Astroglial Glutamine Synthetase and the Pathogenesis of Mesial Temporal Lobe Epilepsy.

The enzyme glutamine synthetase (GS), also referred to as glutamate ammonia ligase, is abundant in astrocytes and catalyzes the conversion of ammonia and glutamate to glutamine. Deficiency or dysfunction of astrocytic GS in discrete brain regions have been associated with several types of epilepsy, including medically-intractable mesial temporal lobe epilepsy (MTLE), neocortical epilepsies, and glioblastoma-associated epilepsy. Moreover, experimental inhibition or deletion of GS in the entorhinal-hippocampal territory of laboratory animals causes an MTLE-like syndrome characterized by spontaneous, recurrent hippocampal-onset seizures, loss of hippocampal neurons, and in some cases comorbid depressive-like features. The goal of this review is to summarize and discuss the possible roles of astroglial GS in the pathogenesis of epilepsy.

Network-Related Changes in Neurotransmitters and Seizure Propagation During Rodent Epileptogenesis.

OBJECTIVE: To test the hypothesis that glutamate and GABA are linked to the formation of epilepsy networks and the triggering of spontaneous seizures, we examined seizure initiation/propagation characteristics and neurotransmitter levels during epileptogenesis in a translationally relevant rodent model of mesial temporal lobe epilepsy. METHODS: The glutamine synthetase (GS) inhibitor methionine sulfoximine was infused into one of the hippocampi in laboratory rats to create a seizure focus. Long-term video-intracranial EEG recordings and brain microdialysis combined with mass spectrometry were used to examine seizure initiation, seizure propagation, and extracellular brain levels of glutamate and GABA. RESULTS: All seizures (n = 78 seizures, n = 3 rats) appeared first in the GS-inhibited hippocampus of all animals, followed by propagation to the contralateral hippocampus. Propagation time decreased significantly from 11.65 seconds early in epileptogenesis (weeks 1-2) to 6.82 seconds late in epileptogenesis (weeks 3-4, paired t test, p = 0.025). Baseline extracellular glutamate levels were 11.6-fold higher in the hippocampus of seizure propagation (7.3 µM) vs the hippocampus of seizure onset (0.63 µM, analysis of variance/Fisher least significant difference, p = 0.01), even though the concentrations of the major glutamate transporter proteins excitatory amino acid transporter subtypes 1 and 2 and xCT were unchanged between the brain regions. Finally, extracellular GABA in the seizure focus decreased significantly from baseline several hours before a spontaneous seizure (paired t test/false discovery rate). CONCLUSION: The changes in glutamate and GABA suggest novel and potentially important roles of the amino acids in epilepsy network formation and in the initiation and propagation of spontaneous seizures.

Crystalline characteristics of annealed AlN films by pulsed laser treatment for solidly mounted resonator applications.

AlN films were deposited on Si substrates using a reactive RF magnetron sputtering process and then the films were annealed by using different laser powers and wavelengths (355 nm, 532 nm and 1064 nm). For all three laser systems, the (002) peak intensity was obviously improved following laser irradiation. The improvement in the crystalline property was particularly obtained in the AlN film processed at 355 nm. In particular, given the use of the optimal laser power (0.025 W), the (002) peak intensity was 58.7% higher than that of the as-deposited film. The resonant frequency and 3 dB bandwidth of a SMR filter with an unprocessed AlN film were found to be 2850 MHz and 227.81 MHz, respectively. Following laser treatment with a wavelength of 1064 nm and a power of 0.25 W, the resonant frequency changed from 2850 to 2858 MHz. Moreover, 3 dB bandwidth changed from 227.81 to 202.49 MHz and the return loss of the filter reduced from 17.28 to 16.48 dB. Overall, the results thus show that the frequency response of the SMR filter can be adjusted and the return loss reduced by means of laser treatment with an appropriate wavelength.

Astrocytes and Glutamine Synthetase in Epileptogenesis.

The cellular, molecular, and metabolic mechanisms that underlie the development of mesial temporal lobe epilepsy are incompletely understood. Here we review the role of astrocytes in epilepsy development (a.k.a. epileptogenesis), particularly astrocyte pathologies related to: aquaporin 4, the inwardly rectifying potassium channel Kir4.1, monocarboxylate transporters MCT1 and MCT2, excitatory amino acid transporters EAAT1 and EAAT2, and glutamine synthetase. We propose that inhibition, dysfunction or loss of astrocytic glutamine synthetase is an important causative factor for some epilepsies, particularly mesial temporal lobe epilepsy and glioblastoma-associated epilepsy. We postulate that the regulatory mechanisms of glutamine synthetase as well as the downstream effects of glutamine synthetase dysfunction, represent attractive, new targets for antiepileptogenic interventions. Currently, no antiepileptogenic therapies are available for human use. The discovery of such interventions is important as it will fundamentally change the way we approach epilepsy by preventing the disease from ever becoming manifest after an epileptogenic insult to the brain.

Resilience is decreased in irritable bowel syndrome and associated with symptoms and cortisol response.

BACKGROUND: Irritable bowel syndrome (IBS) is a stress-sensitive disorder associated with early adverse life events (EALs) and a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. Resilience is the ability to recover and adapt positively to stress but has not been well studied in IBS. The aims of this study are to compare resilience in IBS and healthy controls (HCs) and to assess its relationships with IBS symptom severity, quality of life (QOL), EALs, and HPA axis response. METHODS: Two hundred fifty-six subjects (154 IBS, 102 HCs) completed questionnaires for resilience (Connor-Davidson Resilience Scale [CD-RISC] and Brief Resilience Scale [BRS]), IBS symptoms, IBS-QOL, and EALs. Ninety-six of these subjects had serial serum adrenocorticotropic hormone (ACTH) and cortisol levels to exogenous corticotrophin-releasing hormone (CRH) and ACTH measured. The relationship between IBS status, resilience, and other variables of interest was assessed by regression analysis after adjusting for demographics and neuroticism, a predictor of resilience. KEY RESULTS: Resilience was significantly lower in IBS compared to HCs (CD-RISC: 72.16±14.97 vs 77.32±12.73, P=.003; BRS: 3.29±0.87 vs 3.93±0.69, P<.001); however, only BRS was significant after controlling for neuroticism (P=.001). Lower BRS scores were associated with greater IBS symptom severity (P=.002), poorer IBS-QOL (P<.001), and a higher number of EALs (P=.01). There was a significant interaction between BRS resilience and IBS status for ACTH-stimulated cortisol response (P=.031); more resilient IBS subjects had lower cortisol response, and more resilient HCs had higher cortisol response. CONCLUSIONS AND INFERENCES: Lower resilience is associated with IBS status, worse IBS symptom severity, lower IBS-QOL, greater EALs, and stress hyperresponsiveness.

Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition.

Loss of glutamine synthetase (GS) in hippocampal astrocytes has been implicated in the causation of human mesial temporal lobe epilepsy (MTLE). However, the mechanism by which the deficiency in GS leads to epilepsy is incompletely understood. Here we ask how hippocampal GS inhibition affects seizure phenotype and neuronal activation during epilepsy development (epileptogenesis). Epileptogenesis was induced by infusing the irreversible GS blocker methionine sulfoximine (MSO) unilaterally into the hippocampal formation of rats. We then used continuous video-intracranial electroencephalogram (EEG) monitoring and c-Fos immunohistochemistry to determine the type of seizures and spatial distribution of neuronal activation early (1-5days postinfusion) and late (16-43days postinfusion) in epileptogenesis. Early in epileptogenesis, seizures were preferentially mild (stage 1-2), activating neurons in the entorhinal-hippocampal area, the basolateral amygdala, the piriform cortex, the midline thalamus, and the anterior olfactory area. Late in epileptogenesis, the seizures were generally more severe (stages 4-5) with neuronal activation extending to the neocortex, the bed nucleus of the stria terminalis, the mediodorsal thalamu\s, and the central nucleus of the amygdala. Our findings demonstrate that inhibition of GS focally in the hippocampal formation triggers a process of epileptogenesis characterized by gradual worsening of seizure severity and involvement of progressively larger neuronal populations over a period of several weeks. Knowledge about the underlying mechanism of epileptogenesis is important because such knowledge may result in more specific and efficacious treatments of MTLE by moving away from large and poorly specific surgical resections to highly targeted surgical or pharmacological interventions of the epileptogenic process.

A programmable DNA origami nanospring that reveals force-induced adjacent binding of myosin VI heads.

Mechanosensitive biological nanomachines such as motor proteins and ion channels regulate diverse cellular behaviour. Combined optical trapping with single-molecule fluorescence imaging provides a powerful methodology to clearly characterize the mechanoresponse, structural dynamics and stability of such nanomachines. However, this system requires complicated experimental geometry, preparation and optics, and is limited by low data-acquisition efficiency. Here we develop a programmable DNA origami nanospring that overcomes these issues. We apply our nanospring to human myosin VI, a mechanosensory motor protein, and demonstrate nanometre-precision single-molecule fluorescence imaging of the individual motor domains (heads) under force. We observe force-induced transitions of myosin VI heads from non-adjacent to adjacent binding, which correspond to adapted roles for low-load and high-load transport, respectively. Our technique extends single-molecule studies under force and clarifies the effect of force on biological processes.

The Glutamate-Glutamine Cycle in Epilepsy.

Epilepsy is a complex, multifactorial disease characterized by spontaneous recurrent seizures and an increased incidence of comorbid conditions such as anxiety, depression, cognitive dysfunction, and sudden unexpected death. About 70 million people worldwide are estimated to suffer from epilepsy, and up to one-third of all people with epilepsy are expected to be refractory to current medications. Development of more effective and specific antiepileptic interventions is therefore requisite. Perturbations in the brain's glutamate-glutamine cycle, such as increased extracellular levels of glutamate, loss of astroglial glutamine synthetase, and changes in glutaminase and glutamate dehydrogenase, are frequently encountered in patients with epilepsy. Hence, manipulations of discrete glutamate-glutamine cycle components may represent novel approaches to treat the disease. The goal of his review is to discuss some of the glutamate-glutamine cycle components that are altered in epilepsy, particularly neurotransmitters and metabolites, enzymes, amino acid transporters, and glutamate receptors. We will also review approaches that potentially could be used in humans to target the glutamate-glutamine cycle. Examples of such approaches are treatment with glutamate receptor blockers, glutamate scavenging, dietary intervention, and hypothermia.

Adverse childhood experiences are associated with irritable bowel syndrome and gastrointestinal symptom severity.

BACKGROUND: Early adverse life events (EALs) are associated with irritable bowel syndrome (IBS). Exposure to EALs as assessed by the Adverse Childhood Experiences (ACE) questionnaire is associated with greater disease prevalence, but ACE has not been studied in gastrointestinal disorders. Study aims were to: (i) Estimate the prevalence of EALs in the IBS patients using the ACE questionnaire; (ii) Determine correlations between ACE and Early Trauma Inventory Self Report-Short Form (ETI-SR) scores to confirm its validity in IBS; and (iii) Correlate ACE scores with IBS symptom severity. METHODS: A total of 148 IBS (73% women, mean age = 31 years) and 154 HCs (59% women, mean age = 30 years) completed the ACE and ETI-SR between June 2010 and April 2015. These surveys measured EALs before age 18 in the domains of physical, sexual, and emotional abuse, and general trauma. IBS and abdominal pain severity was measured by a 20-point scale (0 = none, 20 = worst symptoms). KEY RESULTS: The ACE score increased the odds of having IBS (odds ratio [OR] = 2.05, 95% confidence interval [CI]: 1.21-3.48, p = 0.008). Household mental illness (p < 0.001), emotional abuse (p = 0.004), and incarcerated household member (p = 0.019) were significant predictors of IBS. Adverse childhood experiences and ETI-SR scores were strongly correlated (r = 0.59, p < 0.001). ACE, but not ETI-SR, modestly correlated with IBS severity (r = 0.17, p = 0.036) and abdominal pain (r = 0.20, p = 0.015). CONCLUSIONS & INFERENCES: The ACE questionnaire is a useful instrument to measure EALs in IBS based on its use in large studies, its ability to measure prevalence across different EAL domains, and its correlation with symptom severity.

Feasibility of using the International Classification of Functioning, Disability and Health Core Set for evaluation of fall-related risk factors in acute rehabilitation settings.

BACKGROUND: Previously, we reported the use of an International Classification of Functioning (ICF) core set that can provide a holistic framework for evaluating the risk factors of falls; however, data on the feasibility of applying this core set are lacking. AIM: To investigate the feasibility of applying the fall-related ICF risk-factor core set in the case of patients in an acute-rehabilitation setting. DESIGN: A cross-sectional and descriptive correlational design. SETTING: Acute-rehabilitation ward. POPULATION: A total of 273 patients who experienced fall at acute-rehabilitation ward. METHODS: The data on falls were collected from the hospital's Nursing Information System (NIS) and the fall-reporting system (Adverse Event Reporting System, AERS) between 2010 and 2013. The relationship of both systems to the fall-related ICF core set was analyzed to assess the feasibility of their clinical application. We evaluated the feasibility of using the fall-related ICF risk-factor core set by using the frequency and the percentage of the fall patients in of the listed categories. RESULTS: The fall-related ICF risk-factor core set category b735 (muscle tone functions) exhibited a high feasibility (85.95%) for clinical application, and the category b730 (muscle power functions) covered 77.11% of the patients. The feasibility of application of the category d410 (change basic body position) was also high in the case of all fall patients (81.69%). CONCLUSIONS: In the acute-rehabilitation setting, the feasibility of application of the fall-related ICF risk-factor core set is high. CLINICAL REHABILITATION IMPACT: The fall-related ICF risk-factor core set can help multidisciplinary teams develop fall-prevention strategies in acute rehabilitation wards.

Inhibition of glutamine synthetase in the central nucleus of the amygdala induces anhedonic behavior and recurrent seizures in a rat model of mesial temporal lobe epilepsy.

The prevalence of depression and suicide is increased in patients with mesial temporal lobe epilepsy (MTLE); however, the underlying mechanism remains unknown. Anhedonia, a core symptom of depression that is predictive of suicide, is common in patients with MTLE. Glutamine synthetase, an astrocytic enzyme that metabolizes glutamate and ammonia to glutamine, is reduced in the amygdala in patients with epilepsy and depression and in suicide victims. Here, we sought to develop a novel model of anhedonia in MTLE by testing the hypothesis that deficiency in glutamine synthetase in the central nucleus of the amygdala (CeA) leads to epilepsy and comorbid anhedonia. Nineteen male Sprague-Dawley rats were implanted with an osmotic pump infusing either the glutamine synthetase inhibitor methionine sulfoximine [MSO (n=12)] or phosphate buffered saline [PBS (n=7)] into the right CeA. Seizure activity was monitored by video-intracranial electroencephalogram (EEG) recordings for 21days after the onset of MSO infusion. Sucrose preference, a measure of anhedonia, was assessed after 21days. Methionine sulfoximine-infused rats exhibited recurrent seizures during the monitoring period and showed decreased sucrose preference over days when compared with PBS-infused rats (p<0.01). Water consumption did not differ between the PBS-treated group and the MSO-treated group. Neurons were lost in the CeA, but not the medial amygdala, lateral amygdala, basolateral amygdala, or the hilus of the dentate gyrus, in the MSO-treated rats. The results suggest that decreased glutamine synthetase activity in the CeA is a possible common cause of anhedonia and seizures in TLE. We propose that the MSO CeA model can be used for mechanistic studies that will lead to the development and testing of novel drugs to prevent seizures, depression, and suicide in patients with TLE.

Effects of site-specific infusions of methionine sulfoximine on the temporal progression of seizures in a rat model of mesial temporal lobe epilepsy.

Glutamine synthetase (GS) in astrocytes is critical for metabolism of glutamate and ammonia in the brain, and perturbations in the anatomical distribution and activity of the enzyme are likely to adversely affect synaptic transmission. GS is deficient in discrete regions of the hippocampal formation in patients with mesial temporal lobe epilepsy (MTLE), a disorder characterized by brain glutamate excess and recurrent seizures. To investigate the role of site-specific inhibition of GS in MTLE, we chronically infused the GS inhibitor methionine sulfoximine (MSO) into one of the following areas of adult laboratory rats: (1) the angular bundle, n=6; (2) the deep entorhinal cortex (EC), n=7; (3) the stratum lacunosum-moleculare of CA1, n=7; (4) the molecular layer of the subiculum, n=10; (5) the hilus of the dentate gyrus, n=6; and (6) the lateral ventricle, n=6. Twelve animals were infused with phosphate buffered saline (PBS) into the same areas to serve as controls. All infusions were unilateral, and animals were monitored by continuous video-intracranial EEG recordings for 3 weeks to capture seizure activity. All animals infused with MSO into the entorhinal-hippocampal area exhibited recurrent seizures that were particularly frequent during the first 3 days of infusion and that continued to recur for the entire 3 week recording period. Only a fraction of animals infused with MSO into the lateral ventricle had recurrent seizures, which occurred at a lower frequency compared with the other MSO infused group. Infusion of MSO into the hilus of the dentate gyrus resulted in the highest total number of seizures over the 3-week recording period. Infusion of MSO into all brain regions studied, with the exception of the lateral ventricle, led to a change in the composition of seizure severity over time. Low-grade (stages 1-3) seizures were more prevalent early during infusion, while severe (stages 4-5) seizures were more prevalent later. Thus, the site of GS inhibition within the brain determines the pattern and temporal evolution of recurrent seizures in the MSO model of MTLE.

Primary radiotherapy vs conservative management for localized prostate cancer--a population-based study.

BACKGROUND: Radiotherapy is the most common curative cancer therapy used for elderly patients with localized prostate cancer. However, the effectiveness of this approach has not been established. The purpose of this study is to evaluate the long-term outcomes of primary radiotherapy compared with conservative management in order to facilitate treatment decisions. METHOD: This population-based study consisted of 57,749 patients with T1-T2 prostate cancers diagnosed during 1992-2007. We utilized an instrumental variable (IV) analytical approach with competing risk models to evaluate the outcomes of primary radiotherapy vs conservative management. The IV was comprised of combined health service areas with high- and low-use areas corresponding to the top and bottom tertile in radiotherapy usage rates. RESULTS: In patients with low-/intermediate-risk prostate cancer, 10-year prostate cancer-specific and overall survival was similar in high- and low-radiotherapy use areas (96.1 vs 95.4% and 56.6 vs 56.3%, respectively). In patients with high-risk disease, however, areas with high-radiotherapy use had a higher 10-year cancer-specific survival (90.2 vs 88.1%, difference 2.1%; 95% CI 0.3-4.0%) and 10-year overall survival (53.3 vs 50.2%, difference 3.1%; 95% CI 1.3-6.3%). Results were similar irrespective of the type of radiotherapy used. To assess the robustness of our choice of IV, we repeated the IV analytical approach using different IVs (using the median utilization rate as the cutoff) and found the results to be similar. CONCLUSIONS: Among men >65 years of age, the benefit of primary radiotherapy for localized disease is largely confined to patients with high-risk prostate cancer (Gleason scores 7-10).

Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial.

SUMMARY: Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. INTRODUCTION: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. METHODS: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. RESULTS: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. CONCLUSIONS: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.

Effect of yeast with bacteriocin from rumen bacteria on laying performance, blood biochemistry, faecal microbiota and egg quality of laying hens.

The purpose of this study was to evaluate the effect of yeast with bacteriocin from Ruminococcus albus 7 (albusin B) on physiological state and production performance of laying hens. One hundred and twenty 26-week-old Single Comb White Leghorn (Hyline) laying hens were assigned into five groups including: (i) control group, (ii) yeast control (YC), (iii) 0.125% yeast with bacteriocin (0.125B), (iv) 0.25% yeast with bacteriocin (0.25B) and (v) 0.5% yeast with bacteriocin (0.5B). All supplements were added to the experimental diets of the hens from 26 to 46 weeks of age. Samples were collected every 4 weeks. Blood samples were collected from the wing vein for blood biochemical parameters assay, and faecal samples were collected by swab for the microbiota test. The egg production performance was recorded daily, and fresh eggs were collected for quality test. The blood biochemical assay results indicated that the addition of yeast with bacteriocin decreased the AST (aspartate aminotransferase) activity and it also affects the lactate concentration in laying hen blood. The result of egg quality indicated that yeast with bacteriocin supplementation had no effect on the mass of yolk and the strength of eggshell, but it had positive effect on the laying performance under hot environment. Low concentration bacteriocin (0.125B) supplementation could decrease total yolk cholesterol. The faecal microbiota result indicated that the supplementation of bacteriocin increased the lactobacilli counts. The yeast with bacteriocin supplementation significantly decreased the clostridia counts under hot environment condition, especially in hens receiving 0.25B. Combining the data from clinic chemistry, faecal microbiota, egg production and egg quality, the 0.25B supplementation may result in the best physiological parameter and egg production performance of laying hen.

Characterization of symptoms in irritable bowel syndrome with mixed bowel habit pattern.

BACKGROUND: Irritable bowel syndrome (IBS) with mixed bowel habits (IBS-M) is a heterogeneous subtype with varying symptoms of constipation and diarrhea, and has not been well characterized. We aimed to characterize gastrointestinal (GI) and non-GI symptoms in IBS-M patients from a US patient population, and to compare them with IBS with constipation (IBS-C) and diarrhea (IBS-D). METHODS: Subjects answering community advertisements and meeting Rome III criteria for IBS completed symptom questionnaires. KEY RESULTS: Of the initial 289 IBS patients identified, one third (n = 51, 32.5%) who met Rome III criteria for IBS-M endorsed having either loose stools or hard stools due to medication. These patients had more severe symptoms and longer duration of flares compared to the rest of the IBS-M group (p = 0.014, p = 0.005). Excluding IBS-M patients with medication-related extremes in stool form who could not be reclassified by medical history, 247 IBS patients were assessed. IBS-M was the most common (44.1%), followed by IBS-C (27.9%), IBS-D (26.3%), and IBS-U (unsubtyped, 1.6%). While IBS-M shared symptoms with both IBS-C and IBS-D, there were significant differences in the prevalence of bowel habit symptoms (p-value range: <0.001-0.002). IBS-M patients reported most bothersome symptoms that were more similar to IBS-D, with the most common being irregular bowel habits (27.5%), bloating (26.6%), and abdominal pain (20.2%). There were no differences in non-GI symptoms between subtypes. CONCLUSIONS & INFERENCES: IBS-M is a heterogeneous symptom group and thus requires that subclassification criteria be better defined. Use of laxative/antidiarrheal medications adds to the diagnostic complexity in a potentially more severe subset of IBS-M and should be assessed for accurate subclassification.

Autonomic response to a visceral stressor is dysregulated in irritable bowel syndrome and correlates with duration of disease.

BACKGROUND: Previous studies reported altered autonomic nervous system (ANS) responses in irritable bowel syndrome (IBS) at baseline and to colonic balloon distension. This study examined heart rate variability (HRV) and plasma catecholamines as an index of ANS responsiveness in IBS during flexible sigmoidoscopy (FS) and explored associations of HRV with clinical measures. METHODS: Rome III-positive IBS patients and healthy controls completed questionnaires measuring gastrointestinal and psychological symptoms. Heart rate variability measures were calculated using electrocardiogram (ECG) data at rest and during FS. Plasma catecholamines were measured before and after the FS. Linear mixed effects models were used to compare HRV with IBS status and IBS duration across six time points. Significance was assessed at the 0.05 level. KEY RESULTS: Thirty-six IBS patients (53% F, mean age 37.89) and 31 controls (58% F, mean age 37.26) participated. After adjusting for age, sex, body mass index, and current anxiety symptoms, IBS patients had a non-significant lower cardiovagal tone (P = 0.436) and higher cardiosympathetic balance (P = 0.316) at rest. During FS, controls showed a transient increase in cardiosympathetic balance and decrease in cardiovagal tone. However, IBS patients had significantly less cardiosympathetic and cardiovagal responsiveness both leading up to (P = 0.003, P = 0.005) and following (P = 0.001) this stimulus. Those with longer duration of disease had less cardiosympathetic (P = 0.014) and cardiovagal (P = 0.009) responsiveness than those with shorter duration. No differences in catecholamines between IBS and controls were found. CONCLUSIONS & INFERENCES: Irritable bowel syndrome demonstrated dysregulated ANS responses to a visceral stressor which could be related to disease duration. Therefore, autonomic dysregulation is an objective physiologic correlate of IBS.

Regulation of astrocyte glutamine synthetase in epilepsy.

Astrocytes play a crucial role in regulating and maintaining the extracellular chemical milieu of the central nervous system under physiological conditions. Moreover, proliferation of phenotypically altered astrocytes (a.k.a. reactive astrogliosis) has been associated with many neurologic and psychiatric disorders, including mesial temporal lobe epilepsy (MTLE). Glutamine synthetase (GS), which is found in astrocytes, is the only enzyme known to date that is capable of converting glutamate and ammonia to glutamine in the mammalian brain. This reaction is important, because a continuous supply of glutamine is necessary for the synthesis of glutamate and GABA in neurons. The known stoichiometry of glutamate transport across the astrocyte plasma membrane also suggests that rapid metabolism of intracellular glutamate via GS is a prerequisite for efficient glutamate clearance from the extracellular space. Several studies have indicated that the activity of GS in astrocytes is diminished in several brain disorders, including MTLE. It has been hypothesized that the loss of GS activity in MTLE leads to increased extracellular glutamate concentrations and epileptic seizures. Understanding the mechanisms by which GS is regulated may lead to novel therapeutic approaches to MTLE, which is frequently refractory to antiepileptic drugs. This review discusses several known mechanisms by which GS expression and function are influenced, from transcriptional control to enzyme modification.