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.

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.

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.

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.

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.

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.

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.

Optimization of an in vitro assay to detect Streptococcus equi subsp. equi.

Streptococcus equi is the etiologic agent of a highly infectious upper respiratory disease of horses known as strangles. Bacterial culture methods and polymerase chain reaction (PCR) of nasopharyngeal washes and guttural pouch lavages are used routinely to test clinical and carrier animals for the presence of S. equi but no definitive or gold standard test method has been shown to be optimal. We hypothesized that (i) a flocked swab submerged in ten-fold serial dilution suspensions of S. equi prepared in 0.9% NaCl would detect more colony forming units (CFU) than a rayon swab when used to inoculate a blood agar plate, (ii) centrifugation of a 1 ml aliquot of each suspension would improve the limit of detection (LOD) by bacterial culture and PCR compared to the culture or PCR of submerged swab samples, (iii) PCR of the centrifuged samples from each suspension would be more sensitive than aerobic culture alone, and (iv) PCR of a 1 ml aliquot directly from a sample would be more sensitive than PCR of a sample following submersion of a flocked swab in 1 ml saline. Using 7 ten-fold serial dilutions of S. equi in 0.9% NaCl, the LOD for 4 bacterial culture methods and 3 PCR methods were compared. The LOD of direct PCR and flocked swab culture was determined at 1 cfu/ml. All PCR methods were equivalent to each other and were more sensitive than any of the culture methods at the lower dilutions. At higher cell densities (>100 cfu/ml) flocked swab culture was not statistically better than rayon swab culture, but it was superior to all other methods tested.

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

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

Perioperative ruminal pH changes in domestic sheep (Ovis aries) housed in a biomedical research setting.

Little information is available on normal ruminal pH values for domestic sheep (Ovis aries) housed in a research setting and fed a complete pelleted ration. Sheep maintained on pelleted diets undergoing surgical procedures often present with postoperative anorexia and rumen atony. To determine the relationship between diet and postoperative rumen acidosis and associated atony, we studied dietary effects on ruminal pH in an ovine surgical model. Sheep undergoing orthopedic surgical procedures were randomized into 2 diet groups. Group 1 (n = 6) was fed complete pelleted diet during the pre- and postoperative period, and group 2 (n = 6) was fed timothy grass hay exclusively throughout the study. Measures included ruminal pH, ruminal motility, and rate of feed refusal, which was monitored throughout the pre- and postoperative periods. The 2 groups did not differ significantly before surgery, and the ruminal parameters remained largely within normal limits. However, a downward trend in the strength and frequency of rumen contractions was observed in pellet-fed sheep. After surgery, the pellet-fed group showed clinical signs consistent with ruminal acidosis, supported by decreased ruminal motility, anorexia, putrid-smelling ruminal material, and death of ruminal protozoa. Intervention by transfaunation in clinically affected sheep resulted in resolution of signs. Our findings suggest that sheep fed grass hay appear to have a more stable ruminal pH, are less likely to experience anorexia and rumen atony, and thereby exhibit fewer postoperative gastrointestinal complications than do sheep on a pellet diet.

A numerical deconvolution method to estimate C-peptide secretion in humans after an intravenous glucose tolerance test.

Quantitative assessment of pancreatic insulin secretion rate in individuals may help advance our understanding and treatment of diabetes. We describe for the first time the application of a long-established numerical deconvolution procedure in which a prescribed input function is used to represent first-phase pancreatic secretion response to an intravenous glucose challenge (intravenous glucose tolerance test [IVGTT]) in individual subjects. We identify that C-peptide secretory response to an IVGTT can be described by a basal secretion rate (S(b)) (picomoles per liter per minute) and a first-phase secretory response characterized by a Gaussian function. The Gaussian function contains 3 parameters: P(1) (picomoles per liter per minute), which represents the peak rate secretion; P(2) (per square minute), which is related to the inverse of peak width at half-peak height; and P(3) (minutes), which is the time of the peak secretion rate. When applied to data from 8 healthy Chinese subjects, the estimated parameter values (mean +/- SD) were 19.2 +/- 12.9 pmol L(-1) min(-1), 1548 +/- 1143 pmol L(-1) min(-1), 1.09 +/- 1.21 min(-2), and 2.94 +/- 1.13 minutes for S(b), P(1), P(2), and P(3), respectively. The Gaussian input functions are shown to have similar shapes and to be highly concordant in magnitude with secretory responses estimated by means of the method of Eaton et al (1980) and by the ISEC computer program. In conclusion, we have presented a simple, integrated, validated, and easily implemented method suitable for quantifying pancreatic C-peptide and insulin secretion in individual human subjects. The superiority of our method in comparison with other methods is that it uses as an input function the Gaussian, which has been experimentally verified as describing in vivo the profile of pulsatile insulin secretion. The particular strength of our method is that the Gaussian parameters and simple indices derived from them provide a standardized and interpretable means for carrying out comparative investigations aimed at quantifying how pancreatic secretory responses to an IVGTT differ in various demographic groups or in response to therapeutic treatments.

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.

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.

NEFA minimal model parameters estimated from the oral glucose tolerance test and the meal tolerance test.

The kinetics of nonesterified fatty acid (NEFA) metabolism in humans requires quantification to facilitate understanding of diseases like type 1 and 2 diabetes, metabolic syndrome, and obesity, and the mechanisms underpinning various interventions. Oral glucose tolerance tests (OGTT) and glucose meal tolerance tests (MTT) are potentially useful procedures for enabling quantification of NEFA kinetics because they both cause transitory, but substantial, declines and then rebounds in plasma NEFA concentrations in response to physiologically relevant increases in plasma glucose. The Boston MINIMAL model of NEFA kinetics was developed to analyze data from the intravenous glucose tolerance test (IVGTT), but in this work, we present for the first time its application to modeling NEFA data from both OGTT and MTT studies. This model enables estimation of SFFA (micromol.l(-1).min(-1)) (a parameter describing the maximum rate of lipolysis), and KFFA (%/min) (a parameter related to NEFA oxidation rate). The model could well describe the trajectories of NEFA concentrations following an OGTT (R2 in excess of 0.97) but was not as successful with the MTT (R2>0.65). Model parameters derived from analysis of OGTT and MTT data were well identified with coefficients of variation generally less than 15%. Type 2 diabetes, body mass index, and dietary treatment (high-fat vs. high-glycemic-index diets) were all shown to have significant effects on model parameters. Modeling plasma NEFA concentrations over 24 h has helped to identify and quantify the extent that periprandial NEFA peaks and nocturnal elevation in plasma NEFA can be accounted for by our model.

A novel minimal model to describe NEFA kinetics following an intravenous glucose challenge.

Dynamics of nonesterified fatty acid (NEFA) metabolism in humans requires quantification if we are to understand the etiology of such diseases as type 1 and 2 diabetes, as well as metabolic syndrome and obesity, or if we are to elucidate the mechanism of action of various interventions. We present a new compartmental model that employs the pattern of plasma glucose concentrations in healthy young adults to predict dynamic changes that occur in plasma NEFA concentrations during either a glucose-only intravenous glucose tolerance test, or an insulin-modified intravenous tolerance test, or a modified protocol during which variable-rate glucose infusions were administered to prevent plasma glucose from declining below 100 mg/dl. The model described all of the major features of NEFA response to an intravenous glucose tolerance test, including an initial latency phase, a phase during which plasma NEFA concentrations plummet to a nadir, and a rebound phase during which plasma NEFA concentrations may rise to a plateau concentration, which may be substantially higher than the initial basal NEFA concentration. This model is consistent with physiological processes and provides seven adjustable parameters that can be used to quantify NEFA production (lipolysis) and utilization (oxidation). When tested on data from the scientific literature, the range in estimated rate of lipolysis was 24-36 micromol.l(-1).min(-1) and for NEFA oxidation rate was 25-54 micromol.l(-1).min(-1). All model parameters were well identified and had coefficients of variation < 15% of their estimated values. It is concluded that this model is suitable to describe NEFA kinetics in human subjects.