysis to quantitate the relationship between the duration of seizure freedom and EEG variables. RESULTS: We analyzed 6,923 epileptiform discharges from 105 patients with abnormal 24-hour EEGs. In the regression analysis exploring the crude associations, we found significant correlations between 6 EEG variables and the duration of seizure freedom indicating that shorter duration of seizure freedom was associated with higher spike densities and longer paroxysms. These associations were not affected by confounders such as syndrome, age at EEG, age at epilepsy onset, sex, duration of epilepsy, or number of antiepileptic drugs. CONCLUSIONS: Higher densities and longer durations of epileptiform discharges may be retrospectively associated with a shorter duration of self-reported seizure freedom. Hence, EEG can potentially be used as a biomarker of prognosis in GGE. These findings need to be validated in a prospective study in order to define EEG markers of future seizure freedom.

Evaluation of the Biocompatibility of Polypyrrole Implanted Subdurally in GAERS.

This blinded controlled prospective randomized study investigates the biocompatibility of polypyrrole (PPy) polymer that will be used for intracranial triggered release of anti-epileptic drugs (AEDs). Three by three millimeters PPy are implanted subdurally in six adult female genetic absence epilepsy rats from Strasbourg. Each rat has a polymer implanted on one side of the cortex and a sham craniotomy performed on the other side. After a period of seven weeks, rats are euthanized and parallel series of coronal sections are cut throughout the implant site. Four series of 15 sections are histological (hematoxylin and eosin) and immunohistochemically (neuron-specific nuclear protein, glial fibrillary acidic protein, and anti-CD68 antibody) stained and evaluated by three investigators. The results show that implanted PPy mats do not induce obvious inflammation, trauma, gliosis, and neuronal toxicity. Therefore the authors conclude the PPy used offer good histocompatibility with central nervous system cells and that PPy sheets can be used as intracranial, AED delivery implant.

Pharmacokinetics of methylprednisolone acetate after intra-articular administration and its effect on endogenous hydrocortisone and cortisone secretion in horses.

OBJECTIVE: To determine the pharmacokinetics of methylprednisolone (MP) and develop a pharmacokinetic-pharmacodynamic model of the related changes in plasma concentrations of endogenous hydrocortisone (HYD) and cortisone (COR) following intra-articular administration of methylprednisolone acetate (MPA) in horses. ANIMALS: 6 Thoroughbreds. PROCEDURES: In each horse, 200 mg of MPA was injected intrasynovially into a carpal joint, and plasma MP, HYD, and COR concentrations were determined via liquid chromatography-mass spectrometry. RESULTS: A 5-compartment pharmacokinetic-pharmacodynamic model was used to describe the concatenated changes in the plasma concentrations of MP, HYD, and COR and to estimate the instantaneous rate of endogenous HYD production. The median transfer half-life (t(1/2t)) of methylprednisolone from the joint to plasma and elimination half-life (t(1/2e)) from plasma were 1.7 and 19.2 hours, respectively. Maximum plasma concentration of methylprednisolone was 7.26 +/- 3.3 ng/mL at 8 hours, which decreased to 0.11 +/- 0.08 ng/mL at 144 hours after injection. At 3 hours after MPA administration, plasma COR and HYD concentrations were significantly decreased from baseline values (from 2.9 +/- 0.28 ng/mL to 2.10 +/- 1.0 ng/mL and from 61.1 +/- 18.9 ng/mL to 25.7 +/- 12.1 ng/mL, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: The sensitivity of the analytic method used allowed complete description of the related kinetics of MP, HYD, and COR following intra-articular administration of MPA. A single intra-articular administration of MPA profoundly affected the secretion of HYD and COR in horses; secretion of endogenous corticosteroids remained suppressed for as long as 240 hours after injection.

Stavudine entry into cerebrospinal fluid after single and multiple doses in patients infected with human immunodeficiency virus.

STUDY OBJECTIVE: To establish the pharmacokinetics of stavudine within the cerebrospinal fluid (CSF) of patients infected with human immunodeficiency virus (HIV). DESIGN: Pharmacokinetic study. SETTING: General clinical research center. PATIENTS: Thirty-six patients infected with HIV; 21 were receiving long-term stavudine therapy, 15 were not (single-dose treatment group). INTERVENTION: After an overnight fast, all patients received a single dose of stavudine 40 mg. Fifteen patients in the long-term treatment group and all 15 patients in the single-dose treatment group were randomized to undergo lumbar puncture 2, 4, or 6 hours after dosing (five patients for each time point from each group). The six other patients in the long-term treatment group underwent lumbar puncture 0 or 8 hours after dosing. MEASUREMENTS AND MAIN RESULTS: Serum stavudine concentrations were obtained just before dosing, 1 hour after dosing (approximate peak), and at the time of lumbar puncture. The CSF was also analyzed for cell counts, protein, and glucose levels. The mean peak serum stavudine concentration in the long-term treatment group was estimated to be 580.7 ng/ml (2.59 micromol/L), occurring approximately 1.3 hours after dosing. The CSF concentrations over 0-8 hours were 0.0-109.9 ng/ml (0.00-0.49 micromol/L) with an overall mean of 51.6 ng/ml (0.23 micromol/L). Mean peak CSF concentration was estimated to be 62.8 ng/ml (0.28 micromol/L), occurring 4.7 hours after dosing. For the 15 patients not taking stavudine, both the serum and the CSF estimated peaks were significantly lower than those of the long-term group: 475.3 ng/ml (2.12 micromol/L) and 40.4 ng/ml (0.18 micromol/L), respectively. However, time to peak was similar at 1.2 hours and 5.0 hours, respectively. In both groups, no correlation was found between CSF and baseline or peak serum stavudine concentrations, CSF white blood cell count, baseline CD4 + lymphocyte count, or plasma viral load. CONCLUSION: Mean CSF stavudine concentrations equaled or exceeded the mean concentration producing 50% of the maximal effect in vivo (EC 50 ) for HIV. The CSF concentrations were higher in the stavudine-experienced patients, indicating that concentrations rise with progressive doses until steady state is reached.

Uroperitoneum in 32 foals: influence of intravenous fluid therapy, infection, and sepsis.

Foals may present to a referral hospital with the primary diagnosis of uroperitoneum (UP), or they may develop UP while hospitalized for other reasons. Historical, physical, laboratory, and diagnostic variables of foals presenting with UP were compared to those developing UP while hospitalized. Emphasis was placed on the presence of electrolyte abnormalities, evidence of sepsis or infection, and development of anesthetic complications during surgical correction of the defect. Foals developing UP while in the hospital frequently had a history of dystocia and presented at a very young age (< 48 hours) with primary clinical signs compatible with intrauterine compromise or presumed hypoxic or ischemic insult with or without sepsis. Foals referred with suspected UP often had additional problems unrelated to the urinary system. These foals had hyponatremia and hyperkalemia on presentation, whereas foals receiving intravenous fluid therapy consisting of a balanced electrolyte solution did not develop the classical pattern of electrolyte abnormalities, yet a similar increase in serum creatinine and, frequently, decreasing urine production were noted. Infection was present in 63% of the foals, and 78% of foals revealed signs suggestive of sepsis or infection. Intrauterine compromise, presumed hypoxia or ischemia, and sepsis may predispose foals to development of UP. Anesthetic complications occurred in 16% of the foals undergoing surgical correction of the defect, although hyperkalemia was only present in half of the foals with anesthetic complications.

Use of proxies and reference quintiles obtained from minimal model analysis for determination of insulin sensitivity and pancreatic beta-cell responsiveness in horses.

OBJECTIVE: To develop proxies calculated from basal plasma glucose and insulin concentrations that predict insulin sensitivity (SI; L.min(-1) x mU(-1)) and beta-cell responsiveness (ie, acute insulin response to glucose [AIRg]; mU/L x min(-1)) and to determine reference quintiles for these and minimal model variables. ANIMALS: 1 laminitic pony and 46 healthy horses. PROCEDURE: Basal plasma glucose (mg/dL) and insulin (mU/L) concentrations were determined from blood samples obtained between 8:00 AM and 9:00 AM. Minimal model results for 46 horses were compared by equivalence testing with proxies for screening SI and pancreatic beta-cell responsiveness in humans and with 2 new proxies for screening in horses (ie, reciprocal of the square root of insulin [RISQI] and modified insulin-to-glucose ratio [MIRG]). RESULTS: Best predictors of SI and AIRg were RISQI (r = 0.77) and MIRG (r = 0.75) as follows: SI = 7.93(RISQI) - 1.03 and AIRg = 70.1(MIRG) - 13.8, where RISQI equals plasma insulin concentration(-0.5) and MIRG equals [800 - 0.30(plasma insulin concentration 50)(2)]/(plasma glucose concentration - 30). Total predictive powers were 78% and 80% for RISQI and MIRG, respectively. Reference ranges and quintiles for a population of healthy horses were calculated nonparametrically. CONCLUSIONS AND CLINICAL RELEVANCE: Proxies for screening SI and pancreatic beta-cell responsiveness in horses from this study compared favorably with proxies used effectively for humans. Combined use of RISQI and MIRG will enable differentiation between compensated and uncompensated insulin resistance. The sample size of our study allowed for determination of sound reference range values and quintiles for healthy horses.

Effects of oral administration of levothyroxine sodium on concentrations of plasma lipids, concentration and composition of very-low-density lipoproteins, and glucose dynamics in healthy adult mares.

OBJECTIVE: To evaluate glucose and lipid metabolism in healthy adult horses administered levothyroxine sodium (L-T4). ANIMALS: 12 healthy adult mares. PROCEDURE: 8 horses received an incrementally increasing dosage of L-T4 (24, 48, 72, or 96 mg of L-T4/d) for weeks 1 to 8. Each dose was provide between 7 AM and 8 AM in the morning grain meal for 2 weeks. Four additional horses remained untreated. Serum concentrations of nonesterified fatty acids, triglyceride (TG), total cholesterol (TC), and very-low-density lipoprotein (VLDL) were measured and composition of VLDL examined in samples obtained between 8 AM and 9 AM at weeks 0, 2, 4, 6, and 8. Glucose dynamics were assessed by use of a combined IV glucose-insulin tolerance test (IVGITT) conducted before and at the end of the 8-week treatment period. Data for each combined IVGITT were interpreted by use of the minimal model. RESULTS: Plasma TG, TC, and VLDL concentrations significantly decreased over time in treated horses. At the completion of the 8-week treatment period, mean plasma VLDL concentration was 46% of the mean value for week 0 in treated horses. Insulin sensitivity significantly increased (> 2-fold) in treated horses, but glucose effectiveness and net insulin response were not affected. Levothyroxine sodium significantly increased the rate of insulin disposal. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of L-T4 decreases blood lipid concentrations, improves insulin sensitivity, and increases insulin disposal in horses. Levothyroxine sodium may have potential as a treatment for horses with reduced insulin sensitivity.

Subtotal pericardectomy and epicardial excision for treatment of coccidioidomycosis-induced effusive-constrictive pericarditis in dogs: 17 cases (1999-2003).

OBJECTIVE: To determine the history, clinicopathologic findings, and results of surgery for effusive-constrictive pericarditis associated with Coccidioides immitis infection in dogs. DESIGN: Retrospective study. ANIMALS: 17 client-owned dogs that underwent a subtotal pericardectomy and epicardial excision. PROCEDURE: Hospital records from May 1999 to June 2003 were reviewed. Data collected included history, clinicopathologic findings, treatments, and outcome. Follow-up information was obtained via recheck examination and by use of standardized telephone interviews with referring veterinarians and owners. RESULTS: All dogs were of large breeds, and most were male (mean age, 4.66 years). Ten dogs had no prior history of C. immitis infection, and 7 dogs had chronic infection with C. immitis. Having a chronic C. immitis infection reduced the odds of survival, compared with no previous infection. All dogs had clinical signs of right-sided heart failure. All dogs had serum titers (range, 1:8 to 1:256) for antibodies against C. immitis prior to surgery, and titers were not significantly associated with outcome. Predominant echocardiographic findings were thickened pericardium, reduced right ventricular filling, and pleural or pericardial effusion. All dogs underwent a subtotal pericardectomy and epicardial excision and had fibrosing pyogranulomatous pericarditis in biopsy specimens obtained during surgery. The perioperative mortality rate was 23.5%, and the 2-year postdischarge survival rate was 82%. CONCLUSIONS AND CLINICAL RELEVANCE: Surgical treatment via subtotal pericardectomy and epicardial excision is successful at relieving right-sided heart failure in dogs with effusive-constrictive pericarditis secondary to C. immitis infection, but long-term treatment with antifungal agents may still be required.

Focal seizure symptoms in idiopathic generalized epilepsies.

OBJECTIVE: We sought to study the frequency and prognostic value of focal seizure symptoms (FSS) in idiopathic generalized epilepsies (IGE) using a validated tool: Epilepsy Diagnostic Interview Questionnaire and Partial Seizure Symptom Definitions. METHODS: Participants with IGE were recruited from epilepsy clinics at 2 tertiary hospitals. The diagnosis was validated and classified into syndromes according to the International League Against Epilepsy criteria by 2 epileptologists independently with discordance resolved by consensus. The Epilepsy Diagnostic Interview Questionnaire utilizes both open- and closed-ended questions to elicit FSS in association with generalized tonic-clonic seizures, myoclonus, and absences. The elicited FSS were classified according to the Partial Seizure Symptom Definitions. Regression analysis was conducted to examine the relationship between the duration of seizure freedom and FSS. RESULTS: A total of 135 patients were studied, of whom 70 (51.9%) reported FSS. Those symptoms occurred in association with generalized tonic-clonic seizures (53.1%) as well as myoclonus and absences (58%). FSS were reported with similar frequency in juvenile absence epilepsy (62.5%) and juvenile myoclonic epilepsy (60%), and with a lesser frequency in generalized epilepsy with tonic-clonic seizures only (39.5%) and childhood absence epilepsy (33.3%). A strong relationship between FSS and duration of seizure freedom was found (regression coefficient -0.665, p = 0.037). CONCLUSIONS: FSS are frequently reported by patients with IGE. A shorter duration of seizure freedom is associated with FSS. Recognition of the presence of FSS in IGE is important to avoid misdiagnosis and delayed diagnosis as well as to choose appropriate antiepileptic drug therapy.