Evaluative judgments were related to a neural network discussed i

Evaluative judgments were related to a neural network discussed in the context of self-referential processing and theory of mind. More precisely, the neural network consisted of frontomedian regions, the temporal pole, and the posterior superior temporal gyrus and sulcus/angular

gyrus. Patients showed higher activations in this network and the inferior frontal gyrus, whereas healthy control subjects activated more dopaminergic structures, namely the ventral tegmental area, during evaluative judgments. One possible interpretation of the data is that deficits in the ventral tegmental area, and consequently the mesocorticolimbic projection system, have to be compensated for by higher brain activations in the frontomedian and anterior cingulate cortex in patients with diffuse axonal injury. In conclusion, our AZD0530 mouse study supports the hypothesis that traumatic brain injury is characterized by frontomedian dysfunctions, which may be responsible for clinical deficits in the long-term and which might be modified by rehabilitative strategies check details in the future. (C) 2009 Elsevier Ltd. All rights reserved.”
“Background Streptococcus

pneumoniae is a leading cause of bacterial pneumonia, meningitis, and sepsis in children worldwide. However, many countries lack national estimates of disease burden. Effective interventions are available, including pneumococcal conjugate vaccine and case management. To support local and global policy decisions on pneumococcal disease prevention and treatment, we estimated country-specific incidence of serious cases and deaths in children younger than

5 years.

Methods We measured the burden of pneumococcal pneumonia by applying the proportion of pneumonia cases caused by S pneumoniae derived from efficacy estimates from vaccine trials to WHO country-specific estimates of all-cause pneumonia cases and deaths. We also estimated burden of meningitis and non-pneumonia, non-meningitis invasive disease using disease incidence and case-fatality data from a systematic literature review. When high-quality data were available from a country, these were used for national estimates. Otherwise, estimates were based on data from neighbouring countries with similar child mortality. Estimates why were adjusted for HIV prevalence and access to care and, when applicable, use of vaccine against Haemophilus influenzae type b.

Findings In 2000, about 14.5 million episodes of serious pneumococcal disease (uncertainty range 11.1-18.0 million) were estimated to occur. Pneumococcal disease caused about 826 000 deaths (582 000-926 000) in children aged 1-59 months, of which 91 000 (63 000-102 000) were in HIV-positive and 735000 (519 000-825 000) in HIV-negative children. Of the deaths in HIV-negative children, over 61% (449 000 [316 000-501 000]) occurred in ten African and Asian countries.

8 mm(3) and positive control MK-801, 104 4 +/- 22 6 mm(3), both p

8 mm(3) and positive control MK-801, 104.4 +/- 22.6 mm(3), both p < 0.05 compared to vehicle control), whereas Compound-1 treatment initiated at 2 h after occlusion did not affect infarct volume. Compound-1

pretreatment also significantly reduced brain water content at 24 h (vehicle, 80.3 +/- 0.2% vs. Compound-1, 79.7 +/- 0.2%, p < 0.05) but not at 72 h after MCAO. These results demonstrate that early pretreatment administration of a KDR kinase inhibitor elicited an early, transient decrease in edema and subsequent reduction in infarct volume, implicating find more VEGF as a mediator of stroke-related Vascular permeability and ischemic injury. (C) 2008 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.”
“This study examined the effects of early palmar CP673451 order forepaw sensorimotor deprivation on learning and memory in rats. Sensorimotor deprivation was performed on 18-day-old male rats. Controls were sham operated. Studies were performed on rats aged 18, 25, 35, 45 and 60 days.

Morris water maze testing was used to assess learning and memory. Long-term potentiation (LTP) was assessed by electrophysiological means in slices obtained from the hippocampal Schaffer collateral pathway. Nissl staining was performed to assess pyramidal cell number in hippocampal CA1 and CA3 regions. Hippocampal N-methyl-D-aspartate receptor 1 (NMDAR1) mRNA and protein levels were assessed. Learning and short-term memory were significantly depressed in 25 and 35 day old sensorimotor deprived rats (P < 0.01). LTP was also significantly depressed in sensorimotor deprived rats at these ages, while hippocampal CA1 pyramidal cell Counts were significantly decreased (P < 0.05). CA3 cell numbers were significantly lower in 25-day-old

sensorimotor deprived rats (P < 0.05). Both NMDAR1 mRNA and protein levels were significantly lower in sensorimotor deprived rats aged 25 and 35 days (P < 0.05). These findings indicate that palmar Surface forepaw sensorimotor deprivation impairs subsequent learning Parvulin and memory in Young rats. Decreased hippocampal pyramidal cell numbers and altered NMDAR1 expression may underlie this impairment. (C) 2008 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.”
“Lie judgment is an estimation of the speaker’s intention to deceive inevitably accompanied by moral judgment. To depict their neural substrates, we conducted a functional magnetic resonance imaging study. Eighteen subjects read short stories and made judgments in three different tasks: a control gender judgment task, a moral judgment task, and a lie judgment task. Compared with the control task, both the moral and lie judgment tasks activated the left temporal lobe, the medial prefrontal cortex, the lateral orbitofrontal cortex extending to the dorsolateral prefrontal cortex, the caudate nucleus, the left temporo-parietal junction (TPJ), and the right cerebellum.

“BRD4, which is a member of the BET (bromodomains and extr

“BRD4, which is a member of the BET (bromodomains and extraterminal) protein family, interacts preferentially with acetylated chromatin and possesses multiple cellular functions in meiosis,

embryonic development, the cell cycle, and transcription. BRD4 and its family members contain two bromodomains known to bind acetylated lysine, and a conserved ET domain whose function is unclear. Here we show the solution structure of the ET domain of mouse BRD4, which provides the first three-dimensional structure of an ET domain in the BET family. We determined the NMR structure of BRD4-ET with a root-mean-square deviation of 0.41 angstrom for the backbone atoms in the structured region of residues 608-676 on the basis of 1793 upper distance limits derived from NOE intensities measured in three-dimensional NOESY spectra. The structure

of the BRD4-ET domain comprises three 8-Bromo-cAMP RG-7388 manufacturer alpha-helices and a characteristic loop region of an irregular but well-defined structure. A DALI search revealed no close structural homologs in the current Protein Data Bank. The BRD4-ET structure has an acidic patch that forms a continuous ridge with a hydrophobic cleft, which may interact with other proteins and/or DNA.”
“Considerable sex differences occur in the incidence and prevalence of anxiety disorders where women are more anxious than men, particularly in situations where social interaction is required. In preclinical studies, the social interaction test represents a valid animal model to study sex differences in social anxiety. Cepharanthine Indeed, female rats engage less in conspecific interactions than their male counterparts, which are behaviors indicative of higher social anxiety in female rats.

In this work, we implicated extracellular signal-regulated kinase 2 (ERK2) in the medial prefrontal cortex (mPFC) in mediating social interaction. Indeed, female rats’ had lower ERK2 expression compared to male rats, and overexpression of ERK2 in the mPFC increases their social interaction to the level seen in their male counterparts. These data indicate that the sexually dimorphic expression of ERK2 mediates social anxiety-like behaviors. (c) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Microalgae have much higher lipid yields than those of agricultural oleaginosous crops, and they do not compromise arable land. Despite this, current microalga-based processes suffer from several constraints pertaining to the biocatalyst and the bioreactor, which hamper technologically and economically feasible scale-up. Here, we briefly review recent active research and development efforts worldwide, and discuss the most relevant shortcomings of microalgal biofuels.

However, to address the needs of large clinical trials and long-t

However, to address the needs of large clinical trials and long-term monitoring, in which efficiency may compete with precision of measurement, we developed the 8-item self-administered SF-Qualiveen.

Materials and Methods: A total of 180 English speaking and French speaking outpatients with multiple sclerosis

at multiple sclerosis clinics and departments of rehabilitation in Canada and France completed the entire Qualiveen, the Multiple Sclerosis Quality of Life-54 questionnaire or its French version (SEP-59) as well as urinary function assessments at study enrollment and 2 to 10 weeks later. At visit 2 patients also made global ratings of change in urinary health related quality of life. SF-Qualiveen development and testing used this data set.

Results: Correlations selleckchem of SF-Qualiveen with its original form were high (r = 0.70 to 0.92). find more SF-Qualiveen proved reliable (ICC 0.83 to 0.93). Its responsiveness was similar to that of the long form (SRM 0.75 to 1.62).

Correlations with other measures were consistent with our a priori predictions (weighted kappa 0.55 for cross-sectional correlations and 0.66 for correlations of change), supporting the cross-sectional and longitudinal construct validity of SF-Qualiveen.

Conclusions: SF-Qualiveen has excellent measurement properties, similar to those of the long form. The new instrument is likely to perform well in the clinical and research context.”
“Synaptic plasticity depends on the generation, modification and disconnection of synapses. An excitatory synapse is connected to a specialized dendritic compartment called a spine, which undergoes activity-induced remodeling. Here, we discuss a signaling pathway that transduces neuronal activity into the remodeling of spine through p38 mitogen-activated protein kinase ( MAPK) and N-cadherin. Dendritic spines change their morphology and density in response to neuronal activity. In the early phase, posttranslational modifications of synaptic molecules regulate spine morphology, whereas activity-induced gene products reduce

spine density in the late phase. One of the targets of these mechanisms is N-cadherin. An activity-induced protocadherin, Tangeritin arcadlin, stimulates thousand and one 2 beta ( TAO2 beta) kinase, which in turn activates p38 MAPK through MAPK kinase 3 ( MEK3), resulting in the endocytosis of N-cadherin and the decrease in spine number. This pathway also underlies the mechanism of the spine decrease in neuronal disorders, such as Alzheimer’s disease and epilepsy. Development of new p38 MAPK inhibitors brings a ray of hope with respect to the development of more effective therapies for these patients.”
“Neurotrophic factors (NTFs) are a pleiotropic group of secreted growth factors that regulate multiple aspects of neuronal development, including the regressive event of cell death.

However, in recent years more and more conflicting data have sugg

However, in recent years more and more conflicting data have suggested that development of sickness following peripheral immune challenge could be independent of cytokines. Hence, it is confusing as to whether cytokines really do act as primary mediators of sickness, or if they are secondary to alternative inducing factor(s). In this review, we will (1) introduce the relationships between systemic inflammation, cytokines, sickness, and delirium, and (2) attempt to interpret the recent controversies. (c) 2012 Elsevier Ltd. All rights reserved.”
“Low vitamin

B12 and high homocysteine (Hcy) levels are common in older adults and may be associated with worse neurological function. The aim of this study is to determine whether changes in B12 or Hcy levels are associated selleck chemicals with longitudinal changes in peripheral nerve function and clinical neurological signs and symptoms.

Participants aged 60 years and older at baseline (n = 678; 72.2 +/- 6.2 years; 43.5% male) were from the InCHIANTI Study. Low B12 (< 260 pmol/L) and high Hcy (>= 13 mu mol/L) were measured at baseline and 3-year follow-up. Neurological function was assessed by peroneal nerve conduction amplitude (compound motor action potential)

and velocity, neurological examination, and peripheral neuropathy selleck symptoms at baseline, 3-year, and 6-year follow-up.

At baseline, 43.8% had low B12 levels and 58.6% had high Hcy levels. Over 6 years, 12.4% declined to poor compound motor action potential (<

1 mV) and 42.1% declined to poor nerve conduction velocity (< 40 m/s). In mixed models analyses, sustained high Hcy was associated with worse compound motor action potential compared with sustained normal Hcy (p = .04), adjusting for demographics, diabetes, and folate level. Participants whose Hcy level became high at follow-up were more likely to become unable to detect monofilament at 6-year follow-up compared with those with sustained normal Hcy (odds ratio: 5.4; 95% CI: 1.5-19.0), adjusting for demographics, diabetes, body mass index, and peripheral arterial disease. There was no association with vitamin B12 level or with symptoms.

High Hcy may be associated with worse sensory and motor peripheral nerve function. Because poor nerve function Etomidate has been associated with lower strength and physical performance, these results have important implications for disability in older adults.”
“Given the hypothesised association between cannabis use and schizophrenia, and the well documented alterations in pre-pulse inhibition (PPI) that are observed in schizophrenia, it is of interest to examine the effects of cannabis use on PPI.

The objective of the study was to use novel methodology for the measurement and characterisation of attentional modulation of PPI, in order to examine the nature of PPI in chronic cannabis users.

The findings are discussed in theoretical contexts of speech perc

The findings are discussed in theoretical contexts of speech perception and the mirror system. We suggest that this technique may offer a cost-efficient, non-invasive technique for measuring motor activity during speech perception. (C) 2009 Elsevier Ltd. All rights reserved.”
“Infection with a wide variety of viruses often perturbs host cell signaling pathways including the Jun NH(2)-terminal kinase/stress-activated kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase (p38/MAPK), which are important components of cellular signal transduction pathways. The present study

demonstrated for the first time that porcine circovirus type 2 (PCV2), which is the Birinapant mw primary causative agent of an emerging swine disease, postweaning

multisystemic wasting syndrome, can activate JNK1/2 and p38 MAPK pathways in PCV2-infected PK15 cells. www.selleckchem.com/products/tpx-0005.html However, PCV2 at an early stage of infection, as well as UV-irradiated PCV2, failed to activate these two MAPK families, which demonstrated that PCV2 replication was necessary for their activation. We further found that PCV2 activated the phosphorylation of JNK1/2 and p38 MAPK downstream targets c-Jun and ATF-2 with virus replication in the cultured cells. The roles of these kinases in PCV2 infection were further evaluated using specific inhibitors: the JNK inhibitor 1 for JNK1/2 and SB202190 for p38. Inhibition of JNK1/2 and p38 kinases by these specific inhibitors did result in significant reduction of PCV2 viral mRNA transcription and protein synthesis, viral progeny release, and blockage of PCV2-induced apoptotic 2-hydroxyphytanoyl-CoA lyase caspase-3 activation in the infected cells. Taken together, these data suggest that JNK/SAPK and p38 MAPK pathways play important roles in the PCV2 replication and contribute to virus-mediated changes in host cells.”
“Implicit (unconscious/incidental) and explicit (conscious/intentional) learning are considered to have distinct neural

substrates. It is proposed that implicit learning is mediated by the basal ganglia (BG), while explicit learning has been linked to the medial temporal lobes (MTL). To test such a dissociation we investigated implicit and explicit sequence learning in Parkinson’s disease (PD), a disorder characterized by striatal dysfunction. We studied both implicit and explicit learning of a 12-item sequence of target locations in 13 PD patients and 15 age-matched controls. In the implicit sequence learning task all participants completed 10 blocks of a probabilistic serial reaction time (SRT) task in which they were exposed to the sequence without explicit knowledge of it. Participants also completed between I and 10 blocks of an explicit sequence learning task in which the sequence was learned deliberately by trial-and-error.

Conclusions The results

Conclusions. The results AZD2014 in vitro suggest that IQ, executive function and verbal learning deficits in schizophrenia may reflect a common abnormality of information processing in prefrontal cortex rather than specific impairments in different cognitive domains. Verbal memory retention impairments, however, may have a different aetiology.”
“Background About 15% of adults worldwide have a disability. These individuals are frequently reported to be at increased

risk of violence, yet quantitative syntheses of studies of this issue are scarce. We aimed to quantify violence against adults with disabilities.

Methods In this systematic review and meta-analysis, we searched 12 electronic databases to identify primary research studies published between Jan 1, 1990, and Aug 17, 2010, reporting prevalence estimates of violence against adults (aged mainly >= 18 years) with disabilities, or their risk of violence compared with non-disabled adults. We included only studies reporting violence occurring within the 12 months before the study. We assessed studies with six core quality criteria,

and pooled data for analysis.

Findings Of 10 663 references initially identified, 26 were eligible for inclusion, with data for 21 557 individuals with disabilities. 21 studies provided data suitable for meta-analysis of prevalence of violence, and ten for meta-analysis of risks of violence. Pooled prevalence of any (physical, sexual, or intimate partner) recent violence was 24.3% (95% CI 18.3-31.0) in people with mental illnesses, 6.1% (2.5-11.1)

in those with intellectual impairments, and 3.2% (2.5-4.1) in those with non-specific MX69 ic50 impairments. We identified substantial heterogeneity in most prevalence estimates (I-2 > 75%). We noted large uncertainty around pooled risk estimates. Pooled crude odds ratios for the risk of violence in disabled compared with non-disabled individuals were 1.50 (95% CI 1.09-2.05) for all studies combined, 1.31 (0.93-1.84) for people CYTH4 with non-specific impairments, 1.60 (1.05-2.45) for people with intellectual impairments, and 3.86 (0.91-16.43) for those with mental illnesses.

Interpretation Adults with disabilities are at a higher risk of violence than are non-disabled adults, and those with mental illnesses could be particularly vulnerable. However, available studies have methodological weaknesses and gaps exist in the types of disability and violence they address. Robust studies are absent for most regions of the world, particularly low-income and middle-income countries.”
“Background. There is increasing evidence that the frequently reported working memory impairments in schizophrenia might be partly due to in alteration in the functional connectivity between task-relevant areas. However, little is known about the functional connectivity patterns in schizophrenia patients during learning processes. In a previous study, Koch et al.

Clinical courses

Clinical courses LY333531 purchase of three members of the same family, similarly exposed to toxin, who exhibited different clinical courses of the disease are presented. Methods: Questionnaires on AA exposure were taken. Tissue samples were obtained during therapeutic nephrouretectomies. Histopathology, immunohistochemical detection of p53, p53 mutation screening in tumor

DNA and analysis on the presence of aristolactam (AL)-DNA adducts were performed. Results: Case 1 had UUC with typical EN histopathological signs, whereas Case 2 had bilateral UUCs with typical EN histopathological signs. In contrast, the patient in Case 3 initially showed renal insufficiency, complicated afterwards by right UUC, and later on by left UUC with histopathological end-stage chronic changes but without typical EN changes. AA-DNA adducts and specific p53 mutational spectra (A:T -> T:A transversion) were found in tissues of cases 1 and 2. Conclusion: Diverse clinical courses seem to

be related not to differences in exposure but to differences in metabolic activation or detoxification of AA and/or DNA repair resulting from different genetic polymorphisms. Copyright (c) 2013 S. Karger AG, Basel”
“Bipolar disorder (BD) and adult attention deficit hyperactivity disorder (ADHD) usually manifest with shared clinical symptoms, proving quite challenging SB202190 to thoroughly differentiate one from another. Previous research has characterized these two disorders independently, but no study compared both pathologies Morin Hydrate from a neuropsychological perspective. The aim of this study was to compare the neuropsychological profile of adult ADHD and BD with each other and against a control group, in order to

understand the way in which comprehensive cognitive assessment can contribute to their discrimination as distinct clinical entities as well as their differential diagnosis. All groups were successfully matched for age, sex, years of education, and premorbid IQ. Participants were assessed with an extensive neuropsychological battery evaluating multiple domains. Compared to controls, BD patients had a poorer performance on immediate verbal memory tasks. Both clinical groups exhibited significantly lower scores than controls on the recognition phase of verbal and non-verbal memory tasks, as well as on a task of executive functioning with high working memory demand. Noticeably, however, ADHD had significantly better performance than BD on the recognition phase of both the Rey list memory task and the Rey Figure.

The application of all-trans-retinoic acid (ATRA) to the inductio

The application of all-trans-retinoic acid (ATRA) to the induction therapy of APL decreases the mortality of newly diagnosed patients, thereby significantly improving the response rate. Therefore, ATRA combined with anthracycline-based chemotherapy has been widely accepted and used as a classic treatment. It has been demonstrated that high doses of cytarabine have a good effect on the prevention of relapse for high-risk patients. However, as the indications of arsenic trioxide (ATO) for APL are being extended from the original relapse treatment to the first-line treatment of de novo APL, we find that the regimen of ATRA, combined with ATO, seems to be a new

treatment option because of their targeting mechanisms, milder toxicities and improvements of long-term outcomes; this combination may become a potentially curable treatment modality for APL. We discuss the therapeutic strategies for APL, particularly the novel approaches to newly diagnosed patients and the handling of side selleckchem effects of treatment and relapse treatment, so as to ensure each newly diagnosed patient of APL the most timely and best treatment.”
“Blast-induced traumatic brain injury (TBI) and subsequent neurobehavioral

Staurosporine mouse deficits are major disabilities suffered by the military and civilian population worldwide. Rigorous scientific research is underway to understand the mechanism of blast TBI and thereby develop effective therapies for protection and treatment. By using an in vitro shock tube model of blast TBI with SH-SY5Y Urease human neuroblastoma cells, we have demonstrated that blast exposure leads to neurobiological changes in an overpressure and time dependent manner. Paradoxically, repeated blast exposures resulted in less neuronal injury compared to single blast exposure and suggested a potential neuroprotective mechanism involving released cyclophilin A (CPA). In the present study, we demonstrate accumulation of CPA in the culture medium after repeated blast exposures supporting the notion of extracellular CPA mediated neuroprotection.

Post-exposure treatment of the cells with purified recombinant CPA caused significant protection against blast-induced neuronal injury. Furthermore, repeated blast exposure was associated with phosphorylation of the proteins ERK1/2 and Bad suggesting a potential mechanism of neuroprotection by extracellular CPA and may aid in the development of targeted therapies for protection against blast-induced TBI. (c) 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.”
“The kappa opioid receptor (KOR) antagonist, JDTic, was reported to prevent stress-induced reinstatement of cocaine-maintained responding and to have antidepressant-like effects.

Our objectives were to determine whether analogs of JDTic retained KOR antagonist activity and whether an orally effective analog prevented footshock-induced cocaine reinstatement.

RTI-194 (i.g. 1-30 mg/kg, s.c. 0.3-10 mg/kg, and i.p. 30 mg/kg), RTI-212 (s.c.

(C) 2011 IBRO Published by Elsevier Ltd All rights reserved “

(C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.”

The excess mortality associated with depressive disorders has been most often attributed to risks for suicide but diverse findings indicate that depressive disorders also increase risks for cardiovascular (CV) mortality. Among the possible mediators is the hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity that characterizes many cases of relatively severe depressive selleck chemicals llc disorder and severity is characteristic of psychotic depressive disorder.

Methods: The following describes a 17-year mortality follow-up of 54 patients with Research Diagnostic Criteria (RDC) psychotic major depression or schizoaffective, mainly affective, depression. All had baseline assessments that included a 1 mg dexamethasone

suppression test with post-dexamethasone samples at 8 a.m., 4 p.m. and 11 p.m.

Results: Regression analyses showed that both greater age and higher maximum post-dexamethasone cortisol concentrations predicted deaths due to CV causes (t = 4.01, p < 0.001 and t = 3.03, p = 0.004, respectively). The 4 who died from CV disease had a mean (SD) post-dexamethasone cortisol concentration of 18.0 (6.0) mu g/dl white the mean (SD) value for the remaining 50 patients was 7.6 (6.6) mu g/dl (t = 3.03, df = 53, p = 0.004). Regression analyses showed the 11 p.m. post-dexamethasone value to be predictive of suicide (t = 2.05, p = 0.048).

Conclusions: Conclusions should PCI-34051 nmr be tentative because an earlier follow-up of a more heterogeneous, but larger, sample did not find a relationship between DST results and CV mortality, and because only 4 CV deaths occurred in the present study. HPA-axis hyperactivity is probably only one of a number of factors that link depressive disorder to CV mortality. (C) 2008 Elsevier Ltd. All rights reserved.”
“Background We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate Morph lino oligomer (PMO)

in patients with Duchenne muscular dystrophy.

Method We undertook an open-label, phase 2, dose-escalation study (0.5, 1.0, 2.0, 4.0, 10.0, and 20.0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5-15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. Montelukast Sodium The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystroph in restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597.

Findings 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0.