High-protein home parenteral nutrition in malnourished oncology patients: a systematic literature review.

INTRODUCTION: Up to 83% of oncology patients are affected by cancer-related malnutrition, depending on tumour location and patient age. Parenteral nutrition can be used to manage malnutrition, but there is no clear consensus as to the optimal protein dosage. The objective of this systematic literature review (SLR) was to identify studies on malnourished oncology patients receiving home parenteral nutrition (HPN) where protein or amino acid delivery was reported in g/kg bodyweight/day, and to compare outcomes between patients receiving low (< 1 g/kg bodyweight/day), standard (1-1.5 g/kg/day), and high-protein doses (> 1.5 g/kg/day). METHODS: Literature searches were performed on 5th October 2021 in Embase, MEDLINE, and five Cochrane Library and Centre for Reviews and Dissemination databases. Searches were complemented by hand-searching of conference proceedings, a clinical trial registry, and bibliographic reference lists of included studies and relevant SLRs/meta-analyses. RESULTS: Nineteen publications were included; sixteen investigated standard protein, two reported low protein, and one included both, but none assessed high-protein doses. Only one randomised controlled trial (RCT) was identified; all other studies were observational studies. The only study to compare two protein doses reported significantly greater weight gain in patients receiving 1.15 g/kg/day than those receiving 0.77 g/kg/day. CONCLUSION: At present, there is insufficient evidence to determine the optimal protein dosage for malnourished oncology patients receiving HPN. Data from non-HPN studies and critically ill patients indicate that high-protein interventions are associated with increased overall survival and quality of life; further studies are needed to establish whether the same applies in malnourished oncology patients.

Case report: Concomitant use of nightly vitamin A ointment with daily PROSE wear for ocular surface disease associated with chronic Stevens-Johnson syndrome.

Purpose: To describe a case of chronic ocular surface disease associated with Stevens-Johnson Syndrome (SJS) in which the addition of nightly topical ophthalmic preservative free vitamin A ointment to the daily use of a customized ocular surface prosthetic device (PROSE) appears to mitigate disease progression. Observations: A 51-year-old female with SJS secondary to lamotrigine use presented for follow up evaluation. Ocular history was significant for acute SJS twenty-four years prior with chronic ocular surface sequelae predominantly affecting the left eye. The condition had been stabilized without progression by utilizing long term PROSE daytime wear along with nightly application of topical ophthalmic vitamin A ointment. The patient reported non-compliance with vitamin A ointment use for the prior three months. The ocular surface examination of the left eye was notable for significantly progressed inferior keratinization and neovascularization which had been unchanged over the course of the three prior annual exams. After restarting nightly topical ophthalmic vitamin A ointment and continuing regular PROSE use, there was no further ocular surface disease progression in the ensuing 4 years of follow up. Conclusion and Importance: The use of nightly topical ophthalmic vitamin A ointment may be a viable adjuvant therapy alongside daily PROSE use for progressive chronic SJS ocular surface disease.

Comparative efficacy and safety of bimekizumab in axial spondyloarthritis: a systematic literature review and network meta-analysis.

OBJECTIVES: To compare the efficacy and safety of bimekizumab 160 mg every 4 weeks, a selective inhibitor of interleukin­17F and 17A, with biologic/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS). METHODS: A systematic literature review identified randomised controlled trials until January 2023 for inclusion in Bayesian network meta-analyses (NMAs), including three b/tsDMARDs exposure networks: predominantly-naïve, naïve, and experienced. Outcomes were Assessment of SpondyloArthritis international Society (ASAS)20, ASAS40, and ASAS partial remission (PR) response rates at 12-16 weeks. A safety NMA investigated discontinuations due to any reason and serious adverse events at 12-16 weeks. RESULTS: The NMA included 36 trials. The predominantly-naïve network provided the most comprehensive results. In the predominantly-naïve nr-axSpA analysis, bimekizumab had significantly higher ASAS20 response rates vs secukinumab 150 mg (with loading dose [LD]/without LD), and comparable response rates vs other active comparators. In the predominantly-naïve AS analysis, bimekizumab had significantly higher ASAS40 response rates vs secukinumab 150 mg (without LD), significantly higher ASAS-PR response rates vs secukinumab 150 mg (with LD), and comparable response rates vs other active comparators. Bimekizumab demonstrated similar safety to other b/tsDMARDs. CONCLUSION: Across ASAS outcomes, bimekizumab was comparable to most b/tsDMARDs, including ixekizumab, TNF inhibitors and upadacitinib, and achieved higher response rates vs secukinumab for some ASAS outcomes in predominantly b/tsDMARD-naïve nr-axSpA and AS patients at 12-16 weeks. In a pooled axSpA network, bimekizumab demonstrated comparable safety vs other b/tsDMARDs.

Testosterone-Induced Central Serous Chorioretinopathy Mimicking a Choroidal Mass.

PURPOSE: To describe a case of supplemental testosterone-induced central serous chorioretinopathy (CSCR) mimicking a choroidal mass in a 63-year-old male. METHODS: Case report. PATIENT: A 63-year-old male patient on self-prescribed supplemental testosterone with CSCR mimicking a choroidal mass. RESULTS: A 63-year-old male presented with new onset vision loss, subretinal fluid, and choroidal mass in his left eye. Intravenous fluorescein angiography showed an enhancing choroidal mass involving the fovea. B scan ultrasonography revealed diffuse choroidal thickening. Given concern for a diffuse uveal melanoma, the lesion was biopsied showing non-diagnostic rare, atypical melanocytes. Four months after initial presentation, the patient was diagnosed with polycythemia vera. Fourteen months after diagnosis, he admitted to testosterone supplementation. Upon cessation of the testosterone supplement, the lesion progressively flattened to a chorioretinal scar with subretinal fluid resolution, and the return of normal choroidal thickness over the next 14 months. DISCUSSION: Testosterone supplementation has been linked to erythrocytosis and polycythemia vera. In the retina, testosterone supplementation has been linked to CSCR and both central and branch retinal artery and vein occlusions. This case demonstrates the importance of inquiring about all prescribed and over the counter medications in patients presenting with retinal lesions of unknown origin.

Photochemistry and Photophysics of Charge-Transfer Excited States in Emissive d10/d0 Heterobimetallic Titanocene Tweezer Complexes.

Transition-metal complexes that undergo ligand-to-metal charge transfer (LMCT) to d0 metals are of interest as possible photocatalysts due to the lack of deactivating d-d states. Herein, the synthesis and characterization of nine titanocene complexes of the formula Cp2Ti(C2Ar)2·MX (where Ar = phenyl, dimethylaniline, or triphenylamine; and MX = CuCl, CuBr, or AgCl) are presented. Solid-state structural characterization demonstrates that MX coordinates to the alkyne tweezers and CuX coordination has a greater structural impact than AgCl. All complexes, including the parent complexes without coordinated MX, are brightly emissive at 77 K (emission max between 575 and 767 nm), with the coordination of MX redshifting the emission in all cases except for the coordination of AgCl into Cp2Ti(C2Ph)2. TDDFT investigations suggest that emission is dominated by arylalkynyl-to-titanium 3LMCT in all cases except Cp2Ti(C2Ph)2·CuBr, which is dominated by CuBr-to-Ti charge transfer. In room-temperature fluid solution, only Cp2Ti(C2Ph)2 and Cp2Ti(C2Ph)2·AgCl are emissive, albeit with photoluminescent quantum yields ≤2 × 10-4. The parent complexes photodecompose in room-temperature solution with quantum yields, Φrxn, between 0.25 and 0.99. The coordination of MX decreases Φrxn by two to three orders of magnitude. There is a clear trend that Φrxn increases as the emission energy increases. This trend is consistent with a competition between energy-gap-law controlled nonradiative decay and thermally activated intersystem crossing between the 3LMCT state and the singlet transition state for decomposition.

Antipsychotic-Related Stigma and the Impact on Treatment Choices: A Systematic Review and Framework Synthesis.

BACKGROUND: Antipsychotics are a class of medications primarily used to treat individuals with psychotic disorders. They have also been indicated for patients with other psychiatric conditions, such as post-traumatic stress disorder and major depressive disorder. Non-adherence is prominent amongst individuals prescribed antipsychotics, with medication-related self-stigma and social stigma identified as major factors. No previous reviews have focused on stigma associated specifically with antipsychotic medication. This systematic literature review aimed to synthesise evidence on the prevalence of stigmatising attitudes and behaviours related to antipsychotic treatment and understand their impact on antipsychotic treatment initiation and continuation. METHODS: Two independent reviewers screened studies from databases, congress proceedings, ClinicalTrials.gov, and PsychU.org; relevant studies reported quantitative or qualitative data on antipsychotic-related stigma in adults with psychotic disorders, mood disorders, borderline personality disorder or anxiety disorders, or healthcare providers or caregivers of these patients, and any impact on treatment. Framework synthesis facilitated extraction and synthesis of relevant information; quantitative and qualitative data were coded and indexed against a pre-specified thematic framework by two independent reviewers. RESULTS: Forty-five articles reporting on 40 unique studies were included; 22 reported quantitative data, 16 reported qualitative data, and two reported quantitative and qualitative data relating to antipsychotic-related stigma. Framework synthesis identified four themes: 1) impact of antipsychotic treatment on a) social stigma or b) self-stigma; 2) impact of side effects of antipsychotic treatment on a) social stigma or b) self-stigma; 3) impact of route of administration of antipsychotic treatment on stigma; 4) impact of stigma on the use of antipsychotics. CONCLUSION: This systematic literature review found that antipsychotic-related social and self-stigma is a factor in non-adherence to antipsychotics. Further research should examine stigma in a wider range of patients and the extent to which clinicians' treatment decisions are impacted by the potential stigma associated with antipsychotic medications.

Ligand-to-Metal Charge-Transfer Photophysics and Photochemistry of Emissive d0 Titanocenes: A Spectroscopic and Computational Investigation.

Complexes with ligand-to-metal charge-transfer (LMCT) excited states involving d0 metals represent a new design for photocatalysts. Herein, the photochemistry and photophysics of d0 titanocenes of the type Cp2Ti(C2R)2, where C2R = ethynylphenyl (C2Ph), 4-ethynyldimethylaniline (C2DMA), or 4-ethynyltriphenylamine (C2TPA), have been investigated. Cp2Ti(C2Ph)2 and Cp2Ti(C2DMA)2 have also been characterized by single-crystal X-ray diffraction. The two aryl rings in Cp2Ti(C2DMA)2 are nearly face-to-face in the solid state, whereas they are mutually perpendicular for Cp2Ti(C2Ph)2. All three complexes are brightly emissive at 77 K but photodecompose at room temperature when irradiated into their lowest-energy absorption band. The emission wavelengths and photodecomposition quantum yields are as follows: Cp2Ti(C2Ph)2, 575 nm and 0.65; Cp2Ti(C2TPA)2, 642 nm and 0.42; Cp2Ti(C2DMA)2, 672 nm and 0.25. Extensive benchmarking of the density functional theory (DFT) model against the structural data and of the time-dependent DFT (TDDFT) model against the absorption and emission data was performed using combinations of 13 different functionals and 4 basis sets. The model that predicted the absorption and emission data with the greatest fidelity utilized MN15/LANL2DZ for both the DFT optimization and the TDDFT. Computational analysis shows that absorption involves a transition to a 1LMCT state. Whereas the spectroscopic data for Cp2Ti(C2TPA)2 and Cp2Ti(C2DMA)2 are well modeled using the optimized structure of these complexes, Cp2Ti(C2Ph)2 required averaging of the spectra from multiple rotamers involving rotation of the Ph rings. Consistent with this finding, an energy scan of all rotamers showed a very flat energetic surface, with less than 1.3 kcal/mol separating the minimum and maximum. The computational data suggest that emission occurs from a 3LMCT state. Optimization of the 3LMCT state demonstrates compression of the C-Ti-C bond angle, consistent with the known products of photodecomposition.

Comparative analysis of viral infection outcomes in human seminal fluid from prior viral epidemics and Sars-CoV-2 may offer trends for viral sexual transmissibility and long-term reproductive health implications.

BACKGROUND: Viral detection in seminal fluid indicates their potential for both sexual transmission and impairment of reproductive health. Review of the mechanistic entry, sexual transmission and viral impacts for patients during major recent viral outbreaks of Zika virus (ZIKV), Ebola virus (EBOV), severe acute respiratory syndrome (SARS)-coronavirus (CoV), and SARS-coronavirus 2 (CoV-2) (the virus which causes COVID-19) provides a framework to discuss this potential. AIM: Comparative analysis of prior viral presence on seminal fluid against current (preliminary) findings for SARS-CoV-2 to predict biological implications of the novel coronavirus upon current sexual transmissibility, viral presence, and reproductive health. METHODOLOGY AND FINDINGS: Literature review was conducted using PubMed and Google Scholar databases. ZIKV and EBOV were found to be present in semen and to be sexually transmitted, leading the World Health Organization (WHO) to update their guidelines on prevention of the two viruses to include refraining from sexual contact. There are conflicting studies regarding the presence of SARS-CoV in male reproductive tissue, but it has been linked to testicular atrophy and orchitis. To date, two studies have detected SARS-CoV-2 RNA in semen, while seven studies have reported no positive detection. CONCLUSIONS: Though unlikely in the majority of cases, SARS-CoV-2 can potentially be present in seminal fluid, although there are no reports of sexual transmission to date. Prior epidemics raise significant concerns regarding the long-term reproductive health capacity for patients who are affected by entry of Sars-CoV-2 into the reproductive tract, therefore more study is needed to clarify the impacts to reproductive health.

This review describes the detection of viruses in seminal fluid and their sexual transmission, focusing on the major viral outbreaks of Zika virus (ZIKV), Ebola virus (EBOV), severe acute respiratory syndrome (SARS)-coronavirus (CoV), and SARS-coronavirus 2 (CoV-2). ZIKV and EBOV were found to be present in semen and to be sexually transmitted, leading the World Health Organization (WHO) to update their guidelines on prevention of the two viruses to include refraining from sexual contact. There are conflicting studies regarding the presence of SARS-CoV in male reproductive tissue, but it has been linked to testicular atrophy and orchitis. To date, two studies have detected SARS-CoV-2 RNA in semen, while seven studies have reported no positive detection. More studies must be completed to accurately determine its risk of sexual transmission to ensure mitigation of further transmission and understand the long-term implications of SARS-CoV-2 on the reproductive health of recovered patients.

Moderate early life stress improves adult zebrafish (Danio rerio) working memory but does not affect social and anxiety-like responses.

Early life stress (ELS) is defined as a short or chronic period of trauma, environmental or social deprivation, which can affect different neurochemical and behavioral patterns during adulthood. Zebrafish (Danio rerio) have been widely used as a model system to understand human neurodevelopmental disorders and display translationally relevant behavioral and stress-regulating systems. In this study, we aimed to investigate the effects of moderate ELS by exposing young animals (6-weeks postfertilization), for 3 consecutive days, to three stressors, and analyzing the impact of this on adult zebrafish behavior (16-week postfertilization). The ELS impact in adults was assessed through analysis of performance on tests of unconditioned memory (free movement pattern Y-maze test), exploratory and anxiety-related task (novel tank diving test), and social cohesion (shoaling test). Here, we show for the first time that moderate ELS increases the number of alternations in turn-direction compared to repetitions in the unconditioned Y-maze task, suggesting increased working memory, but has no effect on shoal cohesion, locomotor profile, or anxiety-like behavior. Overall, our data suggest that moderate ELS may be linked to adaptive flexibility which contributes to build "resilience" in adult zebrafish by improving working memory performance.

Oxidatively stable ferrocenyl-π-bridge-titanocene D-π-A complexes: an electrochemical and spectroscopic investigation of the mixed-valent states.

The synthesis, spectroscopic, and electrochemical characterization of oxidatively stable D-π-A compounds of the form (Me2CpC2Fc)2TiCl2 and RCp2Ti(C2Fc)2CuX (where Fc = ferrocenyl) are reported. Oxidative stability enabled by the addition of CuX is evidenced by voltammagrams of the RCp2Ti(C2Fc)2CuX compounds which all display two chemically-reversible 1e- FeIII/II couples, indicative of electronic communication between the Fc- termini. Differential pulse voltammetry (DPV) in CH2Cl2/[n-Bu4N][PF6], demonstrated that the redox potential difference between the two 1e- FeIII/II couples (ΔE1/2) is between 112 mV and 146 mV, being most pronounced with the electron rich Cp*2Ti(C2Fc)2CuBr. The ΔE1/2 values were unaffected by solvent (THF) and displayed only a small dependence on the identity of the counterion, either PF6- or B(C6F5)4-. For each complex with a measurable ΔE1/2 value, spectroelectrochemical experiments were performed in CH2Cl2/[n-Bu4N][PF6] and gave clear evidence of both the one-electron oxidized mixed-valent (MV) state and the two-electron oxidized state, each with distinct spectroscopic signatures. The MV states of these complexes showed absorbance between 820 and 940 nm which were replaced with a higher energy feature following a second oxidation. A very similar absorption band was also observed in the one-electron oxidized state of an analogue with only a single Fc substituent, namely TMSCp2Ti(C2Fc)(C2Ph)CuBr, suggesting this feature is not an FeII/FeIII intravalence charge-transfer (IVCT) band. Despite DFT calculations suggesting a pathway exists for electronic coupling, NIR spectroscopy on the MV states gave no evidence of an FeII/FeIII IVCT. Possible contributions to ΔE1/2 from inductive effects and a superexchange mechanism are discussed.

No FAD, No CRY: Redox and Circadian Rhythms.

There is growing evidence of reciprocal interactions between the endogenous circadian clock and subcellular redox pathways. Recently, researchers at the University of California unearthed another possible link between redox metabolism and the mammalian circadian clock: the redox cofactor FAD stabilises the clock protein cryptochrome (CRY), modifying rhythmic clock gene expression.

Searching for cognitive enhancement in the Morris water maze: better and worse performance in D-amino acid oxidase knockout (Dao(-/-)) mice.

A common strategy when searching for cognitive-enhancing drugs has been to target the N-methyl-d-aspartate receptor (NMDAR), given its putative role in synaptic plasticity and learning. Evidence in favour of this approach has come primarily from studies with rodents using behavioural assays like the Morris water maze. D-amino acid oxidase (DAO) degrades neutral D-amino acids such as D-serine, the primary endogenous co-agonist acting at the glycine site of the synaptic NMDAR. Inhibiting DAO could therefore provide an effective and viable means of enhancing cognition, particularly in disorders like schizophrenia, in which NMDAR hypofunction is implicated. Indirect support for this notion comes from the enhanced hippocampal long-term potentiation and facilitated water maze acquisition of ddY/Dao(-) mice, which lack DAO activity due to a point mutation in the gene. Here, in Dao knockout (Dao(-/-) ) mice, we report both better and worse water maze performance, depending on the radial distance of the hidden platform from the side wall of the pool. Dao(-/-) mice displayed an increased innate preference for swimming in the periphery of the maze (possibly due to heightened anxiety), which facilitated the discovery of a peripherally located platform, but delayed the discovery of a centrally located platform. By contrast, Dao(-/-) mice exhibited normal performance in two alternative assays of long-term spatial memory: the appetitive and aversive Y-maze reference memory tasks. Taken together, these results question the proposed relationship between DAO inactivation and enhanced long-term associative spatial memory. They also have generic implications for how Morris water maze studies are performed and interpreted.

Circadian Clocks in the Hematologic System.

The hematologic system performs a number of essential functions, including oxygen transport, the execution of the immune response against tumor cells and invading pathogens, and hemostasis (blood clotting). These roles are performed by erythrocytes (red blood cells), leukocytes (white blood cells), and thrombocytes (platelets), respectively. Critically, circadian rhythms are evident in the function of all 3 cell types. In this review, we describe these oscillations, explore their mechanistic bases, and highlight their key implications. Since erythrocytes are anucleate, circadian rhythms in these cells testify to the existence of a nontranscriptional circadian clock. From a clinical perspective, leukocyte rhythms could underlie daily variation in the severity of allergic reactions, the symptoms of chronic inflammatory diseases, and the body's response to infection, while the rhythmic properties of thrombocytes may explain daily fluctuations in the incidence of heart attack and stroke. Consequently, the efficacy of treatments for these conditions is likely to depend on the timing of their administration. Last, we outline preliminary evidence that circadian disruption in the hematologic system could contribute to the deleterious effects of poor diet, shift work, and alcohol abuse on human health.

Deletion of Metabotropic Glutamate Receptors 2 and 3 (mGlu2 & mGlu3) in Mice Disrupts Sleep and Wheel-Running Activity, and Increases the Sensitivity of the Circadian System to Light.

Sleep and/or circadian rhythm disruption (SCRD) is seen in up to 80% of schizophrenia patients. The co-morbidity of schizophrenia and SCRD may in part stem from dysfunction in common brain mechanisms, which include the glutamate system, and in particular, the group II metabotropic glutamate receptors mGlu2 and mGlu3 (encoded by the genes Grm2 and Grm3). These receptors are relevant to the pathophysiology and potential treatment of schizophrenia, and have also been implicated in sleep and circadian function. In the present study, we characterised the sleep and circadian rhythms of Grm2/3 double knockout (Grm2/3-/-) mice, to provide further evidence for the involvement of group II metabotropic glutamate receptors in the regulation of sleep and circadian rhythms. We report several novel findings. Firstly, Grm2/3-/- mice demonstrated a decrease in immobility-determined sleep time and an increase in immobility-determined sleep fragmentation. Secondly, Grm2/3-/- mice showed heightened sensitivity to the circadian effects of light, manifested as increased period lengthening in constant light, and greater phase delays in response to nocturnal light pulses. Greater light-induced phase delays were also exhibited by wildtype C57Bl/6J mice following administration of the mGlu2/3 negative allosteric modulator RO4432717. These results confirm the involvement of group II metabotropic glutamate receptors in photic entrainment and sleep regulation pathways. Finally, the diurnal wheel-running rhythms of Grm2/3-/- mice were perturbed under a standard light/dark cycle, but their diurnal rest-activity rhythms were unaltered in cages lacking running wheels, as determined with passive infrared motion detectors. Hence, when assessing the diurnal rest-activity rhythms of mice, the choice of assay can have a major bearing on the results obtained.

d-amino acid oxidase knockout (Dao(-/-) ) mice show enhanced short-term memory performance and heightened anxiety, but no sleep or circadian rhythm disruption.

d-amino acid oxidase (DAO, DAAO) is an enzyme that degrades d-serine, the primary endogenous co-agonist of the synaptic N-methyl-d-aspartate receptor. Convergent evidence implicates DAO in the pathophysiology and potential treatment of schizophrenia. To better understand the functional role of DAO, we characterized the behaviour of the first genetically engineered Dao knockout (Dao(-/-) ) mouse. Our primary objective was to assess both spatial and non-spatial short-term memory performance. Relative to wildtype (Dao(+/+) ) littermate controls, Dao(-/-) mice demonstrated enhanced spatial recognition memory performance, improved odour recognition memory performance, and enhanced spontaneous alternation in the T-maze. In addition, Dao(-/-) mice displayed increased anxiety-like behaviour in five tests of approach/avoidance conflict: the open field test, elevated plus maze, successive alleys, light/dark box and novelty-suppressed feeding. Despite evidence of a reciprocal relationship between anxiety and sleep and circadian function in rodents, we found no evidence of sleep or circadian rhythm disruption in Dao(-/-) mice. Overall, our observations are consistent with, and extend, findings in the natural mutant ddY/Dao(-) line. These data add to a growing body of preclinical evidence linking the inhibition, inactivation or deletion of DAO with enhanced cognitive performance. Our results have implications for the development of DAO inhibitors as therapeutic agents.

Sleep and circadian rhythm disruption and recognition memory in schizophrenia.

Schizophrenia patients often show irregularities in sleep and circadian rhythms and deficits in recognition memory. Similar phenotypes are seen in schizophrenia-relevant genetic mouse models, such as synaptosomal associated protein of 25 kDa (Snap-25) point mutant mice, vasoactive intestinal peptide receptor 2 (Vipr2) knockout mice, and neuregulin 1 (Nrg1)-deficient mice. Sleep and circadian abnormalities and impaired recognition memory may be causally related in both schizophrenia patients and schizophrenia-relevant mouse models, since sleep deprivation, abnormal photic input, and the manipulation of core clock genes (cryptochrome 1/2) can all disrupt object recognition memory in rodent models. The recognition deficits observed in patients and mouse models (both schizophrenia-related and -unrelated) are discussed here in terms of the dual-process theory of recognition, which postulates that there are two recognition mechanisms-recollection versus familiarity-that can be selectively impaired by brain lesions, neuropsychiatric conditions, and putatively, sleep and circadian rhythm disruption. However, based on this view, the findings from patient studies and studies using genetic mouse models (Nrg1 deficiency) seem to be inconsistent with each other. Schizophrenia patients are impaired at recollection (and to a lesser extent, familiarity judgments), but Nrg1-deficient mice are impaired at familiarity-based object recognition, raising concerns regarding the validity of using these genetically modified mice to model recognition phenotypes observed in patients. This issue can be resolved in future animal studies by examining performance in different variants of the spontaneous recognition task-the standard, perirhinal cortex-dependent, object recognition task versus the hippocampus-dependent object-place recognition task-in order to see which of the two recognition mechanisms is more disrupted.

Influencing circadian and sleep-wake regulation for prevention and intervention in mood and anxiety disorders: what makes a good homeostat?

All living organisms depend on homeostasis, the complex set of interacting metabolic chemical reactions for maintaining life and well-being. This is no less true for psychiatric well-being than for physical well-being. Indeed, a focus on homeostasis forces us to see how inextricably linked mental and physical well-being are. This paper focuses on these linkages. In particular, it addresses the ways in which understanding of disturbed homeostasis may aid in creating classes of patients with mood and anxiety disorders based on such phenotypes. At the cellular level, we may be able to compensate for the inability to study living brain tissue through the study of homeostatic mechanisms in fibroblasts, pluripotent human cells, and mitochondria and determine how homeostasis is disturbed at the level of these peripheral tissues through exogenous stress. We also emphasize the remarkable opportunities for enhancing knowledge in this area that are offered by advances in technology. The study of human behavior, especially when combined with our greatly improved capacity to study unique but isolated populations, offers particularly clear windows into the relationships among genetic, environmental, and behavioral contributions to homeostasis.

Evaluating the links between schizophrenia and sleep and circadian rhythm disruption.

Sleep and circadian rhythm disruption (SCRD) and schizophrenia are often co-morbid. Here, we propose that the co-morbidity of these disorders stems from the involvement of common brain mechanisms. We summarise recent clinical evidence that supports this hypothesis, including the observation that the treatment of SCRD leads to improvements in both the sleep quality and psychiatric symptoms of schizophrenia patients. Moreover, many SCRD-associated pathologies, such as impaired cognitive performance, are routinely observed in schizophrenia. We suggest that these associations can be explored at a mechanistic level by using animal models. Specifically, we predict that SCRD should be observed in schizophrenia-relevant mouse models. There is a rapidly accumulating body of evidence which supports this prediction, as summarised in this review. In light of these emerging data, we highlight other models which warrant investigation, and address the potential challenges associated with modelling schizophrenia and SCRD in rodents. Our view is that an understanding of the mechanistic overlap between SCRD and schizophrenia will ultimately lead to novel treatment approaches, which will not only ameliorate SCRD in schizophrenia patients, but also will improve their broader health problems and overall quality of life.

Genetic mouse models relevant to schizophrenia: taking stock and looking forward.

Genetic mouse models relevant to schizophrenia complement, and have to a large extent supplanted, pharmacological and lesion-based rat models. The main attraction is that they potentially have greater construct validity; however, they share the fundamental limitations of all animal models of psychiatric disorder, and must also be viewed in the context of the uncertain and complex genetic architecture of psychosis. Some of the key issues, including the choice of gene to target, the manner of its manipulation, gene-gene and gene-environment interactions, and phenotypic characterization, are briefly considered in this commentary, illustrated by the relevant papers reported in this special issue.

Implicit processing of tactile information: evidence from the tactile change detection paradigm.

People can maintain accurate representations of visual changes without necessarily being aware of them. Here, we investigate whether a similar phenomenon (implicit change detection) also exists in touch. In Experiments 1 and 2, participants detected the presence of a change between two consecutively-presented tactile displays. Tactile change blindness was observed, with participants failing to report the presence of tactile change. Critically, however, when participants had to make a forced choice response regarding the number of stimuli presented in the two displays, their performance was significantly better than chance (i.e., implicit change detection was observed). Experiment 3 demonstrated that tactile change detection does not necessarily involve a shift of spatial attention toward the location of change, regardless of whether the change is explicitly detected. We conclude that tactile change detection likely results from comparing representations of the two displays, rather than by directing spatial attention to the location of the change.