The Wilcoxon signed-rank test was used to compare related samples

The Wilcoxon signed-rank test was used to compare related samples. Ingenuity pathway analysis

was used to evaluate potential BEZ235 functional significance of differentially expressed miRNAs. Statistical analysis showed that 3 of 19 miRNAs differed in relation to pathologic response i.e. good versus poor. These differences failed to reach statistical significance, although a trend was observed (p = 0.06). Among these miRNAs, we identified-miR-200b-3p, miR-190a and miR-512-5p. In summary, our results indicate that higher miR-200b-3p, higher miR-190a and lower miR-512-5p expression levels in core biopsies sampled from TNBC patients may be associated with better pathologic response to chemotherapy and the increased feasibility of breast conserving surgery in these patients. Although these results were from a small cohort, they provide an important basis for larger, prospective, multicenter studies to investigate the potential role of miRNAs in neoadjuvant setting.”

information is available on the lives and experiences of black physicians who practiced in the South during the Jim Crow era of legalized segregation. In Mississippi and elsewhere, it is a story of disenfranchised professionals who risked life, limb, and personal success to improve the lot of those they served. In this second article on this topic, we present Nepicastat cell line the stories of some of the physicians who were leaders in the civil rights movement in Mississippi as examples. Because the health disparities they sought to address have, not of their own making, been passed on to the next generation of physicians, the lessons learned from their experience are worthy of consideration. (C) 2014 Elsevier Inc. All rights reserved.”
“The SNS-032 clinical trial bacterial cell wall is a mesh polymer of peptidoglycan linear glycan strands cross-linked by flexible peptides that determines cell shape and provides physical protection. While the glycan strands in thin Gram-negative’ peptidoglycan are known to run circumferentially around

the cell, the architecture of the thicker Gram-positive’ form remains unclear. Using electron cryotomography, here we show that Bacillus subtilis peptidoglycan is a uniformly dense layer with a textured surface. We further show it rips circumferentially, curls and thickens at free edges, and extends longitudinally when denatured. Molecular dynamics simulations show that only atomic models based on the circumferential topology recapitulate the observed curling and thickening, in support of an inside-to-outside’ assembly process. We conclude that instead of being perpendicular to the cell surface or wrapped in coiled cables (two alternative models), the glycan strands in Gram-positive cell walls run circumferentially around the cell just as they do in Gram-negative cells.

Carcass feeding has not previously been seen in N melanostomus a

Carcass feeding has not previously been seen in N. melanostomus and has

potential consequences for transfer of nutrients and contaminants.”
“The size of adult parasitoids is influenced by the quantity and quality of resources available during immature development. Gregarious development of endoparasitoids results in scramble competition where the resources are shared among individuals developing into the same host. Individuals that developed gregariously are therefore smaller and that reduced size generally translates into lower Epigenetic inhibitor fitness due to reductions in several life history traits including longevity, mobility and traits linked to reproduction. We measured the reproductive constraints induced by size in Anaphes listronoti (Hymenoptera: Mymaridae), a facultative gregarious egg parasitoid of Curculionidae. Size decreased with number of immatures developing in a host egg for both male and female A. listronoti. This reduction in size induced a reproductive cost as both males and females produced fewer gametes when developing gregariously. Contrarily to other egg parasitoids, A. listronoti males are not prospermatogenic and produced

some sperm during their adult life. Their spermatogeny index is estimated at 0.6-0.7 that places this species as moderately synspermatogenic. Female A. listronoti have an ovigeny index of 0.70 and are therefore moderately synovigenic. Large females that developed singly received a full sperm complement only when mated by a large male that also developed singly. When mating with a small triplet male, a click here large female received less than half her sperm complement. Large males were able to mate three females before the number of sperm transferred started to decrease. Crown Copyright (C) 2012 Published by Elsevier Ltd. All rights reserved.”
“Background/aim The aim of this study is to report a reduction in the thickness of the ganglion cell complex (GCC)

after vitrectomy with internal limiting membrane (ILM) peeling in eyes with idiopathic macular hole (MH). Methods Twenty-eight consecutive eyes with an idiopathic MH treated by vitrectomy with ILM peeling were studied. All eyes NOV120101 had an intravitreal injection of indocyanine green to make the ILM more visible. The best-corrected visual acuity (BCVA), GCC thickness measured by spectral domain optical coherence tomography, and retinal sensitivity measured by microperimetry were determined before and at 3 and 6 months after the vitrectomy. Results The MH in all eyes was closed after the initial surgery. The BCVA was significantly improved at 3 and 6 months (P<0.001 and P<0.001, respectively). The thickness of the GCC was significantly reduced at 3 and 6 months postoperatively (P<0.001 and P<0.001, respectively). The GCC thickness was significantly correlated with the retinal sensitivity in the central 10 degrees at 6 months (r=0.55, P=0.

This review will focus on the mechanism of alpha(1)-antitrypsin

This review will focus on the mechanism of alpha(1)-antitrypsin

Selleckchem BMS-777607 misfolding and the development of potential therapeutic strategies. (C) 2008 IUBMB”
“Adverse effects following immunization to vaccines (AEFI) are considered extremely rare events, the occurrence of which could gain a major role in optimizing allergy diagnosis by cellular tests. The urgent need to eradicate infectious diseases from population, is the main goal of vaccination campaign, therefore its successful outcome should be almost undisputable. Basophil Activation Test (BAT) is commonly used to ascertain a type I hypersensitivity reaction, often replacing reasability tests. Therefore, flow cytometry assay of basophil, as performed in BATs, is employed to test if a particular antigen elicits some activatory response from cells. The allergic subject may undergo an AEFI to vaccine not necessarily by an atopic reaction with an allergen within vaccines but because of the existence of an asymptomatic or not diagnosed inflammatory

chronic allergy or AICAR other immune-disregulating allergy disorder in the subject. BAT, also in its basilar fashion, might be used from a simple heparinized whole blood specimen, but its application in diagnosing allergy before mandatory of facultative vaccination, must be associated to improve other diagnostic tools, at least in its pivotal application. If the application of BAT can be suggested to improve allergy diagnosis by introducing a cellular test in routinely used tools, such as sIgE and SPT, its use, due to possible expertise-consuming and relatively expensive issues, can be included in a specialized allergy consultancy panel as an exploratory approach of allergy inflammation, for which a subject undergoing CYT387 molecular weight immunization by vaccines is suggested to undergo and advised to sign an informed consent for BAT performing. This may extend BAT use in many other forms of chronic allergy and immunity disorders related to AEFI with vaccines.”
“Malignant peripheral nerve sheath tumour (MPNST) is a very

rare tumour with an incidence of one per 100,000 and constitutes between 3 to 10% of all soft tissue sarcomas. Most of the sarcoma involve the extremities and retroperitoneal regions. However, this case presented with mass in left inguinal region and then spread rapidly to omentum, assuming the appearance of an omental cake. Mass responded well to chemotherapy comprising of Ifosfamide and Doxorubicin.”
“Osteoporosis is one of the commonest silent diseases leading to high morbidity and mortality. The challenge for Primary Health Care (PHC) physicians is to prevent, diagnose, and treat osteoporosis before fractures occur. The lack of knowledge about this disease is considered as an important barrier to appropriate risks identification and management of this common health problem.

Advantages of phosphor imaging in radiotracer distribution St

\n\nAdvantages of phosphor imaging in radiotracer distribution Studies in rat brain as compared to dissection experiments may be more precise measurements, possibility to reanalyze imaging data and 3D-reconstruction. In conclusion, phosphor imaging is an attractive alternative for biodistribution

studies of short-living radiotracers in small animals. (c) 2007 Elsevier B.V. All rights reserved.”
“The Selleck JNK-IN-8 first genome-wide association study for BMI identified a polymorphism, rs7566605, 10 kb upstream of the insulin-induced gene 2 (INSIG2) transcription start site, as the most significantly associated variant in children and adults. Subsequent studies, however, showed inconsistent association

of this polymorphism with obesity traits. This polymorphism has been hypothesized to alter INSIG2 expression leading to inhibition of fatty acid and cholesterol synthesis. Hence, we investigated the association of the INSIG2 rs7566605 polymorphism with obesity-and lipid-related traits in Danish and Estonian children (930 boys and 1,073 girls) from the European Youth Heart Study (EYHS), a school-based, cross-sectional study of pre- and early pubertal children. The association between the polymorphism and obesity traits was tested using additive and recessive models adjusted for age, age-group, gender, maturity and country. Interactions were tested by including the interaction terms in the model. Despite having sufficient power (98%) to detect the previously reported effect size P005091 in vivo for Compound Library clinical trial association with BMI, we did not find significant effects of rs7566605 on BMI (additive, P = 0.68; recessive, P = 0.24). Accordingly, the polymorphism was not associated with overweight (P = 0.87) or obesity (P = 0.34). We also did not find association with waist circumference (WC), sum of four skinfolds, or with total cholesterol, triglycerides, low-density lipoprotein, or high-density lipoprotein. There were no gender-specific ( P = 0.55), age-group-specific (P = 0.63) or country-specific (P = 0.56) effects. There

was also no evidence of interaction between genotype and physical activity (P = 0.95). Despite an adequately powered study, our findings suggest that rs7566605 is not associated with obesity-related traits and lipids in the EYHS.”
“The Hedgehog (HH) signaling pathway leads to activation of GLI, which transcriptionally regulate target genes. Regulated HH signaling activity is critical during embryogenesis while aberrantly activated HH signaling is evident in a variety of human cancers. Canonical HH signaling engages the transmembrane receptor Patched (PTCH) and the signaling intermediate Smoothened (SMO) to activate GLI1 and GLI2. In addition GLI1 and GLI2 are activated by non-canonical oncogenic signaling pathways to further drive HH-dependent survival.

Photosynthetic pigments and proteins, photosynthesis (through mod

Photosynthetic pigments and proteins, photosynthesis (through modulated

chlorophyll fluorescence), the antioxidant enzymes superoxide dismutase (SOD) and glutathione reductase (GR), and the stress-related protein HSP70 were analysed.\n\nKey Results Photosynthetic performance was severely impaired by CuHP in phycobionts, as indicated by decreases in the maximal PSII photochemical efficiency (F-v/F-m), the quantum efficiency of PSII (Phi(PSII)) and the non-photochemical dissipation of energy (NPQ). However, the CuHP-dependent decay in photosynthesis was significantly more severe in TR1, which also showed a lower NPQ and a reduced ability to preserve chlorophyll a, carotenoids and D1 protein. P5091 Ubiquitin inhibitor Additionally, differences were observed in the capacities of the two phycobionts to modulate antioxidant activities and HPS70 levels when exposed to oxidative stress. In TR1, CuHP significantly diminished HSP70 and GR but did not change SOD activities. In contrast, CH5424802 in TR9 the levels of both antioxidant enzymes and those of HSP70 increased in response to CuHP.\n\nConclusions The better physiological performance of TR9 under oxidative conditions may reflect its greater capacity to undertake key metabolic adjustments, including increased non-photochemical quenching, higher antioxidant protection and the induction of repair mechanisms.”
“Objective: Our purpose was, through the comparison of the

characteristics of time-intensity curve on triple-phase dynamic contrast-enhanced MRI among groups of giant cell tumor of bone (GCTB), recurrent benign giant cell tumor of bone (RBGCTB), and secondary malignant giant cell tumor of bone (SMGCTB), to find clues to predict the malignant transformation of GCTB. Subjects and methods: 21 patients diagnosed as GCTB were included in this study. All cases took recurrence after intralesional curettage.

9 cases were confirmed as SMGCTB and 12 cases were confirmed as RBGCTB. Cases were divided into four groups: group A, GCTB (n = 9); group B, SMGCTB (n = 9); group C, GCTB GSK2126458 datasheet (n = 12); group D, RBGCTB (n = 12). Enhancement index(EI) of lesions on DCEMRI was calculated using formula: EI(t) = [S(t) -S(0)]/S(0), where S(0) was signal intensity of lesion on non-contrast-enhanced T1-weighted images and S(t) was signal intensity of lesion on DCEMRI (t = 30, 60, 180 s). Enhancement index of each group in each phase was compared using One-Way ANOVA analysis. Slope values of time-intensity curve were compared by the same way. Results: Time-intensity curve of SMGCTB was characterized by a steep upward slope followed by an early and rapid washout phase. Time-intensity curve of GCTB and RBGCTB was characterized by a steep slope followed by a relatively slow washout phase. No significant difference in enhancement index was found in the first phase (p bigger than 0.05). There was significant difference in the second and the third phase (p smaller than 0.05).

In this paper we discuss in detail the problems of determining th

In this paper we discuss in detail the problems of determining the signs or the orderings of normal means. The resulting confidence procedures from the LR tests are seen to be too complicated and difficult to understand. We therefore propose simplified, less powerful methods. We define an overlapping partition of Omega into simple sets, such that the original omega(a)’s can be expressed as an intersection of such simple sets. For each such set we define rejection regions corresponding to the levels alpha, alpha/2,…,alpha/k.

Then we obtain the acceptance regions for H-a:theta is an element of omega(a) given learn more as the intersection of all acceptance regions for the simple sets containing omega(a) at the level alpha/k, if there are k such simple sets. This method can be extended to obtain sequential confidence procedures.”
“Navigating obstacles is innate to fish in rivers, but fragmentation of the world’s rivers by more than 50,000 large dams threatens many of the fish migrations these waterways support. One limitation

to mitigating the impacts of dams on fish is that we have a poor understanding of why some fish enter routes engineered for their safe travel around the dam but others pass through more dangerous routes. To understand fish movement through hydropower dam environments, we combine a computational fluid dynamics model PF-03084014 datasheet of the flow field at a dam and a behavioral model in which simulated fish adjust swim orientation and speed to modulate their experience to water acceleration and pressure (depth). We fit the model to data on the passage of juvenile Pacific salmonids (Oncorhynchus spp.) at seven dams in the Columbia/Snake River system. Our findings from reproducing observed fish movement and passage patterns across 47 flow field conditions sampled Selleck GSK1120212 over 14 y emphasize the role of experience and perception in the decision making of animals that can inform opportunities and limitations in living resources management and engineering design.”
“PURPOSE. To evaluate the serum fatty acid changes in

Chinese patients with Bietti crystalline dystrophy (BCD) in association with CYP4V2 mutation.\n\nMETHODS. Sixteen Chinese patients with BCD confirmed with CYP4V2 mutation were recruited. Peripheral venous blood was obtained after fasting and serum fatty acid concentrations were measured and compared with those in 13 control subjects. Delta-9-desaturase and Delta-5-desaturase activities were estimated based on serum fatty acid compositions. Serum insulin and glucagon concentrations and their correlations with fatty acid and desaturase activities were also evaluated. Fatty acid concentrations were compared among patients with BCD with different genotypes or phenotypes.\n\nRESULTS. Patients with BCD were found to have a significantly higher concentration of octadecanoic acid (18: 0) than that in control subjects (18.28% versus 13.52%, P = 0.

05) This study indicated that addition of Fe-Gly could obviously

05). This study indicated that addition of Fe-Gly could obviously modify antioxidant status of broiler chickens, and moreover, improve growth performance and immune function partially. (C) 2015 Elsevier B.V. All rights reserved.”
“The progressive restriction of cell fate during lineage differentiation is a poorly understood phenomenon despite its ubiquity mTOR inhibitor in multicellular organisms. We recently used a cell fusion assay to define a mode of epigenetic silencing that we termed “occlusion”, wherein affected genes are silenced by cis-acting chromatin mechanisms irrespective of whether trans-acting transcriptional activators are present. We hypothesized that occlusion of lineage-inappropriate

genes could contribute to cell fate restriction. Here, we test this hypothesis by introducing bacterial artificial chromosomes (BACs), which are devoid of chromatin modifications necessary for occlusion, HM781-36B research buy into mouse fibroblasts. We found that BAC transgenes corresponding to occluded endogenous genes are expressed

in most cases, whereas BAC transgenes corresponding to silent but non-occluded endogenous genes are not expressed. This indicates that the cellular milieu in trans supports the expression of most occluded genes in fibroblasts, and that the silent state of these genes is solely the consequence of occlusion in cis. For the BAC corresponding to the occluded myogenic master regulator Myf5, expression of the Myf5 transgene on the BAC triggered fibroblasts to acquire a muscle-like phenotype. These results provide compelling evidence for a critical role of gene occlusion in cell fate restriction.”
“Antipsychotic drugs are the mainstay pharmacotherapy for schizophrenia and related psychiatric disorders. While the metabolic pathways of antipsychotic drugs have been well defined, the role of drug transporters in the disposition and effects of antipsychotic drugs has not been systematically explored. P-glycoprotein has ubiquitous expression in brain endothelial cells

and plays a protective role by effluxing this website substrates for elimination and by limiting their accumulation in the central nervous system. Risperidone and several other antipsychotic drugs are substrates of P-glycoprotein. Increased antipsychotic drug entry into the brain via blockade of the P-glycoprotein transporter may facilitate the amount of available drug to its targets, particularly dopamine receptors. By increasing available antipsychotic drug concentrations, P-glycoprotein inhibition offers a novel means of enhanced drug delivery. This study evaluated whether selective P-glycoprotein transporter inhibition would increase the effects of risperidone on relevant indices of behaviour (catalepsy and locomotion) and neurochemistry (dopamine release and metabolism as measured by in-vivo microdialysis). We administered the P-glycoprotein inhibitor, PSC 833 (100 mg/kg p.o.), to rats prior to administration of risperidone at varying doses (0.01-4.0 mg/kg s.c.).

Cutaneous myiasis can be divided into three main clinical manifes

Cutaneous myiasis can be divided into three main clinical manifestations: furuncular, creeping (migratory),

and wound (traumatic) myiasis. The flies that produce a furuncular myiasis include Dermatobia hominis, Cordylobia anthropophaga, Wohlfahrtia vigil, and the Cuterebra species. Gasterophilus and Hypoderma are two flies that produce a creeping myiasis. Flies that cause wound myiasis include screwworm flies such as Cochliomyia hominivorax and Chrysomya bezziana, and Wohlfahrtia magnifica. This article reviews current literature, provides general descriptions, and discusses life cycles of each species. It also gives treatment techniques and descriptions of each type of illness that results from interaction/infestation.”
“Cholangiocarcinoma is an epithelial cancer of the bile ducts with poor prognosis and, in recent years, a rapidly selleckchem increasing incidence. In this study, nano-sized thermo-sensitive micelles were investigated as drug carriers to improve chemotherapy in cholangiocarcinoma. Thermo-sensitive amphiphilic block copolymer, P-(N,N-isopropylacrylamide-co-N-hydroxymethylacrylamide)-b-caprolactone [P-(NIPAAmco-NHMAAm)-b-PCL]

with lower critical solution temperature (LCST) at about 38 C was synthesized. Doxorubicin (DOX)-loaded micelles were prepared by dialysis method. The micelles exhibited a sustained and temperature-dependent DOX release. Toxicity of the blank micelles for human cholangiocarcinoma (QBC939) cells was minimal both in vitro and in vivo. In contrast, the DOX-loaded micelles effectively inhibited proliferation and induced

apoptosis of QBC939 cells in vitro (p smaller than 0.05) and inhibited tumor growth in nude mice by 21.49%. These results indicated that thermo-sensitive learn more amphiphilic micelles are a promising and effective drug carrier, and show potential for improving chemotherapy for cholangiocarcinoma. (C) 2014 Elsevier B.V. All rights reserved.”
“The objective of this study is to observe the effect of percutaneous laser disc decompression (PLDD) on lumbar spinal stenosis (LSS). Thirty-two LSS patients were treated using pulsed Nd: YAG laser, of which 21 cases (11 males and 10 females with an average age of 64 years old) were followed up for 2 years. All of the 21 patients had intermittent claudication with negative straight leg raising test results. Fifteen patients suffered from anterior central disc herniation which often compressed the cauda equina but seldom compressed the posterior part; six patients suffered from posterior ligamentum flavum hypertrophy which often compressed the cauda equina but seldom compressed the anterior part. The efficacy was evaluated 1, 3, 6, 12 and 24 months after surgery on 21 patients using the performance evaluation criteria of the lumbago treatment by the Japanese Orthopaedic Association (JOA 29 scores). The fineness (i.e.

The new grading system of screw misplacement was feasible and in

The new grading system of screw misplacement was feasible and in line with the general agreement about the harmlessness of misplacement with minor pedicle breach. The reliability of low-dose spine CT in evaluation of lateral and medial cortical perforations was substantial. To reduce the radiation load, the postoperative assessment of titanium implants should be performed with low-dose CT.”
“Most hibernating animals are thought to be monoestrous because reproductive

activity is subject to strong time Autophagy phosphorylation constraints. In previous studies, female European ground squirrels (Spermophilus citellus) turned out to have elevated oestradiol levels during late lactation and after weaning, indicating ovarian activity during summer. Therefore, we monitored vaginal cytology, endocrine changes, and vulval development in semifree-living female European ground squirrels throughout one active season. Vaginal oestrus, defined by the predominance of cornified cells in smear samples, was found during the mating period shortly after vernal emergence. This phase was followed by metoestrus, characterised by the appearance of leukocytes, and a subsequent anoestrous phase. During weaning or postlactation, a second vaginal oestrus was documented in all experimental females, again followed by a metoestrous and an anoestrous phase

lasting until hibernation. In line with the second vaginal oestrus, plasma oestradiol concentrations peaked during postlactation. Progesterone levels were elevated from gestation to postlactation, and titres were marginally higher during vaginal oestrus in summer than in spring. Vulval swelling was more pronounced during the first than the second vaginal oestrus. The second oestrous cycle was non-reproductive, as males were sexually inactive with regressed testes during summer. AZD1208 clinical trial We assume that the second oestrous cycle and the accompanying

endocrine changes have beneficial effects on prehibernatory fattening and reproductive performance in the subsequent season. This might allow females to become oestrous immediately after emergence from hibernation in spring. (C) 2008 Elsevier B.V. All rights reserved.”
“Anisotropic swelling of wood samples was observed upon treatment with an aqueous NaOH solution with 0-0.20 fraction concentrations. At NaOH concentrations less than 0.10, the swelling occurred only along the tangential axis (T) and not along the radial (R) or longitudinal (L) axes. At greater NaOH levels, the swelling was even more pronounced along T with shrinkage along the other axes. These anisotropic changes along R and L were closely related to the crystallinity of microfibrils in the wood cell wall and simulated with a cell structure model. This exercise revealed microfibril contraction and matrix swelling in the wood cell wall upon NaOH treatment. The observed anisotropy in cross section was caused by differences in the microfibril angles (LR and LT) with the cell wall.

“Vascular risk factors play a significant role in the path

“Vascular risk factors play a significant role in the pathogenesis and progression of AD. MPV is an index of platelet activation and may be a potential marker

of inflammation to demonstrate the vascular damage in AD. The aim of the present study is to assess whether platelet volume would be useful in predicting vascular damage in AD. A total of 126 patients with AD (male/female: 44/82, mean age 76.2 +/- 6.8 years) and 286 patients as controls with normal cognitive function (male/female: 123/163, mean age 75.2 +/- 6.3 years) were enrolled in this cross-sectional study. MPV values were determined for all study participants. Mini-Mental State Examination (MMSE) and clock drawing tests (CDT) were performed for cognitive assessment, DSM-IV and NINCDS-ADRDA criteria were used for diagnosis of AD. The mean MPV values were significantly higher in AD group (8.46 +/- 1.15 vs. Fosbretabulin supplier 8.17 +/- 0.90; p = 0.011). In this study, significantly higher MPV values in patients with AD have been detected. Since increased MPV levels are usually FDA approved Drug Library solubility dmso considered as a vascular risk factor, the results of this study suggested the role of platelet activation in the vascular pathogenetic basis of AD. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“Chemotherapy often causes damage to hematopoietic tissues, leading to

acute bone marrow suppression and the long term development of leukemias. Niacin deficiency, which is common in cancer patients, causes dramatic genomic instability in bone marrow cells in an in vivo rat model. From a mechanistic perspective, niacin deficiency delays excision repair and causes double strand break accumulation, which in turn favors chromosome breaks and translocations. Niacin deficiency AZD7762 datasheet also impairs cell cycle arrest and apoptosis in response to DNA damage, which combine to encourage the survival

of cells with leukemogenic potential. Conversely, pharmacological supplementation of rats with niacin increases bone marrow poly (ADP-ribose) formation and apoptosis. Improvement of niacin status in rats significantly decreased nitrosourea-induced leukemia incidence. The data from our rat model suggest that niacin supplementation of cancer patients may decrease the severity of short- and long-term side effects of chemotherapy, and could improve tumor cell killing through activation of poly(ADP-ribose)-dependent apoptosis pathways. [Mol Cancer Ther 2009;8(4):725-32]“
“Objective: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of GABA degradation leading to elevations in brain GABA and gamma-hydroxybutyric acid (GHB). The effect of chronically elevated GABA and GHB on cortical excitability is unknown. We hypothesized that use-dependent downregulation of GABA receptor expression would promote cortical disinhibition rather than inhibition, predominantly via presynaptic GABAergic mechanisms.