17,18 The dopamine LY294002 ic50 system is important in the experience of motivation to seek our rewards, both wanting to and, quite literally, moving toward a desired object. Dopamine is one of the neurotransmitters that is fundamental in conditioning, in associating the experience of reward with specific objects.19 In the present discussion, this conditioning specifically creates the attachment to a particular figure. Dopamine is important in pursuing rewards, and opioids are important in

the Inhibitors,research,lifescience,medical enjoyment of those rewards.6 Opioids are another endogenous neurochemical, and they are also released in a variety of social interactions, including gentle physical touch. Oxytocin is a neurohormone important in birthing and nursing in all mammals, but in humans it has also been linked to suppression of anxiety during psychosocial Inhibitors,research,lifescience,medical stress and to the enhancement of trust.20,21 However, in order to explain why some individuals develop CG in response to the death of a loved one and others adjust resiliently, we must move beyond models

and theories designed for bereavement generally. A biopsychosocial model of CG posits Inhibitors,research,lifescience,medical first that the symptoms of acute grief result from a temporary failure of biobehavioral regulatory functions resulting from the mental representation of the deceased person, much like what has been described above.22 Acute grief resolves as the bereaved person assimilates the finality

of the loss, and this knowledge is integrated into attachment-related long-term memory and mental schemas. This allows an effective attachment system to function Inhibitors,research,lifescience,medical again, and there is a reduction of overwhelming and intense sadness. Although Inhibitors,research,lifescience,medical acute grief is usually followed by resilient adjustment,23 Shear and Shair22 suggest that adjustment to the death may become complicated by maladaptive attitudes and behaviors (and perhaps new evidence will be discovered that includes physiological constraints of the neurobiological attachment system). Creating a neurobiological model of CG faces a problem with the lack of evidence on a basic point. Does CG represent merely a person with acute grief whose process of adaptation has been interrupted, or does CG represent a wholly other process from noncomplicated bereavement adjustment? For example, CG may stem from a pre-existing individual difference, which is already present Chlormezanone at the time of the death of the attachment figure. However, it may require the removal of the attachment figure for this pre-existing condition to be revealed in behavior. Immunological biomarkers of grief The effect of bereavement on the immune system has been empirically documented since the 1970s. Bartrop and colleagues24 measured T-cell and B-cell functioning in widows at 2 weeks and 8 weeks following the death, and in controls.

Knowing the substrate of the

resilience to cognitive decline in the presence of abundant AD and/or mixed pathology might be crucial not only for the GDC-0199 purchase understanding of the pathophysiology of nondemented aged people, but also to discover new prophylactic and/or therapeutic targets for aging processes. As expected from the significant clinicopathologic Inhibitors,research,lifescience,medical correlations of synaptic and neuronal loss in AD, “high-pathology nondemented” controls have preserved densities of synaptophysinlabeled presynaptic terminals and dendritic spines as compared with AD dementia patients with a similar burden of plaques and tangles.99,168 Greater amounts of specific presynaptic proteins and distinct protein-protein intreactions may

be components of cognitive reserve that reduce the risk of dementia with aging.168 They may have no significant neuronal loss, not even in vulnerable regions, such as the entorhinal cortex and hippocampus,54,169 and have lower levels of neuroinflammatory markers than pathology-matched AD patients.170 This Inhibitors,research,lifescience,medical resistance to AD pathology has also been related to a nucleolar, nuclear, and cell body hypertrophy of the hippocampal and cortical neurons, suggestive of a compensatory metabolic activation to face the neurotoxic effects of AD lesions.108,171 Resilience to AD is also attributed to genetic factors, particularly apolipoprotein Inhibitors,research,lifescience,medical E2 and combinations of other genetic polymorphisms.172 Premorbid brain volume has been found to provide protection against clinical manifestation of dementia despite evidence of AD pathology, supporting the brain reserve hypothesis Inhibitors,research,lifescience,medical of resilience to AD.173 Although multiple factors and possible interventions may influence cognitive reserve and susceptibility to dementia, much work is required on the mechanisms of action in order to determine which, if any, may

improve the clinical Inhibitors,research,lifescience,medical and epidemiological picture.174 On the other hand, the unique observation of a cognitively intact woman aged 115 years with only slight tau pathology corresponding to Braak stage II, almost no plaques or vascular changes, and normal neuron count in the locus ceruleus indicates that the limits of human cognitive function extend far beyond the range that is currently enjoyed by most individuals and that brain disease, even in supercentenarians, is not inevitable.175 The association between Linifanib (ABT-869) “vulnerability” and “protective” factors varies with age, since the effects of these factors on the risk for AD may differ in younger (age <80) versus older (age >80) individuals. The understanding of the dynamic of these factors at different age periods will be essential for the implementation of primary prevention treatments for AD.176 TABLE I. Summary of key points on cerebral aging. The importance of understanding ageing and the complex interplay of multiple influences on successful cognitive ageing is clear.

Figure 7(a) shows an image of a DU145 prostate tumor in a nude mouse obtained with the system following intravenous administration

of PLGA NP (same NP as described in Figure4(b)). The system was capable of detecting the distribution of an unlabeled ultrasound contrast agent (UCA, VisualSonics) and allowed its visualization in the tumor (the areas with high concentration are represented in green). A specially developed computer code allowed to quantify kinetics of this UCA in the tumor (Figure 7(a), right panel). Inhibitors,research,lifescience,medical There was a sharp increase of the concentration in the whole tumor within first 2 to 3 seconds after the injection that was followed by a wash-out process (decrease of the contrast intensity). The necrotic Inhibitors,research,lifescience,medical areas

at the center of the tumor had similar kinetics but less concentration of the UCA due to lower vascularization (Figure 7(b), left panel). In contrast, injection of the PLGA nanoparticles into the same mouse (after clearance from the UCA) demonstrated almost constant concentration of the PLGA nanoparticles 15 seconds after the injection (Figure 7(b) -(2)). This effect resulted from competition of two processes: (1) the Inhibitors,research,lifescience,medical decrease of nanoparticles concentration in blood and (2) the increase of their concentration in the tumor blood vessels due to the EPR effect. Moreover, the contrast intensity MG-132 mouse produced by the PLGA nanoparticles (~175) was much higher compared to that of the UCA (~100). These data indicate Inhibitors,research,lifescience,medical that high-resolution ultrasound small animals imaging systems are able to detect the PLGA nanoparticles in tumors in vivo and that these nanoparticles are highly echogenic. Figure 7 Inhibitors,research,lifescience,medical . Echogenic PLGA nanoparticles can be utilized also as ultrasound contrast agents in vivo. (a) (1) A tumor image obtained with the high-resolution ultrasound system VEVO770 (VisualSonics). (2) Kinetics of the contrast agent in the whole tumor shown in … Further modifications can be made to echogenic PLGA NP to enhance their

potential for longer circulation half-life and for enabling tumor-specific targeting. For example, surface modifications can be made to polymeric nanoparticles to add PEGylated phospholipids in order to escape GPX6 recognition and clearance by the mononuclear phagocyte system and achieve passive tumor targeting. Nanoparticles consisting of a shell of PLGA encapsulating a liquid core of perfluorooctyl bromide (PFOB) can be decorated with poly(ethylene glycol-2000)-grafted distearoylphosphatidylethanolamine (DSPE-PEG) and resulting particles still are echogenic and can allow visualization of MIA-PaCa-2 pancreatic tumors in vivo, following intratumoral or intravenous injection (Figure 8(a)). In this example, the tumor was visualized only following intratumoral UCA injection.

Several types of SMAs have been described based on age onset of clinical features: Acute infantile (SMA type I), chronic infantile (SMA type II), chronic juvenile (SMA type III), and adult onset (SMA type IV) forms. The incidence is about 1:6,000 live births with a carrier frequency of 1:40 for the severe form and 1:80 for the juvenile form. The mortality and/or morbidity rates of SMAs are inversely correlated

with the age at onset. SMAs are believed to only affect skeletal muscles; however, new data on SMA mice models suggest they may also impact the heart. Aim of the study was to retrospectively examine the cardiological records of 37 type molecularly Inhibitors,research,lifescience,medical confirmed II/III SMA patients, aged 6 to 65 years, in order to evaluate the onset and evolution of the cardiac involvement in these disorders. All patients had a standard ECG and a routine echocardiography. The parameters analysed were the following: Heart rate (HR), PQ interval, PQ segment, Cardiomyopathic Index (ratio QT/PQs), ventricular and supraventricular ectopic beats, pauses ≥ 2,5msec, ventricle Inhibitors,research,lifescience,medical diameters, wall and septum thickness, ejection fraction, fiber shortening. The results showed that HR and the other ECG parameters were within the normal limits Inhibitors,research,lifescience,medical except for

the Cardiomyopathic Index that was higher than the normal values (2,6-4,2) in 2 patients. Left ventricular systolic function was within the normal limits in all patients. A dilation of the left ventricle without systolic dysfunction was observed in only 2 patients, Inhibitors,research,lifescience,medical aged respectively 65 and 63 years; however they were hypertensive and/or affected by coronary artery disease. Data here reported contribute to reassure patients and their clinicians

that type II/III SMAs do not present heart dysfunction. Key words: Spinal Muscular Atrophies, Inhibitors,research,lifescience,medical heart involvement, cardiomyopathy Background Spinal muscular atrophies (SMAs) refer to a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to weakness of the lower motor neurons and progressive muscular atrophy. Several types of SMAs have been described based on age onset of clinical features: Acute infantile (SMA type I), Chronic infantile others (SMA type II), Chronic juvenile (SMA type III), and Adult onset (SMA type IV) forms (1). The incidence is about 1:6,000 live births with a mean carrier frequency of 1:50. The mortality and/or morbidity rates of SMAs are inversely AZD5363 chemical structure correlated with the age at onset. Deletions in the survival motor neuron (SMN) gene (5q11.2-5q13.3) are the major determinants of SMA phenotype (2-9) while deletions in the neuronal apoptosis inhibitory protein (NAIP) gene may correlate with the severity of SMA (10-12). Humans express a copy gene, SMN2, from the same region of chromosome 5q as a result of duplication and inversion. SMN2 is nearly identical to SMN1 (2-4); however, mutations in SMN2 have no clinical consequence if intact SMN1 is present.

In a recent meta-analysis, Ciliberto et al. [51] described a statistically superiority in terms of survival and response rate for gemcitabine-based combination compared to gemcitabine alone. Moreover, this advantage was marginal and at the cost of an increased toxicity. The authors concluded that in the era of targeted therapy new approaches were possible only in presence Inhibitors,research,lifescience,medical of solid preclinical

findings. A report by von Hoff et al. [31] demonstrated in a phase I/II study an interesting activity of gemcitabine/nab-paclitaxel combination at gemcitabine 1000mg/m2 and nab-paclitaxel at 125mg/m2 doses weekly for three doses in a 4 week schedule. A 48% response rate was achieved at MTD. The authors additionally demonstrated that SPARC-expressing tumors appeared more sensitive to the drug combination. An interesting finding from a preclinical study reported that nab-paclitaxel demonstrated the Inhibitors,research,lifescience,medical capacity of increasing the gemcitabine bioavailability inside the tumors. These findings led to the design of a phase

III study where gemcitabine/nab-paclitaxel was compared to gemcitabine alone showing an Inhibitors,research,lifescience,medical advantage in OS, PFS, and RR. This study, presented to ASCO GI 2013 (American Society of Clinical Oncology, Gastrointestinal Cancer Symposium) by von Hoff, is clearly a changing practice study and the gemcitabine/nab-paclitaxel, which led to an almost two month longer OS should be now compared to FOLFIRINOX combination (Table 2). The biological bases of the synergistic interaction between nab-paclitaxel and gemcitabine have recently been elucidated by an in vivo study in animal models. In detail, the combination treatment was administered to KPC mice that develop advanced Inhibitors,research,lifescience,medical and metastatic pancreas ductal adenocarcinoma. The authors have demonstrated an increase of intratumoral gemcitabine levels attributable to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase. Correspondingly, paclitaxel reduced the levels of cytidine deaminase

protein in cultured cells through reactive oxygen species-mediated ABT-888 order degradation, Inhibitors,research,lifescience,medical resulting in the increased stabilization of gemcitabine. These findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PC [52]. This study provides mechanistic insight into the Thiamine-diphosphate kinase clinical cooperation observed between gemcitabine and nab-paclitaxel in the treatment of pancreatic cancer. Table 2 Randomized phase I/II and III trials with nab-paclitaxel in aPC. 5. Other Areas of Nab-Paclitaxel Development Melanoma represents 5% and 4% of all cancers in males in females, respectively. However, the rates of incidence of melanoma are steadily increasing in the USA as in most parts of Europe [53]. The survival rates of melanoma become worse with advancing stage. Therefore, early diagnosis in addition to surgical treatment before its spread is the most effective treatment.

OROS® hydromorphone may be particularly

well suited to the long-term management of cancer pain because it provides consistent plasma concentrations, sustained analgesia, and convenient once-daily dosing. In this open-label, single treatment extension study, OROS® hydromorphone was administered to patients with moderate-to-severe chronic cancer pain who had successfully completed a previous short-term equivalence study and whose pain was controlled with a stable dose of medication. Prior opioid therapy in the previous equivalence study (OROS® hydromorphone versus CR morphine) did not affect clinical outcomes such as efficacy or safety in this study. The results demonstrate that pain control achieved Inhibitors,research,lifescience,medical with OROS® hydromorphone is maintained for up to Inhibitors,research,lifescience,medical 1 year with repeated once-daily dosing in patients with chronic cancer pain. This was shown using a variety of measures, including the BPI items pain at its worst, pain at its

least, pain on average, current pain, and pain relief, and patient and investigator global evaluations of overall treatment effectiveness. Throughout the study, pain scores were maintained at mild to moderate levels. These results support short-term studies of OROS® hydromorphone for chronic Inhibitors,research,lifescience,medical cancer pain [20-22,34]. In addition, the degree to which patients’ cancer pain interfered with their general activity, mood, ability to walk, work, relationships, sleep, and enjoyment of life was also maintained, suggesting that there was no Selleck PD0332991 worsening of QoL during the year. This has been demonstrated before; previous studies have shown a positive impact on QoL with CR opioid formulations [11,48]. There were no clear differences in the Inhibitors,research,lifescience,medical results when comparing patients who had received OROS® hydromorphone or CR morphine in the previous equivalence study. Although most efficacy measures were maintained at similar levels Inhibitors,research,lifescience,medical throughout the study, for most

measures, the mean scores were slightly worsened at end point compared with baseline. However, owing to the progressive nature of the disease, some deterioration is to be expected. The most commonly Idoxuridine reported AEs, with an incidence of at least 10%, were nausea, constipation, vomiting, anaemia, peripheral oedema, dyspnoea, asthenia, disease progression, somnolence, and urinary tract infection. These are events typically seen with the use of strong opioids or in a chronic cancer pain population. Slightly more AEs overall and AEs considered related to study treatment were reported in patients who had previously received OROS® hydromorphone compared with CR morphine in the equivalence study; however, the clinical significance of this difference is questionable because of the degree and nature of AEs expected in an advanced cancer population. In addition, the majority of AEs were mild or moderate in severity.

24 Tolerance was seen only in relation to effects like hyperthermia, hypertonia, and anorexia, but not psychomotor stimulation.31,34,35 It should be stressed that the aforementioned side effects are observed not only

in depressed patients, but also in patients treated with psychostimulants for other indications. Development of dependency or tendency to abuse? The possible development of dependency and a withdrawal syndrome Inhibitors,research,lifescience,medical after withdrawing amphetamines has been a controversial issue. Addiction was reported by Kramer et al3 and Edison,36 and a withdrawal syndrome characterized by apathy, decreased activity, and sleep disturbances with an increase in rapid eye movement (REM) sleep Inhibitors,research,lifescience,medical by Oswald and Thacore37 and Watson et al.38 Most studies, however,

report, little or no dependence in depressed patients treated with amphetamines (see overview in refs 2 and 23). Psychostimulants may be withdrawn after several weeks of treatment without any danger of recurrence of depression.21 No tolerance or addiction has been reported to develop in geriatric patients. However, recurrence of mild depression, tiredness, and anxiety have been reported on stopping treatment with psychostimulants.39 Inhibitors,research,lifescience,medical Development of tolerance or abuse after patients are discharged from hospital is practically never reported.22,24,40 Dosage The dosage of the psychostimulants must imperatively be individually adjusted. The daily doses usually recommended in treatment-resistant depressed patients range between 2.5 mg41 and 15 mg20 for amphetamine and between 10 and 60 mg for methylphenidate.42 Indications in depressive disorders Inhibitors,research,lifescience,medical Some depressive disorders remain refractory to treatment despite intensive antidepressant therapy with adequate dosages and even combinations of antidepressants.43,44 These cases may benefit from adjuvant treatment with Inhibitors,research,lifescience,medical psychostimulants. The mood-elevating effects of the tricyclics, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAOIs) usually only manifest, after 10 to 12

days. Side effects and drug interactions are quite common with these drugs. Although psychostimulants themselves are not as effective as conventional antidepressants,45,46 they have the dual advantage of a more rapid onset of action and of inducing a lower rate of adverse events. Because their acute effects develop within less no than a few hours,20 they may be used in combination with traditional antidepressants in order to cover the lattcr’s therapeutic selleck kinase inhibitor latency period and potentiate their effect.13,35 In a review of the literature, Chiarello and Cole2 showed that the majority of studies – even though some were methodologically unsatisfactory – reported beneficial effects following administration of psychostimulants in treatment-resistant depression.

05 was used for all statistical tests. The lack of any interaction with

List (Fs < 1) indicates that the counterbalancing of items in the four experimental lists did not introduce variance in the results. Therefore, all further tests were performed on data collapsed across list. We then submitted the correct behavioral RTs to one-way ANOVAs with Inhibitors,research,lifescience,medical the within-subject factor Relatedness. The main effect of Relatedness was significant for participants (F11,17 = 4.43, P = 0.5, mean square error = 1850.1), indicating that the averaged correct response times were significantly faster for the related (813 msec, SEM = 25) than for the unrelated (843 msec, SEM = 29) condition. In contrast, the main effect Relatedness was not significant for items (F2 < 1). Table 2 Reaction times to correctly answered trials We included Inhibitors,research,lifescience,medical the neutral condition into the experimental design to control for inhibition effects. Behavioral analyses of RTs of the related, unrelated, and neutral condition showed that we observed facilitation but not inhibition effects. Two-tailed paired t-tests revealed that the mean RT of the neutral condition Inhibitors,research,lifescience,medical (894 msec [SEM: 21 msec]) was significantly longer

than the mean RTs of the related (t = 5.337, P < 0.001) and the unrelated conditions (t = 3.082, P < 0.001). Accuracy The error data (in %) are presented in Table ​Table3.3. Relatedness had no effect on errors (Fs < 1). Table 3 Task accuracy: percentages of error Experiment 2 Behavioral data obtained postscanning outside the MRI scanner We assessed accuracy rates for hits (old words correctly identified as “old”) and correct rejections (new words correctly classified

Inhibitors,research,lifescience,medical as “new”). The mean accuracy rates were 80% (SEM = 3%) for hits and 90% (SEM = 2%) for correct rejections. A significant positive correlation between hits and correct rejections (r = 0.56) was found. This correlation indicates Inhibitors,research,lifescience,medical that participants showing a high accuracy rate for hits, showed as well a high accuracy rate for correct rejections. Imaging data All results of the 2 × 2 full-factorial ANOVA and the conjunction analysis are based on Fluorouracil manufacturer whole-brain analyses surviving a significance threshold of P < 0.001 and represent clusters of at least 25 connected voxels. The 2 × 2 full-factorial Ketanserin ANOVA with the within-subject factor Relatedness and the between-subject factor Linguistic task revealed neural associative priming effects and Relatedness × Linguistic task interactions. Comparing neural activity with respect to the factor Linguistic task, no differences were apparent at a significance threshold of P < 0.001. The conjunction analysis revealed that semantic categorization and silently thinking about a word’s meaning activated an overlapping left-lateralized network of infero-temporal and inferior frontal brain areas.

This and other early (eg, refs 12-14) computational models of the BOLD phenomenon are currently understood to be largely accurate, albeit incomplete with respect to the mechanisms contributing to functional mapping signals. Some of these initially overlooked mechanisms (eg, inflow effects) form the basis of the successful use of #learn more randurls[1|1|,|CHEM1|]# lower

field strengths, such as 1.5 T, for the acquisition of functional images in human brain. Nevertheless, increased understanding of the origin of fMRI signals (see ref 15 and references therein) Inhibitors,research,lifescience,medical have also reconfirmed original expectations that there are major advantages in going to very high magnetic fields, and these have largely been experimentally verified by a plethora of studies

conducted with animal models (eg, refs 1, 16-18). For example, in Inhibitors,research,lifescience,medical fMRI, the contrast-to-noise ratio (CNR) of deoxyhemoglobin-based BOLD mapping signals increases linearly in high-resolution imaging for gradient echo (GE)-based techniques, the predominant approach employed in contemporary fMRI experiments. (Contrast in fMRI is defined as the magnitude of the signal change induced by a stimulus or a task. Contrast-to Inhibitors,research,lifescience,medical noise ratio CNR is the ratio of the contrast to the signal fluctuations in the fMRI time series). When image resolution is high, the latter is dominated by the “thermal” noise present in each image of the time series. At low resolution, CNR for GE fMRI increases less than linearly with field magnitude since the temporal fluctuations of signals become dominated by physiological processes (rather than thermal noise) and display a dependence on signal amplitude, hence magnetic field magnitude. For spin echo (SE) BOLD fMRI, which provides more accurate functional Inhibitors,research,lifescience,medical localization,1,16-17 albeit only at high magnetic

fields and with smaller signal changes1,9,20 CNR can exhibit more than a linear dependence on magnetic field magnitude because of suprallnear gains in fractional signal change induced by neuronal activity19-20 and a linear Inhibitors,research,lifescience,medical elevation in intrinsic many image signal-to-noise ratio (SNR).21 The gains in fractional signal change, however, tend to level off at fields above -9 to 10 Tesla,15 leaving the SNR gains as the only potential source of CNR improvements. More importantly, however, higher magnetic fields provide significantly better spatial fidelity in the deoxyhemoglobin-based functional mapping signals (eg, refs 1,16,17). fMRI relies on secondary metabolic and vascular responses invoked by alterations in neuronal activity. Therefore, its accuracy can be degraded by limitations imposed by these secondary responses. However, in a critical experiment performed in the cat visual cortex, it was demonstrated that blood flow increase induced by functional activation is regulated at the level of orientation columns.

32, P = 0.005; grade 4 = 0.77, P = 0.001) [66]. Although there was a clinically relevant improvement in DED symptoms from baseline the Cyclokat and cationic emulsion vehicle treatment arms, no statistically significant differences were observed at month 6 for the mean Adriamycin price change in the global score of ocular discomfort, the DED symptom

coprimary efficacy endpoint. However, there was a statistically significant improvement in symptoms for patients achieving a ≥25% improvement in the VAS score (50.21% versus 41.94%, P = 0.048). The difficulty in demonstrating the benefit of Cyclokat over Inhibitors,research,lifescience,medical its cationic emulsion vehicle was in part attributed to the efficacy of the vehicle itself in improving the symptoms of DED as demonstrated in clinical trials for Cationorm. Additionally, the symptoms coprimary endpoint result can be related to poor correlation between dry eye disease signs and symptoms. At baseline in the Siccanove study, while the mean VAS scores increased with the severity of the CFS, the correlation Inhibitors,research,lifescience,medical between the VAS score, as an expression of DED symptoms, and the CFS grade, as an expression Inhibitors,research,lifescience,medical of a DED sign, at baseline was low (Spearman’s correlation coefficient = 0.23) due to the wide variability in the severity of patient

reported symptoms. Similarly at month 6 the statistical correlation between mean change in CFS grade and VAS score was low (Spearman’s correlation coefficient = 0.094) with only approximately 68% of patients showing Inhibitors,research,lifescience,medical concordance in the direction of change in CFS grade and DED symptoms [65]. Although a poor concordance between dry eye disease signs and symptoms has been recognized in the literature, improvement in both signs and symptoms is an expected outcome in randomized clinical trials investigating new DED treatments. Hence several drugs having shown promise for improving DED have failed due to the inability to demonstrate a statistically significant improvement in signs and symptoms of dry eye disease Inhibitors,research,lifescience,medical using coprimary efficacy endpoints. Fortunately,

sign and symptom composite responder endpoints, used in registration trial supporting the approval of new treatments for other chronic inflammatory diseases, provide an alternate method to satisfy the requirement of regulatory authorities. The methodological approach and of composite responder analysis avoids issues related to high variability when following mean change of signs and symptoms as discontinuous variables. By focusing only on within-patient’s improvements, the composite responder approach could resolve the concern related to the poor correlation between signs and symptoms in evaluating the efficacy of new treatment for DED. As such a pivotal phase III trial, the Sansika study, utilizing a composite responder analysis at month 6, has been initiated to evaluate the efficacy of Cyclokat in patients with severe dry eye disease. 6.