Furthermore, apart from the fact that they had relapsed

no care co-ordinator had identified any other compelling evidence (such as a history of noncompliance or large quantities of medications found at their home) to indicate that they were noncompliant (which would have excluded them from the study). Where there were any doubts concerning an individual’s compliance, they were excluded from the study. As dopamine supersensitivity-induced breakthrough psychosis Inhibitors,research,lifescience,medical occurs in compliant patients, CPNs and other care co-ordinators need to guard against compliance-related complacency. Furthermore, although CPNs and other community care co-ordinators are best placed to monitor for side effects due to their sustained regular contact with patients, it has been found that CPNs tend to assess for a small number of side effects,

such as akathisia, and often do not assess for tardive dyskinesia and other AIMs [Bennett et al. 1995]. However, this has implications for their ability to Inhibitors,research,lifescience,medical assess for, and identify supersensitivity psychosis cases at an early stage. This indicates that there is a need for CPNs to be better trained to assess for the presence of the broad range of side effects associated with both typical and atypical antipsychotics. A limitation of the present study is whether the checklist Inhibitors,research,lifescience,medical could be used in clinical practice. For a trained LEDS interviewer assessing for the presence of life events was not difficult, the main difference was in remembering the 10 domains and using appropriate probing questions. It could be argued that this would Inhibitors,research,lifescience,medical not be the case for most CPNs in practice. However, LEDS is primarily concerned with people in their social context and would complement the assessment skills used Inhibitors,research,lifescience,medical by mental health workers,

for example, asking about increases or decreases in contact with family and friends, satisfaction with the home and local area, financial difficulties or windfalls, physical or psychological health concerns to self or close ties, relationship difficulties with partner and experiences of crime, are the type of questions that staff use frequently in routine assessments. Therefore, as with assessing Carnitine palmitoyltransferase II for side effects, this research identified a need for community staff to be trained in some brief modified form of LEDS to aid clinical assessment. Conclusion This study used a checklist of Sunitinib diagnostic criteria for supersensitivity psychosis and found it present in 39% of relapses. The checklist demonstrated its utility by identifying a probable cause of relapse for 70% of the participants. This study found that supersensitivity psychosis occurred in antipsychotic-compliant patients. Furthermore, there was no evidence of an association with an increased tolerance to antipsychotics indicated by higher doses.

27 Subplate neurons, a transient cell population important for developing thalamocortical connections, are also vulnerable.28 Thalamocortical connections are disrupted in preterm infants,29 and altered functional connectivity in children and adolescents born preterm is an important risk factor for adverse cognitive outcomes.25,30

Importantly, there is altered cortical activation and functional connectivity during language and visual spatial processing in children and adults born preterm who have normal intelligence.30–33 Procedural pain/stress in very preterm infants is associated with abnormal brain development in the NICU, above and beyond other clinical risk factors associated with prematurity.34,35 Inhibitors,research,lifescience,medical These Inhibitors,research,lifescience,medical findings are consistent with animal studies revealing that inflammatory pain or acute pain from repeated injections Etoposide increased apoptosis in the neonatal rat brain.36,37 Altered microstructure may be related to pain-related increases in proinflammatory cytokines in the periphery and the central nervous system, or over-stimulation of immature neurons.35,38,39 Inhibitors,research,lifescience,medical Pain-related stress may also have indirect effects on the brain, or may interact

with other factors implicated in development, since our group found that greater neonatal pain/stress exposure (adjusted for clinical confounders) is associated with slower body and head growth in preterm infants from early in life to term-equivalent Inhibitors,research,lifescience,medical age,40 and on diffusion tensor imaging slower growth was associated with altered cortical gray matter in infants born very preterm.41 Mechanisms whereby pain-related stress exposure may affect multiple systems remain to be addressed. Diffusely abnormal microstructure and metabolism42 and altered functional

connectivity relative to term controls29 are associated with adverse neurodevelopment.22–28,30,41,43 Rodent studies provide strong evidence that early life experience can alter both the structure and function of the developing brain.44 In humans, exposure to stressors in the NICU is associated with regional alterations in brain structure and function. In two independent cohorts, Grunau, Miller, and colleagues Inhibitors,research,lifescience,medical found that greater neonatal procedural pain/stress (adjusted for clinical confounders including gestational age (GA), early illness severity, infection, surgeries, and duration of mechanical ventilation) is associated with altered brain development of preterm infants in the neonatal period35,45 and at school-age.31,46,47 We also Bay 11-7085 showed that neonatal pain/stress is associated at age 7 years with altered IQ that is mediated by brain microstructural changes.46 Others found that neonatal brain maturation on MRI is improved (compared to standard care)by an intervention designed to help parents recognize and respond to stress in their preterm infant in the NICU.48 This parent stress-reduction intervention shows that effects of reduced neonatal stress can be detected on brain images with advanced MRI techniques.

The dropout rate was 25%, with attrition mostly due to

transportation problems and medical comorbidities. Small to moderate pre-post effect sizes were seen in self-reported adherence and some depressive symptoms. These preliminary results suggest that the group treatment was feasible, acceptable, and produced pre-post improvements along important, dimensions, although future clinical trials with objective measures of adherence and a credible control group would be necessary to ascertain its effectiveness. Provider-level interventions The interventions described above are all focused on enhancing adherence Inhibitors,research,lifescience,medical by increasing knowledge, acceptance, and management skills in the patient. However, there are a number of approaches to improve adherence

by changing provider behavior. These can be categorized into attempts to: (i) increase ease of administration and (ii) enhance the working alliance. Simplifying dosing strategics by consolidation can enhance adherence and providing reminders and pillboxes. The working Inhibitors,research,lifescience,medical alliance and satisfaction with treatment can be enhanced by providing client-centered care, making effort to involve the patient in planning Inhibitors,research,lifescience,medical medication strategies and outcomes, and defining patient, values in weighing treatment options.48,69 Emerging directions In addition to discovering the mediators and moderators of psychotherapy’s effectiveness in bipolar disorder, along with broadening access to evidence-based interventions, there are a number of other modalities that are in the earliest stages of development. Integrative interventions addressing medical AZD2281 nmr comorbidities The Inhibitors,research,lifescience,medical medical burden in bipolar disorder appears to be higher than among nonaffected

individuals.70 The convergence of bipolar disorder and chronic physical illnesses, such as cardiovascular (eg, diabetes) and infectious diseases (eg, HIV, hepatitis) arise from a number of shared risk factors, including Inhibitors,research,lifescience,medical unhealthy lifestyles, risk-taking behaviors, and medication side effects.70 In addition to increasing the burden and complexity of adherence vis a vis higher intensity of medication management, comorbid medical conditions negatively impact quality of life and health care utilization.71 secondly Furthermore, access to medical services may be diminished in bipolar disorder. Research identifying shared risk factors for nonadherence and other outcomes in bipolar disorder, such as cognitive impairment (sec Moore et al in this issue, p 256), will inform future interventions. Cognitive training and functional rehabilitation In light of the cognitive deficits that have been identified in bipolar disorder,72 it may be that cognitive remediation, either through restorative interventions (eg, boosting attention skills) or compensatory functional training (eg, using external reminders) could be useful. ‘Ihese interventions have been assessed in patients with schizophrenia.

2012) to include the cochlear sensory structure, as well as confirms the BGJ398 nmr extensive expression of this nAChR in the ascending central auditory system. The novel finding that in addition to expression of α7GFP in developing sensory cells of the cochlear structure and neuronal cells of the spiral ganglion, there is also considerable expression by nonsensory cells. Cells of the spiral prominence and ligament, Deiters’ cells, and some Hensen’s cells. Despite overall agreement between our studies and those

using in situ hybridization (e.g., Happe and Morley 1998; Morley and Inhibitors,research,lifescience,medical Happe 2000), these nonsensory cells were not reported previously to express α7. However, these comparisons are incomplete because Inhibitors,research,lifescience,medical the earlier studies did not necessarily show the comparable structures or the developmental stages at times where we observed peak α7GFP expression. Also, our method of detecting GFP as a marker

of α7 expression offers improved sensitivity and resolution that has previously not been available for this nAChR. The nicotinic receptors α9 and α10 are particularly well characterized in the auditory system (Elgoyhen et al. 1994, 2001a; Vetter et al. 1999, 2007; Katz et al. 2004; Morley 2005). Comparing the expression of Inhibitors,research,lifescience,medical α7GFP to the results from these studies of the sensory hair cells and the nonsensory cells of the cochlea indicate that there are significant spatiotemporal differences during development between the expression of α7 versus α9 Inhibitors,research,lifescience,medical and/or α10. The α9KO mouse also exhibits auditory deficiencies that are not observed in the α7KO mouse, which is largely devoid of a phenotype in this sensory system under normal physiological conditions (Liberman and Brown 1986; Simmons and Morley 1998; Morley 2005; Lustig 2006). The α7GFP is not detected in IHCs, which is consistent

with α9 nAChR being the principle target of alpha-bungarotoxin Inhibitors,research,lifescience,medical in this cell type (Uziel et al. 1981; Glowatzki and Fuchs 2000). Collectively, this suggests that functional redundancy between these receptor subtypes is unlikely (see also Rogers and Gahring 2012). This is also supported by the extensive studies by the Morley group (Happe and Morley 1998, 2004; Morley and Happe 2000; Simmons and Morley Mephenoxalone 2011) who showed that multiple receptor subtypes are expressed in the cochlear and central auditory systems, but each exhibits distinct spatiotemporal patterns that likely preclude substantial or sustained functional overlap. Noteworthy is that the functional contribution of α7 towards modulating physiological systems may not be revealed unless the system is imbalanced as by genetic deficiencies, sustained exposure to pharmacological compounds, or other events such as inflammation (e.g., Faustman et al. 1992; Gahring and Rogers 2005; Venables et al. 2007; Albuquerque et al. 2009; Brown 2011; Severance et al. 2011).

HNPCC related colon cancers account for 3-6% of all colon cancers, and germline mutations in MSH2 and MLH1 have been found in 45-70% of families that meet the Amsterdam criteria for HNPCC (7,8). Since inactivation of both alleles of MSH2 or MLH1 is required to generate MSI, the cancers

that arise in HNPCC kindred frequently show loss of heterozygosity at the loci of these genes, or alternatively show somatic mutation of the sole wild-type MMR allele. The germline mutations that occur in MSH2 and MLH1 are widely distributed throughout either gene and are missense, deletion, or insertion mutations. These mutations result in frame shifts (60% of hMSH2 mutations and 40% of MLH1 Inhibitors,research,lifescience,medical mutations), premature

truncations (23% of MSH2 mutations), or missense mutations (31% of MLH1 mutations) (9). The lack of a mutation hotspot has hampered the development of an inexpensive clinical assay to Inhibitors,research,lifescience,medical detect germline mutations in the genes known to cause HNPCC. Furthermore, because one wild-type allele is sufficient to maintain MMR activity, functional assays to detect MMR gene mutation carriers have not been developed for clinical use to date. However, proof-of-principle studies have demonstrated that it may be possible to develop such an assay by forcing a cell to a haploid state in Inhibitors,research,lifescience,medical which case a mutant MMR allele could be detected (10,11). Studies of the 15% of sporadic colon cancers that display MSI demonstrated these arose due to somatic inactivation of MMR genes and not due to germline MMR gene mutations with low penetrance. While occasional somatic mutations Inhibitors,research,lifescience,medical of MSH2 and MLH1 were detected, the predominant mechanism for inactivating MMR unexpectedly proved to be the epigenetic silencing of the MLH1 promoter due to aberrant promoter methylation (12,13). Clinical implications of MSI The CRC microsatellite Inhibitors,research,lifescience,medical profile provides useful prognostic information (14,15), showing the patients with microsatellite unstable neoplasms have a better overall survival rate and a modified response to conventional chemotherapy

(16-21). MSI Thiamine-diphosphate kinase also helps in predicting the Trichostatin A treatment response of CRC (18,19,22), and could modify the chemotherapy protocols offered to the patients in the future (19), but these results should be applied with caution before this predictive tool is verified. Molecular markers as predictive factors in treatment decisions have been developed in the last few years. The initial studies in sporadic CRC showed that the retention of heterozygosity at one or more 17p or 18q alleles in microsatellite-stable CRCs and mutation of the gene for the type II receptor for TGF-β1 in CRCs with high levels of microsatellite instability correlated with a favorable outcome after adjuvant chemotherapy with fluorouracil based regimens, especially for stage III CRC (18,22).

If an individual receives more or less reward than expected or more or less punishment than expected,

this generates a prediction error; the greater the difference between prediction and reality, the greater the prediction error. Prediction errors are critical for reinforcement-based learning. The greater the prediction error, the faster the system will attempt to learn the new value of the Inhibitors,research,lifescience,medical stimulus or action.52 However, this third impairment will not be considered in any further detail here as the data supporting its existence is obtained with youth with psychopathic traits.53 The relevant studies have yet to be done in adults with psychopathy. Psychopathy: the neural profile Inhibitors,research,lifescience,medical Both structural and functional magnetic

resonance imaging studies can inform an account of psychopathy. We will briefly consider the current state of the literature regarding these studies. Note though that only studies where groups were matched for IQ will be considered. The importance of appropriate matching can be seen from the data presented in a recent sMRI study.54 This study reported a 30% reduction across much of cortex in adults with psychopathy relative to healthy Inhibitors,research,lifescience,medical comparison individuals.54 However, these results were only seen when comparing individuals with psychopathy with healthy comparison individuals. The IQ and, for that matter, the substance dependence rates of these comparison individuals, Inhibitors,research,lifescience,medical was not reported but it is likely, given their job descriptions (students, hospital staff, and skilled workers), that their average IQ was significantly higher and their average substance dependence rate was significantly lower than those of the patients. These confounds may have driven the findings. This suggestion is supported from the authors’ data on only the patients. Groups of PI3K inhibitor patients with high psychopathy vs low psychopathy scores, matched for IQ, showed very minimal differences in cortical volume.54 sMRI studies A series of findings, reported across labs where appropriate IQ comparisons have been made, are worth noting. Not all studies have reported reduced Inhibitors,research,lifescience,medical volumes in these regions in psychopathy but none (at least involving IQ matched

samples) have reported increased volumes in these regions. Thus, three studies have reported reduced amygdala volumes in adults with psychopathy55-57including the largest structural imaging study of this population to date (N=296).55 Similarly, four studies have science reported reductions in temporal pole55,58-60 and two in STS.58,61 Three studies have reported reductions in orbitofrontal cortex.55,58,61 Moreover, and interestingly given the extensive connections between the amygdala and orbitofrontal cortex though the uncinate fasciculus white matter tract, all three DTI studies examining the structural integrity of this tract in individuals with psychopathy have reported reduced structural integrity relative to comparison individuals.

(Since these effects have been extensively summarized in the literature, only a selection of relevant references is given here (please refer to the Discussion CH5424802 mouse section for further detail).) When given in sufficiently

large doses, liposomal formulations may be irritating to subcutaneous (sc) tissues, causing nonspecific local reactions. Particularly during repeated exposure, the presence of exogenous lipid materials in the sc space may serve as a nidus for the development of a foreign body type reaction in surrounding tissues. Therefore, it seems possible that prolonged, repeated Inhibitors,research,lifescience,medical exposure to EXPAREL could intensify the degree of sensitivity to bupivacaine and/or DepoFoam particles particularly in rabbits, because of the thinness of the

skin layer and relative absence of sc fat. As part of the nonclinical development program, the safety of repeat-dose administration of EXPAREL compared to Bsol was evaluated in two species in accordance with International Conference on Harmonization (ICH) guidelines. These multiple-dose Inhibitors,research,lifescience,medical studies in rabbits and dogs (nonsurgical Inhibitors,research,lifescience,medical model) were designed to complement single-dose toxicology testing (surgical hernia repair model) in the same species, in which animals were exposed to the same amount of drug. Groups of animals were given EXPAREL at a dose level of 9mg/kg, 18mg/kg, or 30mg/kg in comparison with Bsol 9mg/kg (7.5mg/mL), or saline via sc twice weekly injection. These studies included evaluation of both local effects as well as the usual broad range of systemic effects. It was possible to meaningfully Inhibitors,research,lifescience,medical compare the toxicology findings and concurrent systemic exposure in rabbits and dogs since the same protocol in a whole-body system, assay methodology, and data acquisition systems were used. The clinical relevance Inhibitors,research,lifescience,medical of the toxicology results was evaluated in relation to the intended clinical use of EXPAREL (single dose) in patients. 2. Materials and Methods 2.1. Materials 2.1.1. Description of DepoFoamTM Technology The DepoFoam drug delivery

system is a proprietary, injectable technology that provides a sustained Calpain release of therapeutic compounds. The DepoFoam system consists of microscopic, polyhedral, lipid-based particles composed of numerous nonconcentric, aqueous chambers containing the drug in solution. Each chamber in this multivesicular liposome is separated from adjacent chambers by lipid membranes [9, 10]. The DepoFoam particle components are naturally occurring or synthetic analogues of common lipids, including phospholipids, cholesterol, and triglycerides. 2.1.2. Test Article EXPAREL (DepoBupivacaine, DB; bupivacaine extended-release liposome injection using multiv-esicular DepoFoam technology), 15mg/mL and 25mg/mL (expressed as anhydrous bupivacaine base), was provided by Pacira Pharmaceuticals, Inc., San Diego, Calif.

MST seizures were found to have shorter duration, lower ictal EEG amplitude, and less postictal suppression than ECT seizures.149 MST might cause fewer

cognitive side effects than ECT, by inducing more focused seizures and sparing cortical regions associated with memory loss. In a nonhuman primate model (Rhesus macaque monkeys), MST was shown to result in a more favorable acute cognitive side effect profile than ECT with regard to long-term memory of a constant target, short-term memory of a variable target, and recall of previously learned three-item lists.150,151 Preliminary clinical data are seen as Inhibitors,research,lifescience,medical suggesting that MST has antidepressant properties and fewer cognitive side effects than ECT152 For example, patients recover orientation more quickly and have fewer attention difficulties or less retrograde amnesia after MST compared with ECT153 Deep brain stimulation Development

of DBS Deep brain stimulation Inhibitors,research,lifescience,medical (DBS) was introduced in the late 1980s by Benabid and colleagues, for the treatment of movement disorders.153 Their original assumption was that chronic high-frequency stimulation of the brain areas might be similar to surgical ablation of these areas.154 For example, thalamic stimulation Inhibitors,research,lifescience,medical for the treatment of intractable tremor was found to have clinical benefits similar to those achieved by surgical thalamotomy155 and stimulation of the subthalamic nucleus or globus pallidus internus for the treatment of Parkinson’s disease could replace the traditional pallidotomy156 Over the last decade, DBS has become a popular treatment for movement disorders such as Parkinson’s disease and essential tremor.157 During the last few years, DBS has been suggested as a Inhibitors,research,lifescience,medical treatment for psychiatric Inhibitors,research,lifescience,medical disorders, such as depression158 and obsessive-compulsive disorder.159 Technical aspects The surgical procedure for the implantation of DBS electrodes is based

on stereotactic techniques that include imaging modalities, physiological mapping, and surgical navigation computers.160 A stereotactic frame is fixed to the patient’s head, and preoperative magnetic resonance images are obtained. Under local anesthesia, a burr hole is drilled, the underlying dura mater is opened, Dipeptidyl peptidase and microelectrodes are inserted using MRI guidance. The electrode location is confirmed by postoperative MRI. Right and left quadripolar electrodes are implanted. The electrodes remain externalized for a week for clinical testing, and then are selleck connected to a pulse generator that is implanted in the infraclavicular region. The frequency, intensity, and pulse width of the stimulation are programmable, within safety limits. The physician sets the stimulus parameters, and the patient might also alter a few parameters by himor herself. Stimulation can be programmed to continuous or intermittent firing, or to on and off cycles during fixed time intervals.

Additionally, functionalization of the NP’s surface with hydrophilic molecules, such as PEG, can also greatly increase their solubility, help evading macrophage-mediated uptake and, thus, avoid removal from the systemic circulation and protect their carriers from enzymatic degradation when used in vivo [30]. For active targeting, NPs can be easily functionalized with a wide variety of biological moieties, such as antibodies, peptides, and/or DNA/RNA to specifically target extracellular and intracellular receptors or pathways [30]. The use of NPs functionalized with multiple peptides or antibodies, such as monoclonal antibodies, have been described

to successfully Inhibitors,research,lifescience,medical target specific cell surface proteins or receptors on cancer cells and further direct their antitumor action, leading to tumor cell death with minimal damage to collateral healthy cells [36, 39–41]. In nucleic-acid

functionalized NPs, DNA and RNA macromolecules can be used to simultaneously target specific Inhibitors,research,lifescience,medical sequences and exert their genetic-based therapy [42, 43]. To help tracking noble metal NPs in vivo and enhance the imaging properties of such moieties, leading to more efficient control of their therapeutic properties, they can also be functionalized with chemical moieties, such as Raman [44, 45] or fluorescent [46, 47] reporters. 2.2. Gene Silencing Antisense Inhibitors,research,lifescience,medical DNA [48, 49] and RNA interference (RNAi) via the use of small-interfering RNA [50–53] have emerged as a Pictilisib mouse powerful and useful tools to block gene function and for sequence-specific Inhibitors,research,lifescience,medical posttranscriptional gene silencing, playing an important role in downregulation of specific gene expression in cancer cells. Small interfering RNAs (siRNAs) can be transfected into mammalian cells by a variety of methods that influence the strength and duration of the silencing response, which in turn is affected

by the amount of siRNA that is delivered and on the potential of each siRNA to suppress its Inhibitors,research,lifescience,medical target. Thus, one drawback of using naked siRNAs is that they show extremely short half-lives, weak protection against action by RNases, poor chemical stability, ever and common dissociation from vector [54]. In fact, the major obstacle to clinical application is the uncertainty about how to deliver therapeutic RNAs (e.g., miRNA and/or siRNA) with maximal therapeutic impact. Nanotechnology offers an unprecedented opportunity to overcome these problems, as nanoscale devices, due to their small size, can readily interact with biomolecules on both the surface of cells and inside of cells for longer periods of time [10]. Gold NPs (AuNPs) have shown potential as intracellular delivery vehicles for antisense oligonucleotides [55] and for therapeutic siRNA by providing protection against RNAses and ease of functionalization for selective targeting [42, 43].

34 Researchers from Italy have investigated the efficacy of intravesical instillation #PFI-2 clinical trial randurls[1|1|,|CHEM1|]# of a naturally occurring peptide, nociceptin/orphanin FQ (N/OFQ) for the treatment of BPS/IC. Twenty-three subjects with BPS/IC received N/OFQ twice a week for 4 weeks by intravesical instillation. The authors noted a statistically significant decrease in the O’Leary-Sant IC problem index but not the O’Leary-Sant IC symptom Inhibitors,research,lifescience,medical index. There was a decrease in Visual Analogue Scale (VAS) and about half of the patients were satisfied with the results of treatment. These preliminary results suggest that N/OFQ may provide benefit to patients with BPS/IC and certainly further

randomized, placebo-controlled trials would be mandatory Inhibitors,research,lifescience,medical to confirm this initial impression.35 Intratrigonal injection of botulinum toxin A has been reported in patients with BPS/IC who have been refractory to first-line therapy. Investigators evaluated the therapeutic effect of repeated intratrigonal injection of onabotulinumA in 14 women with BPS/IC refractory to first-line treatment. The patients received four consecutive intratrigonal injections under general anesthesia. The investigators reported that all patients reported Inhibitors,research,lifescience,medical subjective improvement

following each injection and that each treatment provided symptomatic relief for a period of between 9 and 12 months. No cases of voiding dysfunction or urinary Inhibitors,research,lifescience,medical retention were reported. This study suggested that intratrigonal injection of botulinum toxin A is safe, effective, and has a maintained effect after repeated injection in patients with treatment refractory BPS/IC.36 Two studies that were more basic science in nature suggested further therapeutic avenues that should be explored in BPS/IC. A study with mice showed that treatment with selective cannabinoid receptor 2 (CB2) agonists reduced the severity of acrolein-induced

cystitis and inhibited bladder inflammation-induced increased peripheral sensitization to mechanical stimuli. The data would indicate that CB2 might play an inhibitory role in bladder inflammation and Inhibitors,research,lifescience,medical subsequent changes in pain perception. CB2 agonists have been developed and clinical trials are being initiated in 2011 for this particular indication.37 Another interesting Dipeptidyl peptidase and somewhat innovative basic science study investigated the beneficial effects of honey on histamine release from LAD2 cells. Honey has long been used for the treatment of wounds and has more recently demonstrated to have beneficial effects on wound healing. Mechanisms include antibacterial properties, cytokine interaction, and antioxidant effects as well as on mass cell activity. The investigators concluded that a constituent of most honeys inhibits spontaneous and stimulated mass cell degranulation in a cell line model. Certainly this interesting observation warrants further investigation as a possible intravesical agent in the treatment of BPS/IC.