Biased 5-HT1A receptor agonists F13714 and NLX-101 differentially affect pattern separation and neuronal plasticity in rats after acute and chronic treatment.

Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT1A receptor (5-HT1AR) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT1AR is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT1AR activity affects pattern separation. Object pattern separation (OPS) performance was measured in male Wistar rats after both acute and chronic treatment (i.p.) with 5-HT1AR biased agonists F13714 (0.0025 mg/kg acutely, 0.02 mg/kg/day chronically) or NLX-101 (0.08 mg/kg acutely, 0.32 mg/kg/day chronically), which preferentially activate autoreceptors or postsynaptic receptors respectively, for 14 days. Body temperature - a functional correlate of hypothalamic 5-HT1AR stimulation - was measured daily. Additionally, 5-HT1AR density (DRN) and plasticity markers (hippocampus) were assessed. Acute treatment with F13714 impaired OPS performance, whereas chronic treatment normalized this, and a drop in body temperature was found from day 4 onwards. NLX-101 enhanced OPS performance acutely and chronically, and caused an acute drop in body temperature. Chronic NLX-101 treatment increased doublecortin positive neurons in the dorsal hippocampus, while chronic treatment with F13714 resulted in a downregulation of 5-HT1A autoreceptors, which likely reversed the acute impairment in OPS performance. Chronic treatment with NLX-101 appears to have therapeutic potential to improve brain plasticity and OPS performance.

Soluble guanylate cyclase stimulator riociguat improves spatial memory in mice via peripheral mechanisms.

Soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) signalling is important for healthy memory function and a healthy vascular system. Targeting sGC-cGMP signalling can therefore be a potential strategy to enhance memory processes. sGC can be targeted by using agonists, such as sGC stimulator riociguat. Therefore, this study aimed to target sGC using riociguat to investigate its acute effects on memory function and neuronal plasticity in mice. The effects of riociguat on long-term memory and a biperiden-induced memory deficit model for assessing short-term memory were tested in the object location task, and working memory was tested in the Y-maze continuous alternation task. Pharmacokinetic measurements were performed within brain tissue of mice, and hippocampal plasticity measures were assessed using western blotting. Acute oral administration with a low dose of 0.03 mg/kg riociguat was able to enhance working-, short-, and long-term spatial memory. Under cerebral vasoconstriction higher doses of riociguat were still effective on memory. Pharmacokinetic measurements revealed poor brain penetration of riociguat and its metabolite M-1. Increased activation of VASP was found, while no effects were found on other memory-related hippocampal plasticity measures. Memory enhancing effects of riociguat are most likely regulated by vascular peripheral effects on cGMP signalling. Yet, further research is needed to investigate the possible contribution of hemodynamic or metabolic effects of sGC stimulators on memory performance.

Global concentrations of gaseous elemental mercury and reactive gaseous mercury in the marine boundary layer.

Gaseous elemental mercury (GEM) and reactive gaseous mercury (RGM) were measured during an eight month circumnavigation to obtain knowledge of their worldwide distributions in the marine boundary layer (MBL). Background GEM concentrations were found to be 1.32 ± 0.2 ng/m(3) (summer) and 2.62 ± 0.4 ng/m(3) (spring) in the northern hemisphere and 1.27 ± 0.2 ng/m(3) (spring and summer) in the southern hemisphere. Radiation and relative humidity are shown to control diurnal cycles of RGM. During the cruise the ship passed areas of clean MBL air, air influenced by biomass burning (South Atlantic) and air with high concentrations of GEM and RGM of unknown origin (Antarctic). High GEM concentrations above the Atlantic indicate that emission from the ocean can be an important GEM source. Our data combined with data from earlier cruises provides adequate information to establish a seasonal cycle for the Atlantic. Results show a cycle similar to that found at Mace Head, Ireland but with larger amplitude. We have improved the basic knowledge of mean GEM and RGM concentrations in the MBL worldwide and shown how natural sources and reemissions can affect GEM concentrations in the MBL.

Pharmacological depletion of microglia and perivascular macrophages prevents Vascular Cognitive Impairment in Ang II-induced hypertension.

Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Angiotensin II infusion is associated with increased permeability of the blood-brain barrier (BBB), chronic activation of microglia and myelin loss. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach. Methods: For this study, adult Cx3Cr1 gfp/wtxThy1 yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF1R tyrosine kinase inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory was assessed during an Object Location task and a Morris Water Maze task (MWM). Microglia depletion efficacy was assessed by flow cytometry and immunohistochemistry. BBB leakages, microglia phenotype and myelin integrity were assessed by immunohistochemistry. Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, and partly prevented in Ang II mice treated with PLX5622. Histological and flow cytometry analysis revealed almost complete ablation of microglia and a 60% depletion of brain resident perivascular macrophages upon CSF1R inhibition. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Microglia acquired a pro-inflammatory phenotype at the site of BBB leakages in both Saline and Ang II mice and were successfully depleted by PLX5622. There was however no significant change in myelin integrity at the site of leakages. Conclusion: Our results show that depletion of microglia and PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. We suggest this beneficial effect is mediated by the major decrease of pro-inflammatory microglia within BBB leakages. This novel finding supports the critical role of brain immune cells in the pathogenesis of hypertension-related cognitive impairment. An adequate modulation of microglia /PVM density and phenotype may constitute a relevant approach to prevent and/or limit the progression of vascular cognitive impairment.

Audiovisual assessment of exercise-induced laryngeal obstruction: reliability and validity of observations.

Variable obstruction to airflow at the laryngeal level may cause respiratory distress during exercise. The Continuous Laryngoscopy Exercise (CLE)-test enables direct visualization of the larynx during ongoing exercise. The aims of this study were to establish a scoring system for laryngeal obstruction as visualized during the CLE-test as well as to assess reliability and validity of this scoring system. Continuous video recording of the larynx was performed in parallel with continuous video recording of the upper part of the body, and recording of breath sounds in 80 patients and 20 symptom-negative volunteers, running on a treadmill to respiratory maximal tolerable distress or exhaustion. Each participant scored the degree of symptoms during exercise. The scoring system contains four sub-scores, each graded from 0 to 3. Two independent laryngologists, blinded to clinical data, scored the video recordings of the larynx twice. The proportion of inter- and intra-observer agreement (equal scores) for each sub-score through these four sessions varied between 70 and 100% (weighted kappa values varied from 0.49 to 1.00 correspondingly). A positive correlation was found between CLE-test sum score and symptom score (rho = 0.75, P < 0.001). There was a significant difference in CLE-test sum score between patients (3.34 +/- 1.34) and volunteers (0.65 +/- 0.66) (P < 0.001). The single CLE-test sub-score that correlated most strongly with symptom score was glottic adduction at maximal effort (rho = 0.75, P < 0.001). The presented scoring system is reliable and valid, and we suggest that it can be used when laryngeal function during exercise is evaluated.

Barriers to Emergency Department Utilization of AFIB Protocol in Uncomplicated Lone AFIB Patients-Results from an Online Survey Study.

BACKGROUND: Historically, atrial fibrillation (AFIB) management has focused on rate control and anticoagulation, necessitating hospital admission. Recently, some emergency departments (EDs) have implemented protocols to avoid hospital admission when managing lone AFIB. Despite this recent trend, there is still reluctance toward the implementation of these protocols by some emergency physicians (EPs). OBJECTIVE: This study investigates barriers to implementation of ED AFIB protocols by surveying which aspects may impede their use. METHODS: To analyze the perceived barriers from EPs, we formulated a survey assessing the various components of ED AFIB management to identify which aspects might impede EP utilization. It was distributed as an email to large national ED physician group. Data was analyzed using descriptive means and weighted averages. RESULTS: Of 185 respondents (response rate 6.1%), 17.4% already had AFIB protocols in place at their home institutions and 82.6% did not. Majority opinion of largest barriers toward the implementation of AFIB protocols were the extended ED length of stay and discharge with unclear follow-up. There was little concern with chemical and electrical cardioversion and very limited concern with rate control and initiating oral anticoagulation. EPs supported placement in Observation for implementation and involvement of discharge planning to establish prescriptions and follow-up. CONCLUSION: EP input regarding the development of ED AFib protocols will be essential in order to develop cost effective, convenient and safe methods of treatment. This survey of EP suggests that ED length of stay and insuring close outpatient follow up are key issues to address as protocols are designed.

Inclusion, universal design and universal design for learning in higher education: South Africa and the United States.

Around the world, institutions of higher education are recognising their responsibilities to achieve the full inclusion of individuals with differing needs and/or disabilities. The frameworks of universal design (UD) and universal design for learning (UDL) offer unique ways to build inclusiveness in our systems. The role of UD and UDL to strengthen successful inclusion of persons with differing needs in higher education programmes is presented from literature, inclusive of national and international policies and resources. Examples from South African and US institutions of higher learning are shared. Discussions of online accessibility, environmental issues, professional development, barriers to inclusion and recommendations for future development in an international context provide a vision for developing inclusive learning environments in higher education.

Publisher Correction: Assessing spatial pattern separation in rodents using the object pattern separation task.

In the HTML version of this paper originally published online, text in Table 6 was misaligned in a way that made it difficult to determine which entries in the "Problem," "Possible reason," and "Solution" columns corresponded to one another. Additional but less severe alignment problems were also present in the PDF and print articles. These errors have been corrected in the HTML and PDF versions of the paper.

Validation of the xylazine/ketamine anesthesia test as a predictor of the emetic potential of pharmacological compounds in rats.

The xylazine/ketamine anesthesia test is widely used as a predictor of the emetic potential of pharmacological compounds in rats. An emetic reflex is usually triggered by the emetic center, which is populated with many different chemoreceptors. Inhibition of the α2 adrenergic receptor (α2 receptor) is involved in the initiation of the emetic reflex, and this is the key mechanism behind the xylazine/ketamine anesthesia test. In this study, we attempt to validate this test as a predictor of the emetic potential of pharmacological compounds. Furthermore, it was investigated whether an anti-emetic potential of pharmacological compounds could be assessed within this test as well. Rats were anesthetized with a combination of low doses of ketamine and xylazine, and subsequently treated with PDE4 inhibitor rolipram, α2 receptor antagonist yohimbine, α2 receptor agonist clonidine, tricyclic antidepressant imipramine, D2-receptor antagonist haloperidol, or 5-HT3 receptor antagonist (and anti-emetic drug) ondansetron. We were able to successfully reproduce the reduction in anesthesia time after rolipram or yohimbine treatment, as found in previous studies and has been suggested to be indicative of emetic properties of these treatments is humans. Furthermore, clonidine shortened anesthesia duration whereas imipramine and haloperidol lengthened anesthesia duration. Ondansetron was unable to rescue the reduction in duration of anesthesia induced by either rolipram or yohimbine. Altogether, the xylazine/ketamine anesthesia test is a reliable measure for α2 receptor antagonism. However, it may not be appropriate to assess emesis independent of this mechanism.

Assessing spatial pattern separation in rodents using the object pattern separation task.

Pattern separation is the process of transforming highly similar sensory inputs into distinct, dissimilar representations. It takes place in the hippocampus and is thought to be used in episodic memory. Impaired pattern separation performance has been recognized as a predictor for the development of cognitive impairments such as dementia in humans and as being present in patients with schizophrenia and post-traumatic stress disorder (PTSD). In this protocol, we describe how to implement a simple and robust object pattern separation (OPS) task in mice and rats that we have previously established and validated. This two-trial memory task uses specific object locations so differences in performance can be calibrated with the extent of object movement. Changes in performance are indicative of spatial pattern separation. In contrast to other pattern separation tasks, the OPS task allows detection of spatial pattern separation performance bidirectionally. Furthermore, the OPS task is cheaper and easier to use and interpret than other tasks that use more than two objects or that are touch-screen based. The entire protocol, from vivarium acclimatization to training of the animals, takes ~35-41 d. After successful training, the animals can be tested repeatedly, and three OPS experiments (n = 20-24 per experimental day) can be performed per week. A standard level of expertise in behavioral studies in rodents is sufficient to successfully integrate this paradigm into an existing rodent test battery.

Hypertension-induced cognitive impairment: insights from prolonged angiotensin II infusion in mice.

The causal relation between hypertension and cerebral small vessel disease (cSVD) remains elusive, and appropriate animal models are scarce. We aimed to assess the relevance of prolonged angiotensin II-induced hypertension in mice for the study of cSVD.Adult male C57BL/6 mice were continuously infused for 3 months with Angiotensin II (Ang II; 2 µg/kg/min, sc) or saline (control) via osmotic minipumps. Blood pressure, neurological function, locomotor activity, and working memory (Y-maze alternation task) were assessed throughout the study. Short-term memory performance (object location task) was measured after 3 months of infusion. Blood-brain barrier (BBB) function was assessed by the presence of IgG leakage and quantified in each brain area of interest. Microglial activation and myelin loss were studied in the areas of leakage.Systolic blood pressure increased and remained elevated over the 3 months of Ang II infusion, while neurological scores and locomotor activity did not change. Working memory performance was also not changed, yet short-term memory performance was impaired in Ang II-treated mice compared to controls. While BBB leakages were present in both groups, mainly in the neocortex, hippocampus, and cerebral nuclei, Ang II-treated mice showed greater leakage than control mice, along with greater microglial density and soma size. Myelin loss was observed for the largest leaks.Prolonged Ang II-induced hypertension is associated with large BBB leaks, microglial activation, myelin loss, and memory dysfunction in the absence of stroke.

Diagnosing appendicular osteosarcoma with ultrasound-guided fine-needle aspiration: 36 cases.

OBJECTIVES: To determine the ability to obtain diagnostic cytology samples from appendicular bone lesions using ultrasound-guided needle aspirations. Secondary objectives were to compare cytological evaluations with histopathological results and to determine the utility of staining malignant mesenchymal cells for the presence of alkaline phosphatase. METHODS: Aspirations from 36 aggressive appendicular bone lesions with histological diagnoses were included in the study. Ultrasound was used to guide the needle to the medullary cavity or the adjacent soft tissue mass. The smears stained with Wright-Giemsa and nitroblue tetrazolium chloride/5-bromo-4-chloro-3-indoyl phosphate toluidine salt (NBT/BCIP) were examined. RESULTS: A diagnostic sample was obtained in 32 of the 36 cases. Of the 32 diagnostic samples, cytology indicated sarcoma, with a sensitivity of 97 per cent (confidence interval: 83 to 100 per cent) and a specificity of 100 per cent (confidence interval: 16 to 100 per cent). When a diagnosis of sarcoma was made on cytology, alkaline phosphatase staining indicated osteosarcoma, with a sensitivity of 100 per cent (confidence interval: 87 to 100 per cent). CLINICAL SIGNIFICANCE: The results of this study indicate that ultrasound-guided needle aspiration of aggressive bone lesions is a viable technique for identifying malignant mesenchymal cells and for diagnosing sarcomas. It is cost-effective and minimally invasive. Furthermore, identifying alkaline-phosphatase-negative malignant mesenchymal cells from a bone aspiration may rule out osteosarcoma, whereas alkaline-phosphatase-positive malignant mesenchymal cells are suggestive of osteosarcoma.

Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer's disease.

Memory loss characterizes several neurodegenerative disorders, including Alzheimer's disease (AD). Inhibition of type 4 phosphodiesterase (PDE4) and elevation of cyclic adenosine monophosphate (cAMP) has emerged as a promising therapeutic approach to treat cognitive deficits. However, PDE4 exists in several isoforms and pan inhibitors cannot be used in humans due to severe emesis. Here, we present GEBR-32a, a new PDE4D full inhibitor that has been characterized both in vitro and in vivo using biochemical, electrophysiological and behavioural analyses. GEBR-32a efficiently enhances cAMP in neuronal cultures and hippocampal slices. In vivo pharmacokinetic analysis shows that GEBR-32a is rapidly distributed within the central nervous system with a very favourable brain/blood ratio. Specific behavioural tests (object location and Y-maze continuous alternation tasks) demonstrate that this PDE4D inhibitor is able to enhance memory in AD transgenic mice and concomitantly rescues their hippocampal long-term potentiation deficit. Of great relevance, our preliminary toxicological analysis indicates that GEBR-32a is not cytotoxic and genotoxic, and does not seem to possess emetic-like side effects. In conclusion, GEBR-32a could represent a very promising cognitive-enhancing drug with a great potential for the treatment of Alzheimer's disease.

Continuous laryngoscopy exercise test: a method for visualizing laryngeal dysfunction during exercise.

OBJECTIVES/HYPOTHESIS: To assess the diagnostic feasibility and patient acceptance of a new developed diagnostic test for exercise induced upper airway flow limitation. STUDY DESIGN: Clinical case control study including evaluation of contemporary ergo-spirometry and laryngoscopy continuously performed during exercise. METHODS: Twelve nonsymptomatic controls and four young females with documented dyspnea and noisy breathing during exercise were studied. All subjects exercised to exhaustion on a treadmill while attached to a fully equipped ergo-spirometry unit and a fiberoptic laryngoscope linked to a video camera and a sound recorder. RESULTS: The test situation was well tolerated. Two control subjects had a minor inspiratory synchronous medial motion of the aryepiglottic folds without limitation of laryngeal airflow. In the four symptomatic subjects, exercise induced inspiratory synchronous medial motion of the dorsal part of the aryepiglottic folds as well as vocal cord adduction and inspiratory stridor was demonstrated. CONCLUSION: The continuous laryngoscopy exercise test was easy to perform, well tolerated, and can be implemented in future diagnostic work-up programs of laryngeal dysfunction.

New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment.

Phosphodiesterase type 4D (PDE4D) has been indicated as a promising target for treating neurodegenerative pathologies such as Alzheimer's Disease (AD). By preventing cAMP hydrolysis, PDE4 inhibitors (PDE4Is) increase the cAMP response element-binding protein (CREB) phosphorylation, synaptic plasticity and long-term memory formation. Pharmacological and behavioral studies on our hit GEBR-7b demonstrated that selective PDE4DIs could improve memory without causing emesis and sedation. The hit development led to new molecule series, herein reported, characterized by a catechol structure bonded to five member heterocycles. Molecular modeling studies highlighted the pivotal role of a polar alkyl chain in conferring selective enzyme interaction. Compound 8a showed PDE4D3 selective inhibition and was able to increase intracellular cAMP levels in neuronal cells, as well as in the hippocampus of freely moving rats. Furthermore, 8a was able to readily cross the blood-brain barrier and enhanced memory performance in mice without causing any emetic-like behavior. These data support the view that PDE4D is an adequate molecular target to restore memory deficits in different neuropathologies, including AD, and also indicate compound 8a as a promising candidate for further preclinical development.

Epigenetic modifications in mouse cerebellar Purkinje cells: effects of aging, caloric restriction, and overexpression of superoxide dismutase 1 on 5-methylcytosine and 5-hydroxymethylcytosine.

The aim of the present study was to assess alterations in DNA methylation and hydroxymethylation during aging in cerebellar Purkinje cells and to determine the effects of putatively preventative measures to such age-related changes. Using immunohistochemical techniques, 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) immunoreactivity in cerebellar Purkinje cells of 12-month- and 24-month-old mice was interrogated. Additionally, the modulatory effects of caloric restriction (CR) and normal human Cu/Zn super oxide dismutase 1 overexpression on these changes were assessed. We show that aging is associated with an increase of 5-mC and 5-hmC immunoreactivity in mouse cerebellar Purkinje cells. These age-related increases were mitigated by CR but not super oxide dismutase 1 overexpression. Additionally, the ratio between 5-mC and 5-hmC decreased with age and CR treatment, suggesting that CR has a stronger effect on DNA methylation than DNA hydroxymethylation. These findings enforce the notion that aging is closely connected to marked epigenetic changes, affecting multiple brain regions, and that CR is an effective means to prevent or counteract deleterious age-related epigenetic alterations.

Social blushing.

This article reviews theory and research regarding the physiology, situational and dispositional antecedents, behavioral concomitants, and interpersonal consequences of social blushing and offers a new theoretical account of blushing. This model posits that people blush when they experience undesired social attention. Puzzling questions involving blushing in solitude, the phenomenology of blushing, types of blushing, and blushing in dark-skinned people are discussed.

The triangle model of responsibility.

Responsibility acts as a psychological adhesive that connects an actor to an event and to relevant prescriptions that should govern conduct. People are held responsible to the extent that (a) a clear, well-defined set of prescriptions is applicable to an event (prescription-event link); (b) the actor is perceived to be bound by the prescriptions by virtue of his or her identity (prescription-identity link); and (c) the actor is connected to the event, especially by virtue of appearing to have personal control over it (identity-event link). Studies supported the model, showing that attributions of responsibility are a direct function of the combined strengths of the 3 linkages (Study 1) and that, when judging responsibility, people seek out information that is relevant to the linkages (Study 2). The model clarifies prior multiple meanings of responsibility and provides a coherent framework for understanding social judgment.

Longitudinal sleep EEG power spectral analysis studies in adolescents with minor head injury.

Power spectral analysis (PSA) was used to evaluate the longitudinal overnight electroencephalographic (EEG) sleep recordings of eight subjects, between the ages of 15 and 19 years, who had sustained a minor head injury (MHI). Recordings occurred within 72 h, 6 weeks, and 12 weeks following MHI. A conditioning night preceded the first study night during which EEG electrodes were in place and subjects slept at least 7.5 h with a mean sleep efficiency of 91%. PSA was performed on four channels of EEG data recorded from fronto-temporal (F3-T3, F4-T4), and temporal (T3-T5, T4-T6) electrodes. The three waveforms associated with sleep, Delta, Theta, and Alpha-1 were all significantly elevated within 72 h post-MHI. Over time all wave forms decreased in mean log power. Theta in rapid eye movement (REM) sleep Cycle 1 decreased significantly within 6 weeks postinjury. The greatest number of significant changes, over the 12-week period were recorded during the non-REM (NREM) sleep. Changes included (1) significant decreases in mean log power of Theta and Alpha-1 in Cycle 1 from fronto-temporal leads; (2) significant decreases in Delta, Theta, and Alpha-1 in Cycle 2 from fronto-temporal leads, and (3) significant decreases in Delta and Theta for consistency during Cycle 2 from temporal leads. The intrusion of Theta into the first REM cycle within 6 weeks and its subsequent decrease within 6 weeks suggested the initiation of recovery toward baseline values. This was followed by decreased levels of Theta power during NREM Cycles 1 and 2, and Delta power in Cycle 2, both of which approached their lowest levels within 12 wks. The decrease in Alpha-1 power occurred last. Alpha-1 remained elevated through both Cycles 1 and 2 of the 6th week and then showed a precipitous decrease between the sixth and twelfth week. These findings suggested that following MHI, the brain has a specific sequence of recovery as illustrated by Delta, Theta, and Alpha-1 powers requiring different time frames to reach their lowest levels.

Depression and the explanation of events that happen to self, close others, and strangers.

Depressive and nondepressive college students attributed causality for positive and negative events that happened to either themselves, a close other, or a typical student. Depressives made less optimistic attributions than nondepressives when explaining events that happened to themselves. However, depressives and nondepressives generally made similar attributions about others; both groups were optimistic when explaining events that happened to their best friend or romantic partner and less optimistic when explaining events that happened to the typical student. The results indicate that depressives do not treat close others as extensions of the self, at least in terms of their attributional patterns. Furthermore, depressives were aware of the extent to which their attributions benefitted or harmed the desired identity of the actor.