A literature review of local published research from Pakistan showed no study documenting the characteristics of patients

who leave ED without being seen by a physician in this region. Emergency Medicine as a specialty is still in its infancy in Pakistan [30-32]. Our department was the first one to be established back in 2008. Over the years, we have observed an increase in patient volume as well as acuity. The ED had expanded to 46 beds but the hospital beds remained the same which brought in the selleckchem issues of overcrowding, left without being seen patients and ED through put issues. Therefore, this study is aimed at defining the LWBS population Inhibitors,research,lifescience,medical in a tertiary care hospital while determining percentages and factors associated with LWBS as we do not know the characteristics of our patients who are leaving. This baseline information will be critical Inhibitors,research,lifescience,medical in developing evidence based interventions aimed at improving the health care management of such patients and consequently reducing the morbidity and mortality resulting from leaving. Methods Setting This study was conducted at the Emergency Department of the Aga Khan University Hospital (AKUH) Karachi, Pakistan.

AKUH is a 600-bedded, private tertiary care hospital in Karachi with an annual ED census of approximately 50,000 patients Inhibitors,research,lifescience,medical and an admission rate of 37%. The emergency department of AKUH is the first one established in the country, and the largest ED in Pakistan providing emergency care of international standards. The emergency department of AKUH is the first established department at Pakistan.

It has 46 patient-care beds with well designated Inhibitors,research,lifescience,medical pediatric, critical care areas and non-critical areas. An eight-bedded observation unit is also functioning where patients are kept for 24 hours. Two Fast track clinics for walk in patients provide service 24/7. AKUH-ED is the only department in Pakistan where standard triage is being followed (Additional file 1). It has a separate well defined triage area. It follows 4 levels of triage and categorizes patients from level I-level Inhibitors,research,lifescience,medical IV. We also have a written triage policy approved by the hospital. Triage staff has been given training for Triaging. A nurse initially triages patients by following the triage categories. The nurse assigns beds to the patients or sends them to the waiting area in case the ED capacity is exhausted (Additional file 2). At the triage desk, a triage team Levetiracetam is present 24/ 7 comprising of a trained nurse, nursing assistant and a triage care coordinator. Triage care coordinator is a senior experienced nurse who supervises the whole functioning of triage. In case of any quarry, the triage nurse could seek help from an on-call physician. The triage information is recorded in an electronic computerized based system called ERMS (Emergency Room Management system) (Additional file 3).

The F0 subunit of the ATPase is a hydrophobic membrane-embedded proton channel encoded by genes atpBEF. The F1 subunit constitutes the catalytic ATPase, encoded by atpHAGDC [19] and [21]. The first gene in the operon, atpI, has no defined function and does not appear to form part of the F0F1 ATPase complex [22]. This genetic organisation is conserved between E. coli and S. Typhimurium. A comprehensive identification of genes required for S. Typhimurium infection of mice by our laboratory identified mutation of atpA as an attenuating lesion [23]. A defined atpA deletion mutant was subsequently confirmed to be attenuated for growth in vivo and furthermore was found to offer significant protection against

subsequent Ponatinib challenge [23]. Here we present a full analysis of the role of the F0F1 ATPase in S. Typhimurium infection and the potential use of mutants in the atp operon as live attenuated vaccines. The bacterial strains and plasmids used in this study are shown in Table 1. Bacteria were grown at 37 °C in Luria–Bertani (LB) broth or on LB agar. Media were supplemented www.selleckchem.com/products/PLX-4032.html with antibiotics

where stated, at the following concentrations, inhibitors kanamycin 50 μg/ml, ampicillin 100 μg/ml and chloramphenicol 25 μg/ml. Minimal medium (used to determine carbon source utilisation) consisted of M9 salts (Sigma Dorset UK) supplemented with 0.1 mM CaCl2, 1 mM MgSO4, 4 μg/ml histidine and the stated carbon source at 0.4% (final w/v). Oligo-directed mutagenesis (ODM), an adaptation of ET-cloning, was used to replace the target genes on the Salmonella chromosome with a kanamycin resistance cassette flanked with FRT regions from pBADkanFRT [24] and [25]. PCR was used to amplify the kanamycin resistance FRT cassette with 5′ and 3′ 60 bp arms homologous to DNA flanking the target genes (see Table 2 for primer sequences). S. Typhimurium LB5010 containing pBADλred was grown in

LB broth supplemented with ampicillin to an OD595 of 0.25. Arabinose was added to 0.2% (final much w/v) to induce red gene expression. Cultures were grown to OD595 0.5 and electroporated with the purified ODM PCR product described above. Mutant colonies were selected on LB agar plates supplemented with 50 μg/ml kanamycin. The desired allelic replacement of the target genes was confirmed by PCR (see Table 2 for primer sequences). Mutations in S. Typhimurium LB5010 were transduced into SL1344 by bacteriophage P22 as described previously [26] with selection on LB agar plus kanamycin and gene deletions were confirmed to be correct by PCR and sequencing. The kanamycin resistance FRT cassette was then excised to leave only a 128 bp FRT scar site. Briefly, electrocompetent mutants of SL1344 were transformed with pCP20 [24] grown at 30 °C and then plated onto LB agar containing 100 μg/ml ampicillin. Single colonies were grown in LB at 39 °C (to prevent replication of pCP20) for 6 h then diluted and plated onto LB agar and incubated overnight at 39 °C.

96,150,151 In PD, there is progressive accumulation of intracellular iron in SNc neurons and microglia.152-154 Why this occurs is uncertain,153,155 but the excess nigral iron is likely to enhance local oxidative stress. Ordinarily, accumulation of tissue iron is accompanied by concomitant increases in local ferritin levels, which serve to moderate the risk of local redox toxicity that would Inhibitors,research,lifescience,medical otherwise be associated with the increased iron. However, in PD, the expected increase in local ferritin does not occur.155,156 Iron is chemically inactive when bound to ferritin as Fe3+, whereas unbound iron in the learn more ferrous state (Fe2+) can combine with H2O2 in the Fenton reaction

to produce the reactive hydroxyl radical (OH·).152 This and other reactive oxygen species (ROS) are also generated in the course of DA metabolism and turnover.148 Activities of TH and monoamine oxidase generate H2O2. In the presence of ferrous iron, the superoxide anion and H2O2 – two weakly reactive free radical species – can Inhibitors,research,lifescience,medical combine in the Haber- Weiss reaction to produce the more reactive OH· radical; this is believed to be the dominant, pathway for biological production of the OH· radical.155 Neuromelanin (NM) may play a

role in nigral, and possibly LC, degeneration, but whether that role is toxic or protective Inhibitors,research,lifescience,medical remains uncertain. In humans and nonhuman Inhibitors,research,lifescience,medical primates, both the DA-producing neurons of SNc and the NA-producing neurons of LC are darkly pigmented due to perikaryal accumulation of NM within double-membrancd organelles known as NM granules.152,157 NM. is produced by spontaneous autooxidation of cytosolic DA and NA in SNc and LC neurons, respectively.152 The selective

vulnerability of SNc Inhibitors,research,lifescience,medical and LC neurons in both PD and MPTP-induced parkinsonism prompted early suggestions that NM might contribute to the neurodegenerative process. Recent studies suggest NM may have the opposite effect, at least, early in the disease. For example, it was noted that the nigral DA neurons most susceptible to early loss in PD – those in the ventral tier of the SNc – typically contain lower amounts of NM than do their less vulnerable counterparts in the dorsal tier.16 Biochemical studies have shown that as NM is synthesized and accumulates intracellularly during the life of an SNc neuron, it appears to be capable of binding and inactivating Vasopressin Receptor redox-active metal ions (in particular Fe2+), intrinsically generated quinones and ROS,152,158 and environmental toxins such as paraquat.157 While SNc iron levels are still relatively low early in the course of PD, NM contains a preponderance of highaffinity iron -binding sites that, could oxidize redox-active Fe2+ and chelate the inactive Fe3+ that results, thereby reducing the potential for oxidative stress.

This pattern was not apparent in our review. On the contrary, there were examples of trials that used dosage parameters consistent with WALT guidelines that demonstrated no effect (Dundar et al 2007: 830nm, 7J per point) as well as trials that used doses Professor Bjordal would describe as ‘very low’ (Ozdemir et al 2001: 830nm, 0.9 J per point) that reported very large treatment effects. Additionally, the WALT guidelines suggest that the number of points treated is

a significant dosage parameter. There was very large variation, both between and within the trials reviewed, of the number of points treated (Range 4–50) and hence the total energy delivered during the treatment. The other explanation offered CX-5461 datasheet by Professor Bjordal for the variability in outcomes was that the therapeutic effect of laser therapy

is characteristically delayed. This phenomenon also was not apparent in our review. Any conclusions about the size of the treatment effect over time were difficult to draw because few trials reported Sorafenib molecular weight both short- and medium-term outcomes, and those that did had mixed results regarding immediate and delayed effects. We found evidence in some studies of an immediate analgesic effect and in others an apparent delayed effect and we are not aware of any biologically plausible explanation for this finding. Although not directly related to the discussion on laser therapy, Professor Bjordal also commented on the need to balance benefit and harm in light of our findings regarding pharmacological treatments, and we agree with these comments. The most startling finding regarding pharmacological treatments for neck pain was the lack of quality trials of medication for neck pain. The finding of short-term benefit for orphenadrine/paracetamol, needs consideration in the context of lack of evidence about long term benefit and potential harms. “
“Libraries Healthtalkonline documents the experiences of health and illness of over 2000 people. It is based on research

from the Health Experiences Research Group at the University of Oxford. The website is run by the DIPEx Charity and was previously known as www.dipex.org. It includes videos PD184352 (CI-1040) and transcripts of interviews with people living with over 40 health conditions as well as interviews with carers of people living with health conditions. There are also links to other resources such as overviews by experts and information designed for health care consumers. Many of the featured conditions or settings are of direct relevance to physiotherapists. Chronic pain, diabetes, breast cancer, lung cancer, stroke, motor neurone disease, Parkinson’s disease, congenital heart disease, rheumatoid arthritis, osteoporosis, pain during pregnancy, and the experience of being a patient in an intensive care unit are all covered by the website. This is an impressive website.

Controversially, an immunohistochemical evaluation of a cohort of 127 patients with

primary breast cancer of various stages and grades has demonstrated, that sLex expression was not correlated with prognosis and survival [143]. Studies conducted on primary ovarian carcinomas and metastatic lesions, demonstrated that Inhibitors,research,lifescience,medical Ley and sLex are widely expressed in both, but their expression did not seem to correlate with long- or short-term survival [101,102]. The characteristic changes in total serum N- PF-06463922 cost glycans from patients with advanced ovarian cancer of different type, were examined by HPLC, weak anion exchange HPLC and MS [144]. These changes included increases in levels of core fucosylated, agalactosyl biantennary glycans, presented on IgG heavy chains, and in levels of sLex, linked to acute-phase

proteins, such as haptoglobin, α1-acid glycoprotein, and α1-antichymotrypsin. The mechanisms defining sLex and sLea malignancy are more explained than in other TAC. SLex Inhibitors,research,lifescience,medical and sLea are known ligands for E-selectin [99,100] and are known to facilitate cancer cell metastasis, mediating their extravasations from blood to peripheral tissues via E-selectin, expressed on vascular endothelium [145,146,147,148,149,150]. Some of these investigations were conducted on the breast cancer model and were supported by clinicopathological data [131,146]. Thus, both sLex Inhibitors,research,lifescience,medical and soluble E-selectin were significantly elevated in the serum of breast Inhibitors,research,lifescience,medical cancer patients with advanced and recurrent disease [151]. Both P- and E-selectin expression was significantly elevated on endothelial cells of breast cancer patients [152]. The recent study confirmed E-selectin- driven mechanism of sLex action in carcinogenesis [153]. Importantly, the authors Inhibitors,research,lifescience,medical demonstrated that glycosylation profiles differ between estrogen receptor (ER)-positive

and ER-negative breast cancers with higher incidence of sLex in ER-negative breast tumors due to significantly elevated expression of corresponding glyco-genes. SLex expression had no influence on the survival of patients regardless of their ER-positive or ER-negative status. However, high expression of sLex in ER-positive tumors correlated with bone metastasis – the expression site of E-selectin, the receptor for sLex. The authors suggest Carnitine palmitoyltransferase II that selectins may promote metastasis in breast cancer through protein-associated sLex and heparansulfate (HS) glycosaminoglycans, as their expression was similarly increased in ER-negative tumors and they may engage with selectins (L/P-selectin) via various microdomains [154]. Notably, selectin affinity depends strongly on sLex microenvironment: for example, E-selectin weakly binds to sLex-containing glycolipids [155], but has a strong affinity for O-glycan associated sLex, expressed by neutrophils [156].

Early experimental evidence for stress-induced changes in serotonergic neurotransmission has been extensively corroborated in subsequent pharmacological studies.19 Monitoring of serotonin synthesis, release, and receptor expression have provided valuable insight into the role of this transmitter in certain aspects of the behavioral and neuroendocrine response to stress and the pathogenesis of stress-related

disorders. Evidence for global activation of dopaminergic neuro-transmission under stressful conditions and links Inhibitors,research,lifescience,medical to stress-related pathology suggests possible use of changes in this system for stress monitoring. These include morphological and functional heterogeneity of dopaminergic pathways, intricate involvement of dopaminergic transmission in selective information transfer, and motivation, integration, and adjustment of central nervous system (CNS) responses

to novelty and aversion20; how-ever, the appropriateness of dopamine-related end points in stress research requires careful evaluation. Inhibitors,research,lifescience,medical It should be noted that individual dopaminergic projections display differential degree of activation following stress, with the mesoprefrontal pathway being Inhibitors,research,lifescience,medical particularly vulnerable,21 and the character of changes in dopaminergic transmission might heavily depend on the context of stress and cross-modulation by multiple convergent neurotransmitter input and endocrine variables. Stressinduced changes in reward-mediating neurotransmitters and their interaction with other neurohumoral constituents Inhibitors,research,lifescience,medical of the stress response entail the possibility of using liability to addiction as a measure for the assessment of behavioral impact of stress. Activation of cerebral cholinergic transmission by stress has been documented, Inhibitors,research,lifescience,medical and its established roles in arousal, motivation, and cognition

are suggestive of an involvement in the processing of stressful stimuli. Probably due to differential regional and temporal release patterns, as well as discordant observations on their coincidence with other physiological end points,22 changes in GPCR Compound Library chemical structure acetylcholine release are less frequently used as end points for stress evaluation. Dramatic stress-induced increase in extracellular levels of glutamate, the major excitatory amino acid transmitter, have most been reported in numerous brain regions. Glutamate efflux in the prefrontal cortex has been implicated in the modulation of the dopamine response to stress, and an array of potential pathological consequences was outlined.23 Interactions between adrenocortical secretions and glutamate signaling in the hippocampus have prompted strong interest in the role of this neurotransmitter in long-term consequences of stress and their projections to various aspects of neuro and psychopathology, as well as therapeutic strategies.

Patients require to be monitored as recommended for any cardiac electrophysiological Panobinostat cost effects and for other side effects. Provided the physician adheres to the prescribing

information, neuroleptics may be used safely and effectively in routine clinical practice. Selected abbreviations and acronyms CPMP Committee for Proprietary Medicinal Products EMEA European Medicines Evaluation Agency EM extensive metabolizer EPS extrapyramidal symptoms EDA Food and Drug Administration HERG human ether-a-go-go ICH International Conference on Harmonization IKr delayed rectifier potassium channel NCE new chemical entity PM poor metabolizer SPC summary of product characteristics Inhibitors,research,lifescience,medical TD tardive dyskinesia TdP torsade de pointes Notes I wish to express my gratitude to my colleagues. Prof Barry Lebowitz, Prof John Lewis, and Dr Sarah Branch, for their helpful and very constructive comments. The views expressed Inhibitors,research,lifescience,medical in this paper are those of the author and do not necessarily represent the views or the opinions of the Medicines Control Agency, other regulatory authorities, or any of their advisory committees.
Suicide is a major public health issue in the West, where it is among the top 1 0 causes of death. Throughout world, suicide accounts for about 1 million deaths per year, Inhibitors,research,lifescience,medical ie, 1 death every 40 seconds, according to the World Health Organization,1 and constitutes

a heavy familial, social, and economic burden. Some data concerning suicide are of major interest. First, despite effort in prevention, suicide rates do not appear be decreasing (Figure 1)1 and, in many industrialized countries, the number of people dying through suicide is significantly higher than the number of people dying in automobile accidents. Second, suicide Inhibitors,research,lifescience,medical rates

in adolescents and young adults increased in the last two or three decades, and in many countries suicide mortality rates are the third, or even the second, cause of death among young people. Figure 1 Progression of global suicide rates between 1950 and 1995.1 In view of these data, much effort, has been Inhibitors,research,lifescience,medical made to study the biology of suicide, and a central serotonergic dysfunction is possibly the most studied biological parameter. Initial in vivo evidence comes from a study showing a lower concentration of acid 5-hydroxyindoleacetic acid (5-HI A A) in the cerebrospinal fluid (CSF) of depressed suicidal patients compared with depressed nonsuicidal patients.2 Many because have further confirmed this result, not only in depression but also in schizophrenia and personality disorder,3 showing that lower 5-HI AA CSF concentration is associated with suicidal behavior regardless of psychiatric diagnosis. Neuroendocrine studies A limitation of CSF studies is that they do not address the question of whether overall serotonergic transmission in the brain is decreased, since it is primarily a metabolic measure; furthermore, these studies are rather invasive.

Such components may entail considerable predictive value. Methodological problems in assessment

of residual symptoms, however, emerge. There is paucity of psychometric studies addressing the phenomenology of depressed http://www.selleckchem.com/products/gsk1120212-jtp-74057.html patients after benefiting from treatment. Recovered depressed patients displayed significantly more depression and anxiety than control subjects in one study,81 but not in another.82 Differences in the sensitivity Inhibitors,research,lifescience,medical of the rating scales which were employed may account, for such discrepant results. Using Paykel’s83 Clinical Interview for Depression, only 6 (12.2%) of 49 patients with major depression successfully treated with antidepressant drugs and judged to be fully remitted had no residual symptoms.84 The majority of residual symptoms were present also in the prodromal phase of illness. The most frequently reported symptoms involved anxiety and irritability. This findings were consistent, with previous studies on prodromal symptoms Inhibitors,research,lifescience,medical of depression,85,86 overlapped with results concerned with interpersonal friction,47 irritability,77 and anxiety65 and underwent independent, replication. Using a similar methodology, Paykel et al,34 in fact, found residual symptoms to be

present in 32% of 60 patients who remitted from major depression. Previous diagnosis of dysthymia did not predict, residual symptoms. Depressed mood, guilt, hopelessness, Inhibitors,research,lifescience,medical impaired work and interest, anxiety, and anorexia were identified by the Clinical Interview for Depression.36

These symptoms tended to persist, at, 8- to 10-year Inhibitors,research,lifescience,medical follow-up.87 Nierenberg et al37 found that only 18% of full responders to fluoxetine were free of residual symptoms. Gastò et al39 reported the same percentage in elderly patients with Inhibitors,research,lifescience,medical major depressive disorders. Judd et al88 found that incomplete recovery from the first, lifetime major depressive episode was linked to a chronic course of illness during a 12-year prospective naturalistic follow-up. Angst, et al89 observed that clinical trials overestimate the likelihood of full recovery on a single antidepressant. The usual response rates of 60% to 70% are typically reported when a reduction of 50% or more in the Hamilton Depression Rating Scale occurs. However, using a more conservative score for defining response, only 45% of approximately 900 depressed patients achieved a satisfactory response. Cornwall Bumetanide and Scott90 reviewed publications relating to a precise definition of partial remission.1 Partial remission was found to affect at least one third of subjects treated for depression, to increase the risk of further depressive relapse, and to adversely affect social and work performance. In a large, multicentcr trial involving 2876 outpatients receiving flexible doses of citalopram, only 28% of subjects were found to have remitted.

1 Many biochemical pathways associated with

hyperglycemia increases generation of free radicals leading to overt oxidative stress.2 Diabetic patients have reduced anti-oxidant defenses and suffer from increased risk of free-radical mediated biomolecular damage.3 It is hypothesized therefore that supplementation of antioxidant may help reduce burden of oxidative stress and generation of oxidative stress mediated Rucaparib molecular weight AGEs in hyperglycemia.4 Potential health benefits of antioxidant compounds present in traditional medicinal plants arise due to their free radicals scavenging properties and inhibition of free radicals induced biomolecular including inhibition of AGEs generation and accumulation.5 The fruits and Modulators leaves of Duranta repens L. (Family. Verbenaceae) are used for treatment of malaria and abscess in Chinese traditional medicines. 6 However, enough literature is not available regarding the chemical constituents and other biological

activities in this plant. We report in this communication isolation of phytochemicals like irridoid glycoside, lignan and phenyl propanoids and evaluate their potentials for free radicals scavenging and AGEs inhibitory activities. The plant material stem and bark of Duranta repens L. (Family. Verbenaceae) were collected during the June–July 2010 from Tirumala forest, Pictilisib mw Tirupati (Andhra Pradesh, India), and identification was made by Prof. Dr. K. Madhava Chetty, Department of Linifanib (ABT-869) Botany, Sri Venkateswara University. A voucher specimen was deposited at the herbarium of Indian Institute of Chemical Technology, Hyderabad, India. The solvents used were all of AR grade were distilled under positive pressure of dry nitrogen atmosphere where necessary. Melting points were recorded on a Fisher Johns apparatus and are uncorrected. 1H and 13C spectra were measured on a Bruker 300 Hz spectrometer using tetramethylsilane as an internal standard. Mass spectra

were recorded on Agilent LC/MSD trap SL 1100 series with a 70 ev (ESI probe) and the infrared spectra on a thermo Nicolet Nexus 670 FTIR spectrometer. Visualization was performed with 5% H2SO4 solution followed by heating. Column chromatography was performed on silica gel (100–200 mesh). Thin layer chromatography (TLC) involved the use of precoated silica gel 60 F254 TLC plates of Merck. The optical rotations were measured on JASCODIP 300 digital polarimeter at 25 °C. The shade dried stem and bark of D. repens were powdered in a pulvarizer (8 kg) and extracted with methanol for 48 h followed by the concentration under reduced pressure. The resulting extract (250 g) was subjected to column chromatography over silica gel (60–120 mesh) and eluted with chloroform/methanol in the increasing order of polarity to give four fractions. Fraction I and III (1.2 g) containing the crude iridoid mixture, which were further purified by preparative HPLC on a C18 waters HR column (300 × 3.9 mm, flow rate 1.

In a study from our group (Dolbcrg et al, unpublished data), changes in MT

were explored in a group of 46 patients with MDD treated with rTMS and in normal controls. No differences were identified in MT between patients and controls. In addition, MT did not change with treatment, and showed no association with severity, age, or the presence of psychosis. It is possible that, the differences observed in our study and those reported by Triggs et al were related to differences in the methods of determining MT. Triggs et al defined MT as 100-μV MET deflections in the EMG, whereas we used the more widely Inhibitors,research,lifescience,medical accepted cutoff of 50 μV. Postexercise facilitation It is well established that muscular activation increases the size of the MEPs during TMS. Samii et al59 and Shajahan et al60,61 explored this paradigm in

patients with acute depression, in recovered depressed patients, and in normal controls. They found that patients in the acute stage of the illness had significantly less postexercise facilitation Inhibitors,research,lifescience,medical than normal controls or recovered patients. They speculated that this lack of facilitation in depressed patients is due to decreased cortical excitability (which may be secondary to increased inhibitory outflow from interneurons), and that the normalization seen with recovery reflects the normalization of underlying neurobiological processes. Silent period A variable period of EMG absence follows Inhibitors,research,lifescience,medical an MEP This period is referred to as the silent, period

and it is XL184 concentration believed to be, at least in part, secondary to increased inhibitory forces in the motor cortex.13 Steele et Inhibitors,research,lifescience,medical al62 looked at the post-TMS silent, period in patients with depression and compared it with that of normal controls. They found that depressed patients had longer post-TMS silent, periods than normal controls. They concluded that their findings were indirect evidence for the presence of state-dependent increased inhibitory mechanisms in the motor cortex, and possibly Inhibitors,research,lifescience,medical other areas of the brain, in depression. It has not been reported whether recovery from depression was associated with a normalization of the silent, period. Paired-pulse stimulation Paired-pulse stimulation of the motor cortex is considered today to be the gold standard of motor cortex excitability.13,56,63 The paired TMS stimulations unless are given with short, intervals between them (interstimulus intervals [ISIs]). The effects depend on the intensity of the conditioning and test, stimulus, and on the ISI. Short ISIs are believed to reveal inhibitory cortical mechanisms, whereas long ISI are thought to reveal excitatory cortical mechanisms. Paired-pulse stimulation has been studied extensively in neurology, but much less in depression. Maeda et al63 studied eight subjects with major depression with the paired-pulse paradigm and compared their responses with that of normal controls.