Cognitive impairment and depression symptoms are independently associated with suicidal ideation in US Veterans.

Depression is associated with cognitive impairment and suicidality. The independent association between cognitive impairment and suicidality is less clear. We examined the relationship between suicidal ideation and cognitive impairment in a sample of 50 veterans with depressive disorder diagnoses. Using zero-inflated Poisson regression, the severity of suicidal ideation was negatively associated with attention (incidence rate ratio [IRR] = 0.78, p < .001), memory (IRR = 0.87, p < .001), and total cognition (IRR = 0.90, p = .007) index scores as measured by the Dementia Rating Scale 2 (DRS-2). These three indices continued to significantly predict suicidal ideation severity once depression symptoms were controlled for.

Reduced transfer of visuomotor adaptation is associated with aberrant sense of agency in schizophrenia.

One deficit associated with schizophrenia (SZ) is the reduced ability to distinguish self-caused sensations from those due to external sources. This reduced sense of agency (SoA, subjective awareness of control over one's actions) is hypothesized to result from a diminished utilization of internal monitoring signals of self-movement (i.e., efference copy) which subsequently impairs forming and utilizing sensory prediction errors (differences between the predicted and actual sensory consequences resulting from movement). Another important function of these internal monitoring signals is the facilitation of higher-order mechanisms related to motor learning and control. Current predictive-coding models of adaptation postulate that the sensory consequences of motor commands are predicted based on internal action-related information, and that ownership and control of motor behavior is modified in various contexts based on predictive processing. Here, we investigated the connections between SoA and motor adaptation. Schizophrenia patients (SZP, N=30) and non-psychiatric control subjects (HC, N=31) adapted to altered movement visual feedback and applied the motor recalibration to untested contexts (i.e., the spatial generalization). Although adaptation was similar for SZP and controls, the extent of generalization was significantly less for SZP; movement trajectories made by patients to the furthest untrained target (135o) before and after adaptation were largely indistinguishable. Interestingly, deficits in generalization were correlated with positive symptoms of psychosis in SZP (e.g., hallucinations). Generalization was also associated with measures of SoA across both SZP and HC, emphasizing the role action awareness plays in motor behavior, and suggesting that misattributing agency, even in HC, manifests in abnormal motor performance.

Social rehabilitation for military veterans with traumatic brain injury, psychological trauma, and chronic neuropsychiatric symptoms: Intervention development and initial outcomes.

OBJECTIVE: A subset of military veterans who have experienced both traumatic brain injury and psychological trauma present with chronic neuropsychiatric symptoms and experience persistent obstacles to social reintegration. This project aimed to develop a novel treatment targeting the unmet social rehabilitation needs of these veterans. Initial intervention development, feasibility, and outcome data are explored. METHOD: Four treatment groups were conducted (n = 20). A treatment workbook was developed during Groups 1 and 2 (n = 10) and research data were collected from Groups 3 and 4 (n = 10). RESULTS: There was a 0% attrition rate across all groups with unanimous requests for additional sessions. T test effect sizes were analyzed with bias-corrected Hedges' g. Improvements were observed on measures of depression (p = .026, g = 0.73), empathic perspective taking (p = .007, g = 0.94), social cognition (p = .002-.678, g = 0.27-1.30 across multiple measures), social relationships (p = .007, g = 1.50), traumatic brain injury-related quality of life (social: p = .014, g = 0.68, emotional: p = .009, g = 1.28) and nonsocial executive functioning (p = .006, g = 0.54). CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Preliminary evidence from this exploratory study suggests that targeting multiple layers of social competence using a combined psychotherapy and cognitive rehabilitation approach holds promise. Larger, controlled studies are needed to further evaluate the feasibility and efficacy of this intervention. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

An Exploratory Study of Exercise-related Effects on Memory and Hippocampal Connectivity in Schizophrenia.

Memory impairment in schizophrenia has been linked to abnormal functioning of fronto-temporal networks. In this pilot study, we investigated whether 12-weeks of exercise improved hippocampal-dependent memory functions and resting-state functional connectivity in middle-aged adults with schizophrenia. The exercise regimen was feasible, well-attended, and safe. There was a pre- to post-intervention increase in spatial memory accuracy that was correlated to an increase in hippocampal-prefrontal cortex connectivity. No increase was found in pattern separation performance or hippocampal volume. A controlled trial is needed to replicate these findings and elucidate the functional brain networks underlying exercise-induced cognitive improvement in schizophrenia.

Transsaccadic Perception Deficits in Schizophrenia Reflect the Improper Internal Monitoring of Eye Movement Rather Than Abnormal Sensory Processing.

BACKGROUND: Symptoms of psychosis in schizophrenia reflect disturbances in sense of agency-difficulty distinguishing internally from externally generated sensory and perceptual experiences. One theory attributes these anomalies to a disruption in corollary discharge (CD), an internal copy of generated motor commands used to distinguish self-movement-generated sensations from externally generated stimulation. METHODS: We used a transsaccadic shift detection paradigm to examine possible deficits in CD and sense of agency based on the ability to perceive visual changes in 31 schizophrenia patients (SZPs) and 31 healthy control subjects. We derived perceptual measures based on manual responses indicating the transsaccadic target shift direction. We also developed a distance-from-unity-line measure to quantify use of CD versus purely sensory (visual) information in evaluating visual changes in the environment after an eye movement. RESULTS: SZPs had higher perceptual thresholds in detecting shift of target location than healthy control subjects, regardless of movement direction or amplitude. Despite producing similar hypometric saccades, healthy control subjects overestimated target location, whereas SZPs relied more on the experienced visual error and consequently underestimated the target position. We show that in SZPs the postsaccadic judgment of the initial target location was largely aligned with the measure based only on visual error, suggesting a deficit in the use of CD. This CD deficit also correlated with positive schizophrenia symptoms and disturbances in sense of agency. CONCLUSIONS: These results provide a novel approach in quantifying abnormal use of CD in SZPs and provide a framework to distinguish deficits in sensory processing versus defects in the internal CD-based monitoring of movement.

Neuropsychological measurement of inhibitory control in posttraumatic stress disorder: An exploratory antisaccade paradigm.

OBJECTIVE: The aim of the study was to uncover inhibitory control dynamics and assess antisaccade eye-tracking tasks for relevance in a veteran posttraumatic stress disorder (PTSD) population. METHOD: Participants were 36 veterans enrolled at the Washington DC Veterans Affairs Medical Center. The groups (PTSD diagnosed vs. controls) did not vary between age and sex. Participants completed a testing battery of clinical neuropsychological measures and two different eye-tracking conditions, one that utilized face stimuli and one with standard shape stimuli, which test pro- (PS) and antisaccade (AS) eye movements. RESULTS: Veterans with PTSD, t(33) = 2.2, p = .04, took longer to respond than controls in the standard condition AS. In the face condition, a group by task interaction was seen with increased latency for PTSD veterans in the AS versus PS task, F(3, 33) = 3.99, p = .05, with a large overall effect (Hedges' g = 1.18, p < .001) compared to controls. After controlling for depression, analyses suggested that only the face condition AS task significantly predicted dimensions of PTSD symptomology measured by the Clinician Administered PTSD Scale (CAPS) for veterans with PTSD. CONCLUSIONS: This is the first study to extend AS findings to PTSD and suggests a specific capability to measure inhibitory control using eye-tracking technology. We discuss the notion that reduced capacity to regulate facial-related processing affects cognitive and attentional control networks of PTSD patients, potentially representing a core cognitive deficit.

A pilot study of the trauma recovery group for veterans with post traumatic stress disorder and co-occurring serious mental illness.

BACKGROUND: Many Veterans may not benefit from gold-standard evidence-based treatments for post-traumatic stress disorder (PTSD) because they suffer from co-occurring serious mental illness (SMI). AIMS: This pilot study is the first to evaluate the feasibility and preliminary effectiveness of the Trauma Recovery Group in a sample of Veterans with PTSD and SMI. METHODS: Fourteen Veterans with PTSD and SMI were enrolled in a 21-session group-based cognitive behavioral therapy program targeting PTSD. The PTSD Checklist was the primary outcome measure; secondary outcomes included the Participant Health Questionnaire, the Post Traumatic Cognitions Inventory, and the Beck Cognitive Insight Scale. RESULTS: Seventy-one percent of participants completed the trial. The intervention was associated with a significant reduction of PTSD symptoms and a trend-level reduction of maladaptive post-traumatic cognitions. There was a significant positive correlation between change in PTSD symptoms and change in post-traumatic cognitions. CONCLUSIONS: The findings support the feasibility and preliminary effectiveness of the Trauma Recovery Group for Veterans with co-occurring PTSD and SMI, and suggest that controlled research on the program is warranted.

Evaluation of STAT medication ordering process in a community hospital.

BACKGROUND: In most health care facilities, problems related to delays in STAT medication order processing time are of common concern. OBJECTIVE: The purpose of this study was to evaluate processing time for STAT orders at Kimball Medical Center. METHODS: All STAT orders were reviewed to determine processing time; order processing time was also stratified by physician order entry (physician entered (PE) orders vs. non-physician entered (NPE) orders). Collected data included medication ordered, indication, time ordered, time verified by pharmacist, time sent from pharmacy, and time charted as given to the patient. RESULTS: A total of 502 STAT orders were reviewed and 389 orders were included for analysis. Overall, median time was 29 minutes, IQR 16-63; p<0.0001.). The time needed to process NPE orders was significantly less than that needed for PE orders (median 27 vs. 34 minutes; p=0.026). In terms of NPE orders, the median total time required to process STAT orders for medications available in the Automated Dispensing Devices (ADM) was within 30 minutes, while that required to process orders for medications not available in the ADM was significantly greater than 30 minutes. For PE orders, the median total time required to process orders for medications available in the ADM (i.e., not requiring pharmacy involvement) was significantly greater than 30 minutes. [Median time = 34 minutes (p<0.001)]. CONCLUSION: We conclude that STAT order processing time may be improved by increasing the availability of medications in ADM, and pharmacy involvement in the verification process.

Evaluation of STAT medication ordering process in a community hospital

Background: In most health care facilities, problems related to delays in STAT medication order processing time are of common concern. Objective: The purpose of this study was to evaluate processing time for STAT orders at Kimball Medical Center. Methods: All STAT orders were reviewed to determine processing time; order processing time was also stratified by physician order entry (physician entered (PE) orders vs. non-physician entered (NPE) orders). Collected data included medication ordered, indication, time ordered, time verified by pharmacist, time sent from pharmacy, and time charted as given to the patient. Results: A total of 502 STAT orders were reviewed and 389 orders were included for analysis. Overall, median time was 29 minutes, IQR 16-63; p<0.0001.) . The time needed to process NPE orders was significantly less than that needed for PE orders (median 27 vs. 34 minutes; p=0.026). In terms of NPE orders, the median total time required to process STAT orders for medications available in the Automated Dispensing Devices (ADM) was within 30 minutes, while that required to process orders for medications not available in the ADM was significantly greater than 30 minutes. For PE orders, the median total time required to process orders for medications available in the ADM (i.e., not requiring pharmacy involvement) was significantly greater than 30 minutes. [Median time = 34 minutes (p<0.001)]. Conclusion: We conclude that STAT order processing time may be improved by increasing the availability of medications in ADM, and pharmacy involvement in the verification process (AU)

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Sleep health literacy in head start families and staff: exploratory study of knowledge, motivation, and competencies to promote healthy sleep.

CONTEXT: Healthy child development requires sufficient, quality sleep. Sleep problems in early childhood impair social-emotional and cognitive function and increase obesity risk. From a health literacy framework, "sleep health literacy" denotes the knowledge, motivation, and competencies to promote healthy sleep and to recognize a sleep problem. DESIGN: To explore the untapped potential of early childhood education (ECE) programs to promote sleep health literacy, we surveyed staff (n=63) and parents (n=196) in Head Start about sleep-related knowledge, attitudes/beliefs, sleep hygiene, and sleep problems. Head Start is the largest ECE program in the United States. RESULTS: Most parents believed that their child had healthy sleep habits (81%); few believed that he or she had a sleep problem (10%). Yet, unhealthy bedtime practices and insufficient sleep for age were reported in 50% and 33% of children, respectively. Between 10% and 12% of children had 1 or more sleep onset or awakening problems. Every unhealthy bedtime practice but one was associated with a sleep problem; parental presence at bedtime was associated with the most problems. Insufficient sleep was significantly associated with unhealthy sleep practices. More children with late vs early bedtimes (48% vs14%, P < .01) and frequent vs less frequent parental presence at bedtime (50% vs 26%-30%, P < .02) failed to obtain sufficient sleep. Staff members are more comfortable discussing healthy sleep with parents (87%) than counseling them (45%). CONCLUSION: Among parents, there is a "disconnect" between actual and perceived sleep hygiene. Similarly, staff perceived a gap between their competencies to promote healthy sleep in families and their capacity to address sleep problems. US health literacy goals include the need to embed accurate, accessible, and actionable health information in ECE programs. Study findings strongly support the need to work toward sleep health literacy in ECE programs.

Ligand-independent interaction of the type I interferon receptor complex is necessary to observe its biological activity.

Ectopic coexpression of the two chains of the Type I and Type III interferon (IFN) receptor complexes (IFN-αR1 and IFN-αR2c, or IFN-λR1 and IL-10R2) yielded sensitivity to IFN-alpha or IFN-lambda in only some cells. We found that IFN-αR1 and IFN-αR2c exhibit FRET only when expressed at equivalent and low levels. Expanded clonal cell lines expressing both IFN-αR1 and IFN-αR2c were sensitive to IFN-alpha only when IFN-αR1 and IFN-αR2c exhibited FRET in the absence of human IFN-alpha. Coexpression of RACK-1 or Jak1 enhanced the affinity of the interaction between IFN-αR1 and IFN-αR2c. Both IFN-αR1 and IFN-αR2c exhibited FRET with Jak1 and Tyk2. Together with data showing that disruption of the preassociation between the IFN-gamma receptor chains inhibited its biological activity, we propose that biologically active IFN receptors require ligand-independent juxtaposition of IFN receptor chains assisted by their associated cytosolic proteins.

Targeting alpha-7 nicotinic neurotransmission in schizophrenia: a novel agonist strategy.

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) agonists may be valuable treatments for negative symptoms and cognitive impairment in schizophrenia. Unfortunately, chronic exposure to an agonist may reduce the receptor's sensitivity. Therefore, we combined CDP-choline, a dietary source of the direct agonist choline, with galantamine, a positive allosteric modulator (PAM) of nicotinic acetylcholine receptors, to improve the efficiency of transducing the choline signal and, possibly, preserve the receptor in a sensitive state. We conducted a single-site, double-blind randomized clinical trial comparing galantamine/CDP-choline to placebos in schizophrenia patients with negative symptoms who were receiving second generation antipsychotics. Forty-three subjects received galantamine and CDP-choline or matching placebos for 16weeks. The primary outcome measure was the 5-item Marder negative-symptoms factor of the Positive and Negative Syndrome Scale (PANSS). Cognition and functioning were also assessed. Trial completion was high; 79%. There was no significant treatment effect on negative symptoms, other PANSS symptom factors, or the MATRICS Cognitive Consensus Battery. There were significant treatment effects in overall functioning and a test of free verbal recall. Three subjects discontinued treatment in the active treatment group for gastro-intestinal adverse events (AE). The most common AE for galantamine/CDP-choline was abdominal pain; for placebo it was headache and sweating. Although there was no significant treatment effect on negative symptoms, the direction of effect mirrored the effects on a cognitive measure and overall functioning. Further study of α7 nAChR agonist/PAMs is warranted in larger studies that will have greater power.

Neural basis of implicit memory for socio-emotional information in schizophrenia.

Individuals with schizophrenia are impaired in processing social signals such as facial expressions of emotion. Perceiving facial expressions is a complex process that depends on a distributed neural network of regions involved in affective, cognitive, and visual processing. We examined repetition priming, a non-conscious form of perceptual learning, to explore the visual-perceptual processes associated with perceiving facial expression in people with schizophrenia. Functional magnetic resonance imaging (fMRI) was also employed to probe the sensitivity of face-responsive regions in the ventral pathway to the repetition of stimuli. Subjects viewed blocks of novel and repeated faces displaying fear expressions and neutral expressions and identified each face as male or female. Gender decisions were faster for repeated encoding relative to initial encoding of faces, indicating significant priming for facial expressions. Priming was normal in schizophrenia patients, but, as expected, recognition memory for the expressions was impaired. Neuroimaging findings showed that priming-related activation for patients was reduced in the left fusiform gyrus, relative to controls, regardless of facial expression. The findings suggest that schizophrenia patients have altered neural sensitivity in regions of the ventral visual processing stream that underlie early perceptual learning of objects and faces.

Short communication: adhesion pathways utilized by HIV-infected lymphocytes.

We recently reported a novel adhesion pathway in lymphocytes that is mediated by cyclin-dependent kinase (Cdk) 4 activity and mediates lymphocyte interactions with endothelial matrix. We now demonstrate that HIV-infected lymphocytes also use Cdk4 to mediate spontaneous adhesion to fibronectin and endothelial matrix. We further demonstrate that HIV-infected lymphocytes require Rap-1 activity for phorbol-stimulated adhesion. Understanding adhesion pathways used by HIV-infected lymphocytes may lead to interventions to regulate aberrant adhesion and migration.

Hematopoietic Fas deficiency does not affect experimental atherosclerotic lesion formation despite inducing a proatherogenic state.

The Fas death receptor (CD95) is expressed on macrophages, smooth muscle cells, and T cells within atherosclerotic lesions. Given the dual roles of Fas in both apoptotic and nonapoptotic signaling, the aim of the present study was to test the effect of hematopoietic Fas deficiency on experimental atherosclerosis in low-density lipoprotein receptor-null mice (Ldlr(-/-)). Bone marrow from Fas(-/-) mice was used to reconstitute irradiated Ldlr(-/-) mice as a model for atherosclerosis. After 16 weeks on an 0.5% cholesterol diet, no differences were noted in brachiocephalic artery lesion size, cellularity, or vessel wall apoptosis. However, Ldlr(-/-) mice reconstituted with Fas(-/-) hematopoietic cells had elevated hyperlipidemia [80% increase, relative to wild-type (WT) controls; P < 0.001] and showed marked elevation of plasma levels of CXCL1/KC, CCL2/MCP-1, IL-6, IL-10, IL-12 subunit p70, and soluble Fas ligand (P < 0.01), as well as systemic microvascular inflammation. It was not possible to assess later stages of atherosclerosis because of increased mortality in Fas(-/-) bone marrow recipients. Our data indicate that hematopoietic Fas deficiency does not affect early atherosclerotic lesion development in Ldlr(-/-) mice.

Extracellular administration of BCL2 protein reduces apoptosis and improves survival in a murine model of sepsis.

BACKGROUND: Severe sepsis and septic shock are major causes of morbidity and mortality worldwide. In experimental sepsis there is prominent apoptosis of various cell types, and genetic manipulation of death and survival pathways has been shown to modulate organ injury and survival. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effect of extracellular administration of two anti-apoptotic members of the BCL2 (B-cell lymphoma 2) family of intracellular regulators of cell death in a murine model of sepsis induced by cecal ligation and puncture (CLP). We show that intraperitoneal injection of picomole range doses of recombinant human (rh) BCL2 or rhBCL2A1 protein markedly improved survival as assessed by surrogate markers of death. Treatment with rhBCL2 or rhBCL2A1 protein significantly reduced the number of apoptotic cells in the intestine and heart following CLP, and this was accompanied by increased expression of endogenous mouse BCL2 protein. Further, mice treated with rhBCL2A1 protein showed an increase in the total number of neutrophils in the peritoneum following CLP with reduced neutrophil apoptosis. Finally, although neither BCL2 nor BCL2A1 are a direct TLR2 ligand, TLR2-null mice were not protected by rhBCL2A1 protein, indicating that TLR2 signaling was required for the protective activity of extracellularly adminsitered BCL2A1 protein in vivo. CONCLUSIONS/SIGNIFICANCE: Treatment with rhBCL2A1 or rhBCL2 protein protects mice from sepsis by reducing apoptosis in multiple target tissues, demonstrating an unexpected, potent activity of extracellularly administered BCL2 BH4-domain proteins.

Role of Cdk4 in lymphocyte function and allergen response.

We recently described a new adhesion pathway in lymphocytes that is dependent on Cyclin-dependent kinase (Cdk) 4 activity and mediates lymphocyte interactions with endothelial matrix. We showed that Cdk4(-/-) mice had impaired recruitment of lymphocytes following bleomycin model of acute lung injury. In this study, we characterized the development and function of hematopoietic cells in Cdk4(-/-) mice and assessed the response of Cdk4(-/-) mice to allergen challenge. Cdk4(-/-) mice had hypoplastic thymuses with decreased total thymocyte cell numbers and increased CD4/CD8 double negative cells. Cdk4(-/-) bone marrow (BM) chimeric mice showed similar findings. Thymocytes from either Cdk4(-/-) or Cdk4(-/-) BM chimeric mice proliferated equally well as wild type controls in response to IL-2 activation. However Cdk4(-/-) thymocytes had decreased adhesion to both endothelial cell matrix and fibronectin compared to wildtype (WT) controls, whereas Cdk4(-/-) and WT splenocytes had similar adhesion. When Cdk4(-/-) BM chimeric mice and wild type BM chimeric mice were sensitized and challenged by intranasal administration of ovalbumin, we found no differences in allergic responses in the lung and airways between the two groups, as measured by inflammatory cell infiltrate, airway hyperreactivity, IgE levels and cytokine levels. In summary, we show that Cdk4 plays a previously unrecognized role in thymocyte maturation and adhesion, but is not required for thymocyte proliferation. In addition, Cdk4 is not required for lymphocyte trafficking to the lung following allergen sensitization and challenge.

Attention to gaze and emotion in schizophrenia.

OBJECTIVE: Individuals with schizophrenia have difficulty interpreting social and emotional cues such as facial expression, gaze direction, body position, and voice intonation. Nonverbal cues are powerful social signals but are often processed implicitly, outside the focus of attention. The aim of this research was to assess implicit processing of social cues in individuals with schizophrenia. METHOD: Patients with schizophrenia or schizoaffective disorder and matched controls performed a primary task of word classification with social cues in the background. Participants were asked to classify target words (LEFT/RIGHT) by pressing a key that corresponded to the word, in the context of facial expressions with eye gaze averted to the left or right. RESULTS: Although facial expression and gaze direction were irrelevant to the task, these facial cues influenced word classification performance. Participants were slower to classify target words (e.g., LEFT) that were incongruent to gaze direction (e.g., eyes averted to the right) compared to target words (e.g., LEFT) that were congruent to gaze direction (e.g., eyes averted to the left), but this only occurred for expressions of fear. This pattern did not differ for patients and controls. CONCLUSION: The results showed that threat-related signals capture the attention of individuals with schizophrenia. These data suggest that implicit processing of eye gaze and fearful expressions is intact in schizophrenia.

Regulation of intermittent oscillatory activity of pyramidal cell neurons by GABA inhibitory interneurons is impaired in schizophrenia: rationale for pharmacotherapeutic GABAergic interventions.

GABA, the major inhibitory neurotransmitter in the brain, is synthesized from L-glutamate and packaged within a family of highly differentiated inhibitory interneurons. Individual GABA inhibitory interneurons in the frontal cortex can make terminal synaptic connections with more than 200 distinct pyramidal neurons, the principal output neuron. Moreover, the sites of these synaptic connections include shafts of dendritic spines, soma, dendritic branches, and initial axon segments. The phasic activity of GABAergic neurons regulate intermittent oscillations of assemblies of pyramidal cell neurons, which are critical for many higher cortical functions such as working memory. Potentially, there are several viable pharmacotherapeutic strategies for facilitating GABAergic neurotransmission. A major research question is whether tonically-administered, selective GABAergic therapeutic interventions can mimic and correct disruptions of the intermittent oscillatory activity of assemblies of cortical pyramidal cell neurons.

Extracellular BCL2 proteins are danger-associated molecular patterns that reduce tissue damage in murine models of ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion (I/R) injury contributes to organ dysfunction in a variety of clinical disorders, including myocardial infarction, stroke, organ transplantation, and hemorrhagic shock. Recent investigations have demonstrated that apoptosis as an important mechanism of cell death leading to organ dysfunction following I/R. Intracellular danger-associated molecular patterns (DAMPs) released during cell death can activate cytoprotective responses by engaging receptors of the innate immune system. METHODOLOGY/PRINCIPAL FINDINGS: Ischemia was induced in the mouse hind limb by tourniquet or in the heart by coronary artery ligation. Reperfusion injury of skeletal or cardiac muscle was markedly reduced by intraperitoneal or subcutaneous injection of recombinant human (rh)BCL2 protein or rhBCL2-related protein A1 (BCL2A1) (50 ng/g) given prior to ischemia or at the time of reperfusion. The cytoprotective activity of extracellular rhBCL2 or rhBCL2A1 protein was mapped to the BH4 domain, as treatment with a mutant BCL2 protein lacking the BH4 domain was not protective, whereas peptides derived from the BH4 domain of BCL2 or the BH4-like domain of BCL2A1 were. Protection by extracellular rhBCL2 or rhBCL2A1 was associated with a reduction in apoptosis in skeletal and cardiac muscle following I/R, concomitant with increased expression of endogenous mouse BCL2 (mBCL2) protein. Notably, treatment with rhBCL2A1 protein did not protect mice deficient in toll-like receptor-2 (TLR2) or the adaptor protein, myeloid differentiation factor-88 (MyD88). CONCLUSIONS/SIGNIFICANCE: Treatment with cytokine-like doses of rhBCL2 or rhBCL2A1 protein or BH4-domain peptides reduces apoptosis and tissue injury following I/R by a TLR2-MyD88-dependent mechanism. These findings establish a novel extracellular cytoprotective activity of BCL2 BH4-domain proteins as potent cytoprotective DAMPs.