Impact of blue light therapy on plasma adrenocorticotropic hormone (ACTH) and hypertrichosis in horses with pituitary pars intermedia dysfunction.

Blue light therapy can be used in horses to alter the natural photoperiod and inhibit winter hair coat growth. Seasonal increases in ACTH occur in the fall season but are exaggerated in horses with pituitary pars intermedia dysfunction (PPID). Additionally, PPID horses frequently present with hypertrichosis. Thus, blue light therapy was proposed as a potential management tool for hypertrichosis and for investigating the impact of photoperiod manipulation on ACTH. Eighteen PPID horses, aged 18 to 31 yr, from a university-owned research herd were selected and assigned to either the control group (n = 10) or the treatment (blue light therapy) group (n = 8) based on age and clinical history, which included the results of multiple endocrine tests. Consistent daylength of approximately 14.5 h was maintained for the treated horses from July 15 through approximately late October via the extension of natural daylength using wearable masks that provided short wavelength blue light (465 nm) to 1 eye. The control group was exposed to only the natural photoperiod during this time. All horses were housed on the same farm and remained on pasture for the duration of the study. On Day 0, thyrotropin-releasing hormone (TRH) stimulation tests were performed to confirm PPID status; there were no differences between the 2 groups in resting plasma ACTH or plasma ACTH at 10 min after TRH administration. To determine an effect of treatment on ACTH, blood was collected via jugular venipuncture for measurement of ACTH at sequential timepoints over a 16-h period in mid-October. Hair weights were also assessed throughout the study. No differences in resting plasma ACTH were observed between the 2 groups across the seasonal analysis (July and October) or during the 16-h testing. The PPID horses receiving blue light therapy had lighter hair weights compared to the PPID control horses. These results suggest that blue light therapy does not alter ACTH concentrations but could potentially be used as an additional management tool for hypertrichosis in PPID horses. Manipulation of the photoperiod using blue light therapy did not affect seasonal changes in ACTH in this study.

Effects of blue monochromatic light directed at one eye of pregnant horse mares on gestation, parturition and foal maturity.

Blue light directed at 1 eye advances the equine ovulatory season but may also advance foaling. In this study, effects of blue LED light on pregnancy outcome were assessed. A total of 20 mares with singleton pregnancies were studied over 2 consecutive years in a cross-over design. In 1 year, mares received an extended photoperiod using 50 lux of blue LED light (468 nm) directed at a single eye from 08:00 until 23:00 daily via head-worn light masks starting mid-December and in the other year remained untreated as controls. Gestation was shorter in blue LED light-treated than in control pregnancies (median 333.0 vs 338.5 days, P = 0.036). Foals born to blue LED light-treated mares had lower wither heights (median 103.0 vs 104.5 cm, P = 0.023), similar weights (median 55.8 vs 54.8 kg, P = 0.732) and took less time to stand after birth than control foals (median 35.0 vs 53.5 min, P = 0.036). Foals born to blue LED light-treated mares had reduced hair length compared to controls (median 12.0 vs 20.0 mm, P = 0.009) and hair regrowth in treated mares was reduced (P = 0.036). In conclusion, blue LED light directed at 1 eye advanced foaling and influenced height and hair coat but not weight in foals.

Red light at night permits the nocturnal rise of melatonin production in horses.

Exposure to white light at night suppresses melatonin production, impacts circadian rhythms and contributes to ill-health in humans. Human interaction with horses frequently occurs at night. We tested the hypothesis that dim red light would not suppress the nightly rise in serum melatonin levels in horses. In a crossover design, six horses were maintained for consecutive 48h periods under a Light: Red (LR) and a Light: Dark (LD) photo-schedule. Transitions from light (>200lux, polychromatic white light) to red (5lux, peak wavelength 625nm) or dark (<0.5lux), and vice versa, coincided with ambient sunset and sunrise times. Blood was collected at 2h intervals for 24h during each treatment via indwelling jugular catheters. Samples were harvested for serum and stored at -20°C until assayed for melatonin by radioimmunoassay. Repeated measures two-way ANOVA and t-tests analysed for differences in LR and LD melatonin profiles and their circadian rhythm parameters. No time×treatment interaction or effect of treatment on serum melatonin levels were demonstrated (P>0.05). A robust main effect of time (P<0.0001) predominated, with melatonin levels rising at night under both treatments. Statistically significant differences were not observed when LR and LD were compared for circadian rhythm measures of night time peak, area under the curve (AUC), or for times of onset (evening rise), offset (morning decline), or peak duration. Low intensity red light at night did not impact the pattern of melatonin secretion in this study and is, therefore, unlikely to impact the physiology of circadian or seasonal regulation.

Evidence of a molecular clock in the ovine ovary and the influence of photoperiod.

The influence of the central circadian clock on reproductive timing is well established. Much less is known about the role of peripheral oscillators such as those in the ovary. We investigated the influence of photoperiod and timing of the LH surge on expression of circadian clock genes and genes involved in steroidogenesis in ovine ovarian stroma. Seventy-two Suffolk cross ewes were divided into two groups, and their estrous cycles were synchronized. Progestagen sponge removal was staggered by 12 hours between the groups such that expected LH peak would occur midway through either the light or dark phase of the photoperiodic cycle. Four animals from each group were killed, and their ovaries were harvested beginning 36 hours after sponge removal, at 6-hour intervals for 48 hours. Blood was sampled every 3 hours for the period 24 to 48 hours after sponge removal to detect the LH surge. The interval to peak LH did not differ between the groups (36.2 ± 1.2 and 35.6 ± 1.1 hours, respectively). There was an interaction between group and the time of sponge removal on the expression of the core clock genes ARNTL, PER1, CRY1, CLOCK, and DBP (P < 0.01, P < 0.05, P < 0.01, P < 0.01, and P < 0.01, respectively). As no significant interaction between group and time of day was detected, the datasets were combined. Statistically significant rhythmic oscillation was observed for ARNTL, CLOCK, CRY1 (P < 0.01, respectively), PTGS2, DBP, PTGER2, and CYP17A1 (P < 0.05, respectively), confirming the existence of a time-sensitive functionality within the ovary, which may influence steroidogenesis and is independent of the ovulatory cycle.

A 3'-UTR KRAS-variant is associated with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

BACKGROUND: A germline mutation in the 3'-untranslated region of KRAS (rs61764370, KRAS-variant: TG/GG) has previously been associated with altered patient outcome and drug resistance/sensitivity in various cancers. We examined the prognostic and predictive significance of this variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: We conducted a retrospective study of 103 HNSCCs collected from three completed clinical trials. KRAS-variant genotyping was conducted for these samples and 8 HNSCC cell lines. p16 expression was determined in a subset of 26 oropharynx tumors by immunohistochemistry. Microarray analysis was also utilized to elucidate differentially expressed genes between KRAS-variant and non-variant tumors. Drug sensitivity in cell lines was evaluated to confirm clinical findings. RESULTS: KRAS-variant status was determined in 95/103 (92%) of the HNSCC tumor samples and the allelic frequency of TG/GG was 32% (30/95). Three of the HNSCC cell lines (3/8) studied had the KRAS-variant. No association between KRAS-variant status and p16 expression was observed in the oropharynx subset (Fisher's exact test, P = 1.0). With respect to patient outcome, patients with the KRAS-variant had poor progression-free survival when treated with cisplatin (log-rank P = 0.002). Conversely, KRAS-variant patients appeared to experience some improvement in disease control when cetuximab was added to their platinum-based regimen (log-rank P = 0.04). CONCLUSIONS: The TG/GG rs61764370 KRAS-variant is a potential predictive biomarker for poor platinum response in R/M HNSCC patients. CLINICAL TRIAL REGISTRATION NUMBERS: NCT00503997, NCT00425750, NCT00003809.

Exercise influences circadian gene expression in equine skeletal muscle.

Circadian rhythms are endogenously generated 24-h oscillations that coordinate numerous aspects of mammalian physiology, metabolism and behaviour. The existence of a molecular circadian clock in equine skeletal muscle has previously been demonstrated. This study investigates how the circadian 24-h expression of exercise-relevant genes in skeletal muscle is influenced by a regular exercise regime. Mid-gluteal, percutaneous muscle biopsies were obtained over a 24-h period from six Thoroughbred mares before and after an 8-week exercise programme. Real-time qPCR assays were used to assess the expression patterns of core clock genes ARNTL, PER2, NR1D1, clock-controlled gene DBP, and muscle genes MYF6, UCP3, VEGFA, FOXO1, MYOD1, PPARGC1A, PPARGC1B, FBXO32 and PDK4. Two-way repeated measures ANOVA revealed a significant interaction between circadian time and exercise for muscle genes MYF6, UCP3, MYOD1 and PDK4. A significant effect of time was observed for all genes with the exception of VEGFA, where a main effect of exercise was observed. By cosinor analysis, the core clock genes, ARNTL (P <0.01) and NR1D1 (P <0.05), showed 24-h rhythmicity both pre- and post-exercise, while PER2 expression was rhythmic post-exercise (P <0.05) but not pre-exercise. The expression profiles of muscle genes MYOD1 and MYF6 showed significant fits to a 24-h cosine waveform indicative of circadian rhythmicity post-exercise only (P <0.01). This study suggests that the metabolic capacity of muscle is influenced by scheduled exercise and that optimal athletic performance may be achieved when exercise times and competition times coincide.

Blue light from individual light masks directed at a single eye advances the breeding season in mares.

REASONS FOR PERFORMING STUDY: Artificial lighting is commonly used to advance the breeding season in horses. Light masks have been developed that direct light at a single eye to inhibit the production of melatonin, the decoder of photoperiod for seasonally breeding animals. OBJECTIVES: To investigate whether low-intensity blue light from light masks was effective at advancing the breeding season in mares. STUDY DESIGN: Controlled experiment. METHODS: Data on reproductive activity was collected from 3 groups of mares maintained on Kentucky horse farms under various lighting conditions between 20 November 2011 and 10 February 2012: 59 nonpregnant, healthy Thoroughbred mares were used. On 1 December 2011, Group 1 (n = 16) was housed indoors under barn lighting (250 Lux) until 23.00 h daily. Group 2 (n = 25) wore light masks programmed to turn on from 16.30 h until 23.00 h daily and was maintained outdoors. Group 3 (n = 19) was maintained outdoors under the natural photoperiod as control. At 2-week intervals, rectal ultrasound examinations were performed and blood was collected for progesterone analysis. Oestrous cyclicity was defined as the presence of follicles >20 mm diameter detected in conjunction with serum progesterone >1 ng/ml and confirmation of ovulation by transrectal ultrasound examination. RESULTS: On 10 February, the number of mares exhibiting oestrous cyclicity was 14/16 (87.5%) in Group 1; 20/25 (80%) in Group 2; and 4/19 (21%), in Group 3. Pairwise comparison of groups revealed no difference in the number of cycling mares between Groups 1 and 2 (χ(2) test, P = 0.3348) whereas differences were observed between Groups 1 and 3 (χ(2) test, P<0.0001) and Groups 2 and 3 (χ(2) test, P<0.0003). CONCLUSIONS: Low-intensity blue light to a single eye from a light mask is an effective alternative to maintenance of mares indoors under lights for advancing the breeding season. Mobile light therapy for horses could have economic benefits for the breeder by reducing the costs of maintaining mares indoors, and welfare benefits for horses by permitting outdoor maintenance.

Selective changes in cerebellar-cortical processing following motor training.

The aim of this study was to investigate the effect of varying stimulation rate and the effects of a repetitive typing task on the amplitude of somatosensory evoked potential (SEP) peaks thought to relate to cerebellar processing. SEPs (2,000 sweep averages) were recorded following median nerve stimulation at the wrist at frequencies of 2.47, 4.98, and 9.90 Hz from 12 subjects before and after a 20-min repetitive typing task. Typing and error rate were recorded 2-min pre- and post-typing task. Effect of stimulation rate was analysed with ANOVA followed by pairwise comparisons (paired t tests). Typing effects were analysed by performing two-tailed paired t tests. Increasing stimulation frequency significantly decreased the N30 SEP peak amplitude (p < 0.02). Both the 4.98 and 9.90 Hz rates lead to significantly smaller N30 peak amplitudes compared to the 2.47 Hz (p ≤ 0.01). The N24 amplitude significantly increased following the typing task for both 4.98 and 2.47 Hz (p ≤ 0.025). In contrast, there was a highly significant decrease (p < 0.001) in the N18 peak amplitude post-typing at all frequencies. Typing rate increased (p < 0.001) and error rate decreased (p < 0.05) following the typing task. The results suggest that the N24 SEP peak amplitude is best recorded at 4.98 Hz since the N30 amplitude decreases and no longer contaminates the N24 peak, making the N24 visible and easier to measure, while still enabling changes due to repetitive activity to be measured. The decrease in N18 amplitude along with an increase in N24 amplitude with no change in N20 amplitude may be explained by the intervention reducing inhibition at the level of the cuneate nucleus and/or interior olives leading to alterations in cerebellar-cortical processing.

Blue light from light-emitting diodes directed at a single eye elicits a dose-dependent suppression of melatonin in horses.

The production of melatonin during night-time hours decodes day length for seasonally breeding animals. The use of artificial light to advance the breeding season in mares is common practice within the equine industry. Four healthy Thoroughbred mares were used to evaluate the minimum intensity of light required to inhibit serum melatonin. Mares were fitted with indwelling jugular catheters and using a crossover design blood samples were collected following 1h exposure to light (barn lighting approximately 200 lux), dark (<0.1 lux), and 3, 10, 50, and 100 lux intensities. The light source was a light-emitting diode (LED; 468 nm) directed at either a single eye or both eyes. All treatments, except the sample collected after 1 h exposure to light, occurred during the dark phase of the 24 h cycle. Serum melatonin levels were determined by radioimmunoassay. Two-way repeated measures ANOVA revealed that there was no difference between the level of melatonin inhibition achieved when light was administered to one or two eyes (P = 0.7028). One-way ANOVA of melatonin levels at light intensities of 10, 50 and 100 lux were significantly different to dark (P < 0.05) and not different to light (P > 0.05) intensities. There was no difference between melatonin levels at 3 lux (P > 0.05) and dark intensities. The threshold level of low wavelength light required to inhibit melatonin production in the horse lies between 3 and 10 lux. Melatonin inhibition can be achieved by exposing a single eye to low wavelength blue light. This is a novel finding with important implications for management of artificial lighting regimens in horses.

Osteomark: a surgical navigation system for oral and maxillofacial surgery.

The purpose of this project was to test a surgical navigation tool designed to help execute a surgical treatment plan. It consists of an electromagnetically tracked pencil that is used to mark bone intraoperatively. The device was tested on a precision block, an ex vivo pig mandible and during performance of six endoscopic vertical ramus osteotomies on pig cadavers. The difference between actual pencil position and that displayed by the computer was measured three times each at ten 2mm holes on the block (n=30 observations) and on the ex vivo mandible (n=11 measurements). Errors between planned and actual osteotomy locations for the cadaver procedures were measured. The mean distance between known and displayed locations was 1.55 ± 0.72 mm on the precision block and 2.10 ± 0.88 mm on the pig mandible. The error measured marking the same point on the block multiple (n=5) times was 0.58 ± 0.37 mm. The mean error on the simulated osteotomies was 2.35 ± 1.35 mm. Osteomark was simple to use and permitted localisation of holes and osteotomies with acceptable accuracy. In the future, the device and algorithms will be revised to further decrease error and the system will be tested on live animals.

Morphological variation in the horse: defining complex traits of body size and shape.

Horses, like many domesticated species, have been selected for broad variation in skeletal size. This variation is not only an interesting model of rapid evolutionary change during domestication, but is also directly applicable to the horse industry. Breeders select for complex traits like body size and skeletal conformation to improve marketability, function, soundness and performance in the show ring. Using a well-defined set of 35 measurements, we have identified and quantified skeletal variation in the horse species. We collected measurements from 1215 horses representing 65 breeds of diverse conformation such as the American Miniature, Shetland Pony, Arabian Horse, Thoroughbred, Shire and Clydesdale. Principal components analysis has identified two key dimensions of skeletal variation in the horse. Principal component 1 is positively correlated with every measurement and quantifies overall body size. Principal component 2 captures a pattern of bone widths vs. lengths and thus quantifies variation in overall bone thickness. By defining these complex skeletal traits, we have created a framework for whole genome association studies to identify quantitative trait loci that contribute to this variation.

How best to measure the levator hiatus: evidence for the non-Euclidean nature of the 'plane of minimal dimensions'.

OBJECTIVE: To clarify whether the 'plane of minimal dimensions' of the levator hiatus on three-dimensional (3D) ultrasound accurately represents the minimal anatomical transverse hiatal dimension during a Valsalva maneuver. METHODS: In this retrospective study of 3D transperineal ultrasound and magnetic resonance (MR) imaging, datasets from 19 female participants were used to measure the transverse diameter of the levator hiatus using the plane of minimal dimensions on maximum Valsalva maneuver. The term 'apparent minimal transverse diameter' (aMTD) was used to define the transverse diameter measured using axial ultrasound and comparable axial or coronal MR images. Coronal MR images, using the plane of the vagina as a reference, were also obtained on maximum Valsalva. The transverse diameter measured between the caudal margin of the pubococcygeus/puborectalis on the MR coronal image is denoted by the term 'true minimal transverse diameter' (tMTD). Statistical comparisons between the aMTD and tMTD were made using Student's t-test. RESULTS: No significant difference was demonstrated between the aMTD as measured by ultrasonography and MRI. However, there were significant differences found between the aMTD measured by both ultrasound and MRI and the tMTD measured on coronal MR images (both P < 0.01), with mean ( ± SD) values of 4.36 ± 0.85, 4.13 ± 1.09 and 3.23 ± 0.49 cm, respectively. CONCLUSION: This study highlights the complexity and 3D nature of the levator hiatus and pelvic floor muscles. Investigators have previously assumed that the plane of minimal dimensions of the hiatus can be measured in a flat plane, however, the 3D nature of the hiatus means that the true levator hiatus occupies a warped (non-Euclidean) plane. Hiatal measurements on Valsalva may be subject to systematic error if performed in a single section, i.e. using a flat (Euclidean) plane.

Nuclear factor-kappa B pathway and response in a phase II trial of bortezomib and docetaxel in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Our previous study has shown that nuclear factor-kappa B (NF-kappaB)-signaling pathway was associated with a higher rate of recurrence in head and neck squamous cell carcinoma (HNSCC). The combination of bortezomib, an NF-kappaB inhibitor by inhibition of proteasomes, plus docetaxel was assessed for efficacy and toxicity. MATERIALS AND METHODS: Patients with recurrent and/or metastatic HNSCC were enrolled on a phase II bortezomib/docetaxel trial (bortezomib 1.6 mg/m(2) and docetaxel 40 mg/m(2) on days 1 and 8 of a 21-day cycle). Response was assessed using RECIST. Tissue specimens were evaluated for the presence of human papillomavirus (HPV) and expression of NF-kappaB-associated genes. RESULTS: Twenty-one of 25 enrolled patients were assessable for response; one partial response (PR, 5%), 10 stable disease (SD, 48%) and 10 progressive disease (PD, 48%). Patients with PR/SD had significantly longer survival compared with patients with PD and the regimen was well tolerated. Only one of 20 tumors was positive for HPV. Patients with PD had higher expression of NF-kappaB and epidermal growth factor receptor-associated genes in their tumors by gene expression analysis. CONCLUSION: Further understanding of treatment resistance and interactions between bortezomib and docetaxel may provide novel approaches in managing HNSCC.

Local drug delivery with a self-contained, programmable, microfluidic system.

The development and optimization of many new drug therapies requires long-term local delivery with controlled, but variable dosage. Current methods for chronic drug delivery have limited utility because they either cannot deliver drugs locally to a specific organ or tissue, do not permit changes in delivery rate in situ, or cannot be used in clinical trials in an untethered, wearable configuration. Here, we describe a small, self-contained system for liquid-phase drug delivery. This system enables studies lasting several months and infusion rates can be programmed and modified remotely. A commercial miniature pump is integrated with microfabricated components to generate ultralow flow rates and stroke volumes. Solutions are delivered in pulses as small as 370 nL, with pulses delivered at any interval of 1 min or longer. A unique feature of the system is the ability to infuse and immediately withdraw liquid, resulting in zero net volume transfer while compounds are exchanged by mixing and diffusion with endogenous fluid. We present in vitro results demonstrating repeatability of the delivered pulse volume for nearly 3 months. Furthermore, we present in vivo results in an otology application, infusing into the cochlea of a guinea pig a glutamate receptor antagonist, which causes localized and reversible changes in auditory sensitivity.

Pelvic floor function in nulliparous women using three-dimensional ultrasound and magnetic resonance imaging.

OBJECTIVE: To compare biometric measures of pelvic floor function obtained using three-dimensional (3D) ultrasound and magnetic resonance imaging (MRI) in a group of nulliparous asymptomatic young women. METHODS: Twenty-seven asymptomatic nulliparous volunteers were assessed prospectively, using translabial 3D ultrasound and multiplanar 3D MRI. Levator hiatal dimensions were measured in the axial plane in both modalities. All participants were imaged supine, after voiding with data acquired at rest, on maximum Valsalva and maximum pelvic floor contraction. Interobserver variability was determined for both methods. Normally distributed continuous ultrasound data were compared with equivalent MRI parameters, and intraclass correlation coefficients were used to estimate correlation between the two methods. Bland-Altman analysis was also used to estimate agreement between methods. RESULTS: Interobserver repeatability was fair to excellent for all parameters measured with both methods. Moderate-to-substantial agreement between methods was shown for all tested parameters (intraclass correlation coefficients 0.587-0.783). There was a systematic but nonsignificant difference between methods, in that measurements on Valsalva tended to be larger for MRI, and the poorest agreement (intraclass correlation coefficient 0.587) was found for hiatal area on Valsalva. CONCLUSION: Agreement between the two methods was moderate to substantial for all parameters except for hiatal area on Valsalva. Magnetic resonance imaging yielded higher area measurements on Valsalva, which may indicate difficulties in identifying the plane of minimal dimensions due to poorer temporal resolution compared with ultrasound imaging.

Pelvic floor function in elite nulliparous athletes.

OBJECTIVE: There is preliminary evidence linking long-term participation in high-impact exercise with poor performance in labor and increased incidence of stress urinary incontinence, which may be due to altered pelvic floor function. Recent work has shown that HIFIT (high-impact, frequent intense training) athletes have an increased cross-sectional area of the levator ani muscle group as visualized using magnetic resonance imaging (MRI). The aim of this study was to further characterize pelvic floor muscle function and pelvic organ descent in a nulliparous athletic population and compare it with non-athletic controls matched for age and body mass index, using three-dimensional/four-dimensional (3D/4D) pelvic floor ultrasound imaging. METHODS: In this prospective comparative study translabial ultrasound imaging was used to assess pelvic floor anatomy and function in 46 nulliparous female volunteers (aged 19-39 years), 24 HIFIT and 22 controls. Two-dimensional (2D) and 3D translabial ultrasonography was performed on all subjects, after voiding and in the supine position. Descent of the pelvic organs was assessed on maximum Valsalva maneuver, whilst volume datasets were acquired at rest, during pelvic floor muscle contraction and during a Valsalva maneuver. Participants performed each maneuver at least three times and the most effective was used for evaluation. RESULTS: HIFIT athletes showed a higher mean diameter of the pubovisceral muscle (0.96 cm vs. 0.70 cm, P < 0.01), greater bladder neck descent (22.7 mm vs. 15.1 mm, P = 0.03) and a larger hiatal area on Valsalva maneuver (21.53 vs. 14.91 cm(2), P = 0.013) compared with the control group. There were no significant differences in hiatal area at rest or on maximal voluntary contraction between the two groups. CONCLUSION: HIFIT athletes show significant differences in several of the measured parameters for both function and anatomy of the pelvic floor. Further research into the impact of this altered function on childbirth and continence mechanisms is needed.

Relationships among inflammatory cytokines, obesity, and insulin sensitivity in the horse.

Recent studies associate obesity and insulin resistance in horses with development of abnormal reproductive function and debilitating laminitis. The factors contributing to insulin resistance in obese horses are unknown. However, human studies provide evidence that elevated inflammatory cytokines such as tumor necrosis factor alpha (TNFalpha), IL1, and IL6 play direct roles in development of obesity-associated insulin resistance. Thus, inflammation may be a key link between obesity and insulin resistance in horses. The aim of the current investigation was to examine possible relationships between obesity, inflammatory cytokines, and insulin sensitivity (IS) in the horse. Age was recorded and BCS and percent body fat (% FAT) were determined as measures of obesity in 60 mares. In addition, blood mRNA expression of IL1, IL6, and TNFalpha and circulating concentrations of TNFalpha protein (TNFp) were determined in each mare. Finally, fasted concentrations of insulin were determined, and IS was determined using the hyperinsulinemic, euglycemic clamp. Significant correlations between several variables provided evidence for the design of 4 population regression models to estimate relationships between measures of obesity, inflammatory factors, and IS in the sample population. The results of these analyses revealed that IS decreased as BCS and % FAT increased (P < 0.001) in the sample population. Additionally, increased IL1 (P < 0.05) and TNFp (P < 0.01) were associated with decreased IS. However, increased TNFalpha (P < 0.001) was associated with decreased IS only in mares 20 yr of age and older. Increased BCS and % FAT were associated with increased expression of TNFalpha (P = 0.053) and IL1 (P < 0.05), and increased TNFp (P < 0.05). Surprisingly, increased BCS and % FAT were associated with decreased IL6 expression (P = 0.05) in mares <20 yr of age. Finally, evaluation of the influence of obesity and inflammatory cytokines on IS within the same model suggested that BCS and % FAT (P < 0.001) with TNFalpha [mRNA (P = 0.07) and protein (P < 0.05)] are inversely associated with IS independently of one another. Combined, these results provide the first evidence associating obesity with increased inflammatory factors in the horse. Furthermore, the results suggest that an interrelationship exists among obesity, inflammatory cytokines, and IS in the horse and emphasize the need for further studies to elucidate the nature of these relationships.

Changes in excitability of the cortical projections to the human tibialis anterior after paired associative stimulation.

Paired associative stimulation (PAS) based on Hebb's law of association can induce plastic changes in the intact human. The optimal interstimulus interval (ISI) between the peripheral nerve and transcranial magnetic stimulus is not known for muscles of the lower leg. The aims of this study were to investigate the effect of PAS for a variety of ISIs and to explore the efficacy of PAS when applied during dynamic activation of the target muscle. PAS was applied at 0.2 Hz for 30 min with the tibialis anterior (TA) at rest. The ISI was varied randomly in seven sessions (n = 5). Subsequently, PAS was applied (n = 14, ISI = 55 ms) with the TA relaxed or dorsi-flexing. Finally, an optimized ISI based on the subject somatosensory evoked potential (SEP) latency plus a central processing delay (6 ms) was used (n = 13). Motor-evoked potentials (MEPs) were elicited in the TA before and after the intervention, and the size of the TA MEP was extracted. ISIs of 45, 50, and 55 ms increased and 40 ms decreased TA MEP significantly (P = 0.01). PAS during dorsi-flexion increased TA MEP size by 92% (P = 0.001). PAS delivered at rest resulted in a nonsignificant increase; however, when the ISI was optimized from SEP latency recordings, all subjects showed significant increases (P = 0.002). No changes in MEP size occurred in the antagonist. Results confirm that the excitability of the corticospinal projections to the TA but not the antagonist can be increased after PAS. This is strongly dependent on the individualized ISI and on the activation state of the muscle.

Altered cortical integration of dual somatosensory input following the cessation of a 20 min period of repetitive muscle activity.

The adult human central nervous system (CNS) retains its ability to reorganize itself in response to altered afferent input. Intracortical inhibition is thought to play an important role in central motor reorganization. However, the mechanisms responsible for altered cortical sensory maps remain more elusive. The aim of the current study was to investigate changes in the intrinsic inhibitory interactions within the somatosensory system subsequent to a period of repetitive contractions. To achieve this, the dual peripheral nerve stimulation somatosensory evoked potential (SEP) ratio technique was utilized in 14 subjects. SEPs were recorded following median and ulnar nerve stimulation at the wrist (1 ms square wave pulse, 2.47 Hz, 1x motor threshold). SEP ratios were calculated for the N9, N11, N13, P14-18, N20-P25 and P22-N30 peak complexes from SEP amplitudes obtained from simultaneous median and ulnar (MU) stimulation divided by the arithmetic sum of SEPs obtained from individual stimulation of the median (M) and ulnar (U) nerves. There was a significant increase in the MU/M + U ratio for both cortical SEP components following the 20 min repetitive contraction task, i.e. the N20-P25 complex, and the P22-N30 SEP complex. These cortical ratio changes appear to be due to a reduced ability to suppress the dual input, as there was also a significant increase in the amplitude of the MU recordings for the same two cortical SEP peaks (N20-P25 and P22-N30) following the typing task. No changes were observed following a control intervention. The N20 (S1) changes may reflect the mechanism responsible for altering the boundaries of cortical sensory maps, changing the way the CNS perceives and processes information from adjacent body parts. The N30 changes may be related to the intracortical inhibitory changes shown previously with both single and paired pulse TMS. These findings may have implications for understanding the role of the cortex in the initiation of overuse injuries.