Classical center-surround receptive fields facilitate novel object detection in retinal bipolar cells.

Antagonistic interactions between center and surround receptive field (RF) components lie at the heart of the computations performed in the visual system. Circularly symmetric center-surround RFs are thought to enhance responses to spatial contrasts (i.e., edges), but how visual edges affect motion processing is unclear. Here, we addressed this question in retinal bipolar cells, the first visual neuron with classic center-surround interactions. We found that bipolar glutamate release emphasizes objects that emerge in the RF; their responses to continuous motion are smaller, slower, and cannot be predicted by signals elicited by stationary stimuli. In our hands, the alteration in signal dynamics induced by novel objects was more pronounced than edge enhancement and could be explained by priming of RF surround during continuous motion. These findings echo the salience of human visual perception and demonstrate an unappreciated capacity of the center-surround architecture to facilitate novel object detection and dynamic signal representation.

Exposure to socioenvironmental stress as a predictor of physical and mental health.

The literature demonstrates links between socioenvironmental characteristics, dysregulation of the stress response system, and PTSD, though few studies integrate these factors in one model. In a secondary analysis of cross-sectional data collected by the Survey of the Health of Wisconsin (SHOW), structural equation modeling evaluated the relationships between socioenvironmental stress, cumulative biological risk (CBR), and PTSD symptom severity. The model hypothesized that exposure to socioenvironmental stress was associated with PTSD and that this relationship is mediated by increased CBR. Indices suggest the model provided a good fit to the data and supported socioenvironmental stress and CBR as valid latent constructs. Although the association between CBR and PTSD was not found to be statistically significant in this study, socioenvironmental stress was a significant predictor of PTSD and CBR. Given the role of socioenvironmental factors on CBR and PTSD symptoms, providers need to better assess and incorporate social stressors within evaluation and treatment.

Inhibitory neurons in the superior colliculus mediate selection of spatially-directed movements.

Decision making is a cognitive process that mediates behaviors critical for survival. Choosing spatial targets is an experimentally-tractable form of decision making that depends on the midbrain superior colliculus (SC). While physiological and computational studies have uncovered the functional topographic organization of the SC, the role of specific SC cell types in spatial choice is unknown. Here, we leveraged behavior, optogenetics, neural recordings and modeling to directly examine the contribution of GABAergic SC neurons to the selection of opposing spatial targets. Although GABAergic SC neurons comprise a heterogeneous population with local and long-range projections, our results demonstrate that GABAergic SC neurons do not locally suppress premotor output, suggesting that functional long-range inhibition instead plays a dominant role in spatial choice. An attractor model requiring only intrinsic SC circuitry was sufficient to account for our experimental observations. Overall, our study elucidates the role of GABAergic SC neurons in spatial choice.

Validation of the Injured Trauma Survivor Screen: An American Association for the Surgery of Trauma multi-institutional trial.

BACKGROUND: Psychological distress is common following a traumatic injury event. The Injured Trauma Survivor Screen (ITSS) was developed at a level 1 trauma center to assess for posttraumatic stress disorder (PTSD) and major depressive episode (MDE) following admission for a traumatic injury. The ITSS sensitivity and specificity were analyzed 1 to 3 and 6 to 9 months postinjury to test the validity across trauma centers. METHOD: Four level 1 trauma centers from the East, Midwest, South, and West in the United States recruited 375 eligible adult inpatients (excluded participants included those with moderate or severe traumatic brain injury, whose injury was self-inflicted, were noncommunicative, or were non-English speaking). Baseline sample (White/Caucasian, 63.2%; male, 62.4%; mean (SD) age, 45 (17.11) years; injured by motor vehicle collision, 42.4%) measurements were conducted during index hospitalization. At first follow-up, 69.6% (n = 261) were retained; at second follow-up, 61.3% (n = 230) were retained. Measurements included the ITSS, PTSD Checklist for DSM-5, Center for Epidemiologic Studies Depression Scale-Revised, and Clinician-Administered PTSD Scaled for DSM 5. RESULTS: At follow-up 1, the ITSS PTSD subscale had a sensitivity of 75% and specificity of 78.8%, and the MDE subscale had a sensitivity of 80.4% and specificity of 65.6%. At follow-up 2, the PTSD subscale had a sensitivity of 72.7% and specificity of 83.1%, and the MDE subscale had a sensitivity of 76.1% and specificity of 68.3%. A combined risk group using two symptom based measures administered at baseline produced increased specificity. CONCLUSION: The nine-item ITSS continues to be an efficient and effective risk screen for PTSD and MDE following traumatic injury requiring hospitalization. This multi-institutional validation study creates a solid foundation for further exploration of the generalizability of this screen's psychometric properties in distinct populations. LEVEL OF EVIDENCE: Prognostic study, level III.

Identification of risk for posttraumatic stress disorder symptom clusters early after trauma.

The current study examined how the injured trauma survivor screen (ITSS), a hospital-administered screener of posttraumatic stress disorder (PTSD) and depression, differentially predicted PTSD symptom cluster severity. Participants from a Level 1 trauma center (n = 220) completed the ITSS while inpatient and PTSD symptoms were assessed one-month post discharge. Perceived life threat and intentionality of injury were key predictors of avoidance, re-experiencing, and hyperarousal symptom clusters. However, negative alterations in mood and cognition cluster seemed best predicted by mood and cognitive risk factors. Therefore, the ITSS provides utility in differentially predicting symptom clusters and treatment planning after traumatic injury.

A Randomized Trial of Modified Prolonged Exposure to Prevent the Development of Posttraumatic Stress Disorder in Patients Hospitalized With Traumatic Injuries.

Individuals who require hospitalization after traumatic injuries are at increased risk for developing posttraumatic stress disorder (PTSD); however, few early behavioral interventions have been effective at preventing PTSD within this population. The aim of this pilot study was to assess the feasibility and effectiveness of modified prolonged exposure therapy (mPE) to prevent PTSD and depression symptoms among patients hospitalized after a DSM-5 single-incident trauma. Hospitalized patients were eligible if they screened positive for PTSD risk. Participants (N = 74) were randomly assigned in a parallel-groups design to receive mPE (n = 38) or standard of care treatment (SoC; n = 36) while admitted to the hospital after a traumatic injury. Individuals randomized to the intervention condition received one (42.1%), two (36.8%), or three sessions (15.8%) of mPE, mainly depending on length of stay. There were no significant differences between groups regarding PTSD or depression severity at 1- or 3-months posttrauma, except for more PTSD diagnoses in the intervention group after 1 month, ϕ = -.326. Intervention differences were nonsignificant when we took baseline PTSD symptoms and the nonindependence of the repeated measurements within the data into account. No adverse events were reported. Overall, mPE was no more effective than SoC for hospitalized, traumatic injury survivors with a high PTSD risk. The results may point to a need for a stepped-care approach, where intervention protocols focus on first briefly treating individuals who are actively exhibiting acute stress reactions, then extensively treating those whose symptoms do not decrease over time.

Validation of Abbreviated Four- and Eight-Item Versions of the PTSD Checklist for DSM-5 in a Traumatically Injured Sample.

Rates of posttraumatic stress disorder (PTSD) are three times higher in traumatically injured populations than the general population, yet limited brief, valid measures for assessing PTSD symptom severity exist. The PTSD Checklist for DSM-5 (PCL-5) is a valid, efficient measure of symptom severity, but its completion is time consuming. Subsequently, abbreviated four- and eight-item versions were developed using the Mini-International Neuropsychiatric Interview-7 PTSD module and validated in Veteran samples. This study aimed to validate these abbreviated versions using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), the gold standard for PTSD diagnosis, in a traumatically injured civilian population. Participants were 251 traumatically injured adults (Mage = 42.52 years; 69.3% male; 50.2% Caucasian) recruited from a Level 1 trauma center inpatient unit; 32.3% and 17.9% of participants experienced a motor vehicle crash or gunshot wound, respectively. The CAPS-5 and PCL-5 were administered approximately 6.5 months postinjury. We examined whether compared to the full PCL-5, the abbreviated versions would adequately differentiate between participants with and without a CAPS-5 PTSD diagnosis. The abbreviated versions were highly correlated with the total scale and showed good-to-excellent internal consistency. The diagnostic utility of the abbreviated measures was comparable to that of the total scale regarding sensitivity, suggesting they may be useful as abbreviated screening tools; however, the total scale functioned better regarding specificity. The abbreviated versions of the PCL-5 may be useful screening instruments in the long-term care of traumatic injury survivors and may be more likely to be implemented across routine clinical and research contexts.

Interaction Between Psychiatric Symptoms and History of Mild TBI When Evaluating Postconcussion Syndrome in Veterans.

INTRODUCTION: Symptoms of postconcussive syndrome (PCS) after mild TBI (mTBI) have been shown to resolve quickly, yet new research raises questions about possible long-term effects of this condition. It is not clear how best to address assessment and treatment when someone reports lingering symptoms of PCS. One self-report measure used by the VA and the DoD is the Neurobehavioral Symptom Inventory (NSI), but this measure may be affected by underlying psychiatric symptoms. We investigated whether the NSI is sensitive to mTBI after considering a number of psychiatric and demographic factors. METHODS: This study examined which factors are associated with NSI scores in a Veteran sample (n = 741) that had recently returned from deployment. RESULTS: Post-traumatic stress disorder (PTSD) and depression accounted for most of the variance on the NSI. Although history of mTBI was initially related to NSI, this association was no longer significant after other covariates were considered. CONCLUSIONS: The NSI score was primarily explained by symptoms of PTSD and depression, suggesting that the NSI is not specific to the experience of a brain injury. We recommend cautious interpretation when this measure is used in the chronic phase after mTBI, especially among patients with comorbid depression or PTSD.

Screening and treating hospitalized trauma survivors for posttraumatic stress disorder and depression.

Traumatic injury affects over 2.6 million U.S. adults annually and elevates risk for a number of negative health consequences. This includes substantial psychological harm, the most prominent being posttraumatic stress disorder (PTSD), with approximately 21% of traumatic injury survivors developing the disorder within the first year after injury. Posttraumatic stress disorder is associated with deficits in physical recovery, social functioning, and quality of life. Depression is diagnosed in approximately 6% in the year after injury and is also a predictor of poor quality of life. The American College of Surgeons Committee on Trauma suggests screening for and treatment of PTSD and depression, reflecting a growing awareness of the critical need to address patients' mental health needs after trauma. While some trauma centers have implemented screening and treatment or referral for treatment programs, the majority are evaluating how to best address this recommendation, and no standard approach for screening and treatment currently exists. Further, guidelines are not yet available with respect to resources that may be used to effectively screen and treat these disorders in trauma survivors, as well as who is going to bear the costs. The purpose of this review is: (1) to evaluate the current state of the literature regarding evidence-based screens for PTSD and depression in the hospitalized trauma patient and (2) summarize the literature to date regarding the treatments that have empirical support in treating PTSD and depression acutely after injury. This review also includes structural and funding information regarding existing postinjury mental health programs. Screening of injured patients and timely intervention to prevent or treat PTSD and depression could substantially improve health outcomes and improve quality of life for this high-risk population. LEVEL OF EVIDENCE: Review, level IV.

Detecting PTSD in a traumatically injured population: The diagnostic utility of the PTSD Checklist for DSM-5.

BACKGROUND: The posttraumatic stress disorder (PTSD) Checklist for DSM-5 (PCL-5) is among few validated measures of PTSD severity in line with the DSM-5. Validation efforts among veteran samples have recommended cut scores of 33 and 38 to indicate PTSD; cut scores vary across populations depending on factors such as trauma type. The purpose of this study was to evaluate the diagnostic utility of and identify optimal cut scores for the PCL-5 in relation to the gold standard Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) among traumatically injured individuals 6 months after discharge from a level I trauma center. METHODS: A total of 251 participants completed the PCL-5 and CAPS-5 6 months after discharge from a level I trauma center following traumatic injury. Receiver operating characteristic curve analyses detailed diagnostic accuracy of the PCL-5 and identified the optimal cut score via Youden's J index. Cut scores were also broken down by intentional versus nonintentional injury. RESULTS: The PCL-5 produces satisfactory diagnostic accuracy, with adequate sensitivity and specificity, in a traumatically injured population. Estimates indicate the optimal cut score as >30; the optimal cut score for intentional injuries was >34 and >22 for nonintentional injuries. CONCLUSIONS: This investigation provides support for the PCL-5 in detection of PTSD among injured individuals 6 months after discharge from a level I trauma center. PCL-5 specificity and sensitivity suggest clinicians working with this population can feel confident in using this measure over more onerous structured interviews (e.g., CAPS-5). This study signifies a move toward ensuring those experiencing mental health difficulties after traumatic injury are identified and connected to resources.

Six-month follow-up of the injured trauma survivor screen: Clinical implications and future directions.

BACKGROUND: The injured trauma survivor screen (ITSS) has been shown to predict posttraumatic stress disorder (PTSD) and depression risk at 1 month after traumatic injury. This study explored the ability of the ITSS to predict chronic distress after injury, as well as the impact of combining the ITSS with an additional screening measure. METHODS: Patients were enrolled following admission to a Level I trauma center. Baseline measurements were collected during initial hospitalization, and follow-up measures were collected an average of 6.5 months after injury. Receiver operating characteristic (ROC) curve analyses were run to determine predictive accuracy, controlling for participants who had mental health intervention and for those who experienced additional potentially psychologically traumatic events since their injury event. RESULTS: Utilizing a cut score of 2, the ITSS PTSD scale had a sensitivity of 85.42%, specificity of 67.35%, negative predictive value (NPV) of 91.9% and positive predictive value (PPV) of 51.4%. The combined PTSD risk group (risk positive on the baseline ITSS and the PTSD checklist for the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) had a sensitivity of 72.92%, specificity of 81.63%, NPV of 88.2%, and PPV of 61.6%. Also using a cut score of 2, the ITSS Depression Scale had a sensitivity of 72.50%, specificity of 70.29%, NPV of 91.1%, and PPV of 37.9%. CONCLUSION: The nine-item ITSS, which takes approximately 5 minutes to administer, is a stable screening tool for predicting those most at risk for PTSD and/or depression 6 months after admission to a Level I trauma center following traumatic injury. The combined PTSD risk group data provide evidence that symptom evaluation by a psychologist can improve specificity. These results further inform the recommendation of the American College of Surgeons Committee on Trauma regarding PTSD and depression screening in trauma centers. LEVEL OF EVIDENCE: Prognostic study, level III.

Exploring the gold-standard: Evidence for a two-factor model of the Clinician Administered PTSD Scale for the DSM-5.

OBJECTIVE: The latent factor structure of posttraumatic stress disorder (PTSD) remains a source of considerable variability. The current study compared several a priori factor structures, as well as a novel 2-factor structure of posttraumatic psychological distress as measured by the Clinician Administered PTSD scale for the DSM-5 (CAPS-5). In addition, variability in diagnostic rates according to the divergent DSM-5 and ICD-11 criteria were explored. METHOD: The setting for this study was a Level 1 trauma center in a U.S. metropolitan city. Data were pooled from 2 studies (N = 309) and participants were administered the CAPS-5 at 1 (n = 139) or 6 months postinjury (n = 170). Confirmatory factor analysis (CFA) was used to compare several factor models, and prevalence rates based on DSM-5 and ICD-11 criteria were compared via z tests and kappa. RESULTS: CFAs of 5 factor structures indicated good fit for all models. A novel 2-factor model based on competing models of PTSD symptoms and modification indices was then tested. The 2-factor model of the CAPS-5 performed as well or better on most indices compared to a 7-factor hybrid. Comparisons of PTSD prevalence rates found no significant differences, but agreement was variable. CONCLUSIONS: These findings indicate that the CAPS-5 can be seen as measuring 2 distinct phenomena: posttraumatic stress disorder and general posttraumatic dysphoria. This is an important contribution to the current debate on which latent factors constitute PTSD and may reduce discordance. (PsycINFO Database Record

A regulatory perspective on the evaluation of hallucinogen drugs for human use.

In recent years, there is renewed interest in the study of various hallucinogens for their potential therapeutic effects. In the United States of America (USA), the abuse potential assessment of a drug is carried out as part of the general safety and efficacy evaluation of a drug. Additionally, the abuse potential assessment is taken under consideration in determining if a drug needs to be subject to controls to minimize the abuse of the drug once on the market. This assessment is conducted for all new drugs with central nervous system (CNS) activity, that are chemically or pharmacologically similar to other drugs with known abuse potential, or drugs that produce psychoactive effects predictive of abuse, such as euphoria and hallucinations. This paper describes the regulatory framework for evaluating the abuse potential of new drugs, with emphasis on hallucinogens. The paper discusses the role of the United States Food and Drug Administration (FDA) in the evaluation of the abuse potential of drugs and its role in drug control, and provides an overview of the controlled status of hallucinogens and the requirements to conduct research with Schedule I substances in the USA. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Subchronic anesthetic ketamine injections in rats impair choice reversal learning, but have no effect on reinforcer devaluation.

Previous exposure to a variety of drugs of abuse has been shown to cause long-term impairments in reversal learning and reinforcer devaluation tasks. However, there is mixed evidence in the literature for a long-term effect of ketamine exposure on reversal learning and the long-term effect of ketamine exposure on devaluation is not known. We determined whether repeated injections of an anesthetic dose of ketamine would lead to impairments in choice reversal learning after discrimination learning or impairments in reinforcer devaluation. In two experiments, rats received three injections once-daily of ketamine (100 mg/kg, intraperitoneally) or saline and then began behavioral training 19 days later so that the key reversal learning and devaluation tests would occur about 1 month after the final ketamine injection. This ketamine exposure regimen did not impair learning in our discrimination task, but led to an increase in perseverative errors in reversal learning. However, the same ketamine exposure regimen (or injections of a lower 50 mg/kg dose) had no effect on behavior in the devaluation task. The behavioral patterns observed suggest possible neural mechanisms for the effects of ketamine, but future neurobiological investigations will be needed to isolate these mechanisms.

Utility of the injured trauma survivor screen to predict PTSD and depression during hospital admission.

BACKGROUND: The brief, easily administered screen, the Injured Trauma Survivor Screen (ITSS), was created to identify trauma survivors at risk for development of posttraumatic stress disorder (PTSD) and depression. METHODS: An item pool of PTSD risk factors was created and given, along with a previously created screen, to patients admitted to two Level 1 trauma centers. The Clinician Administered PTSD Scale for DSM-5, the PTSD Checklist for DSM-5, and the Center for Epidemiological Studies Depression Scale Revised were given during a 1-month follow-up. A total of 139 participants were included (n = 139; µ age = 41.06; 30.9% female; 47.5% White/Caucasian; 39.6% Black/African American; 10.1% Latino/Hispanic; 1.4% American Indian; and 1.4% other). Stepwise bivariate logistic regression was used to determine items most strongly associated with PTSD and depression diagnosis 1 month after injury. RESULTS: Forty participants met criteria for a PTSD diagnosis and 28 for depression at follow-up (22 comorbid). ROC curve analysis was used to determine sensitivity (PTSD = 75.00, Depression = 75.00), specificity (PTSD = 93.94, Depression = 95.5), NPV (PTSD = 90.3, Depression = 80.8), and PPV (PTSD = 83.3, Depression = 93.8) of the final nine-item measure. CONCLUSIONS: This study provides evidence for the utility of a predictive screen, the ITSS, to predict which injured trauma survivors admitted to the hospital are at the most risk for developing symptoms of PTSD and depression 1 month after injury. The ITSS is a short, easily administered tool that can aid in reducing the untreated cases of PTSD and depression. LEVEL OF EVIDENCE: Prognostic study, level III.

AO type-C distal radius fractures: the influence of computed tomography on surgeon's decision-making.

BACKGROUND: Computed tomography (CT) has become a widely accepted adjunct imaging tool in the preoperative evaluation of complex intra-articular distal radius fractures. The aim of this study was to evaluate the impact of CT scanning compared with plain X-rays on the choice of intervention in complex distal radius fractures. METHODS: Five orthopaedic surgeons were given the de-identified plain films (AP, lateral and oblique) of 20 closed complex intra-articular distal radius fractures (AO23-C), randomly selected from our institution's prospectively maintained fracture database. Each surgeon individually selected a management option for each patient from a series of five interventions, ranked in increasing level of invasiveness. The same patients' CT scans (in randomized order) were blindly reviewed after a 1-week interval by the same clinicians with the same management options again offered. Kappa statistic was used to measure the intra-observer agreement between X-ray and CT decisions, and inter-observer agreement within each modality. RESULTS: The intra-observer agreement on management between X-rays alone versus CT scan was poor, with an average kappa score of 0.038. Inter-observer agreement based on X-ray alone was higher than that based on CT alone. Regression analysis indicated a trend towards a slightly higher level of invasiveness when the management decision was based on the CT compared with plain X-rays. CONCLUSION: There is a very poor intra- and inter-rater agreement between decision-making based on X-ray and on CT. Decision-making based on CT could increase the level of invasiveness in the surgical management of complex distal radius fractures.

Lisfranc injury and Jones fracture in sports.

This article provides an update and overview of Lisfranc injury and Jones fracture in the athletic population. Sports-related Lisfranc sprains or fractures are subtle injuries that can be easily missed. Now, there is greater understanding of midfoot sprains that represent a spectrum of injury to the Lisfranc ligament complex. Most types of fifth metatarsal fractures have a favorable prognosis and can be treated conservatively. The treatment options for Jones fractures in athletes have been much debated. This article discusses issues related to anatomy, mechanism of injury, clinical presentation, imaging, and diagnosis, which are necessary to appropriately treat these injuries.

Open tibia fractures: timely debridement leaves injury severity as the only determinant of poor outcome.

BACKGROUND: Recent retrospective studies suggest that the time to debridement of open tibia fractures is not a major determinant of outcome. The aim of this prospective study was to determine the modifiable independent predictors of poor outcomes. METHODS: A 36-month prospective observational study ending in December 2009 was performed on consecutive open tibia shaft fracture patients (age >18 years) admitted to a Level 1 trauma center. Demographics, mechanism, Injury Severity Score, fracture type/grade, local contamination, time to debridement, time to antibiotics, and interventions were prospectively recorded. Outcome measures were as follows: length of stay, deep infection, secondary procedures, and presence of union at 6 months and 12 months. Univariate, multivariate, and logistic regression analyses were performed. RESULTS: Eighty-nine consecutive patients (74% male, age 41 years±17 years, Injury Severity Score 15±3, and 37% multiple injured) met inclusion criteria. The mean time to surgical debridement and operative stabilization was 8 hours±4 hours (48% within 6 hours). The average length of stay was 21 days±13 days. Fifteen patients (17%) had deep infection and 5 (6%) required amputation (1 acute and 4 late because of the infection). The 6-month and 12-month union rates were 39% and 67%, respectively. Fifty-six patients (63%) required further procedures (a total of 312). The multivariate regression model (18 variables) showed no independent significant predictors for deep infection or nonunion at 6 months and 12 months (multiple injuries and smoking were closest to reach significance, p=0.08). CONCLUSION: Timely management of open tibia fractures (mean, 8 hours) eliminates time to debridement and contamination as predictors of poor outcome. Patient factors and local and general injury severity determine the outcomes. Aiming for the earliest safe time to debridement minimizes the negative effects of modifiable factors on the outcome.

Serum glutathione transferase does not respond to indole-3-carbinol: A pilot study.

BACKGROUND: Despite the well recognized protective effect of cruciferous vegetables against various cancers, including human colorectal cancers, little is known about how this effect is conferred. It is thought that some phytochemicals found only in these vegetables confer the protection. These compounds include the glucosinolates, of which indole-3-carbinol is one. They are known to induce carcinogen-metabolizing (phase II) enzymes, including the glutathione S-transferase (GST) family. Other effects in humans are not well documented. We wished to assess the effect of indole-3-carbinol on GST enzymes. METHODS: We carried out a placebo-controlled human volunteer study. All patients were given 400 mg daily of indole-3-carbinol for three months, followed by placebo. Serum samples were tested for the GSTM1 genotype by polymerase chain reaction. Serum GST levels were assessed using enzyme-linked immunosorbent assay and Western Blot methodologies. RESULTS: Forty-nine volunteers completed the study. GSTM1 genotypes were obtained for all but two volunteers. A slightly greater proportion of volunteers were GSTM1-positive, in keeping with the general population. GST was detected in all patients. Total GST level was not affected by indole-3-carbinol dosing compared with placebo. Although not statistically significant, the GSTM1 genotype affected the serum GST level response to indole-3-carbinol. CONCLUSION: Indole-3-carbinol does not alter total serum GST levels during prolonged dosing.

Maraviroc, a CCR5 coreceptor antagonist that blocks entry of human immunodeficiency virus type 1.

Inhibition of the human immunodeficiency virus type 1 (HIV-1) coreceptor is an encouraging new approach to pharmacotherapy against HIV. The HIV-1 strain makes use of either the CCR5 or the CXCR4 coreceptor to gain access into host CD4+ cells. Maraviroc, the first HIV-1 CCR5 coreceptor antagonist, blocks entry of HIV-1. This recently approved drug has demonstrated clinically significant decreases in plasma concentrations of HIV-1 RNA and increases in CD4+ cell counts; however, it is indicated only for use as salvage therapy. Drug resistance is a concern, as is selective pressure on viral coreceptor use, because viral coreceptor targets may switch as disease progresses. In addition, before maraviroc therapy can be started, costly assays are required to determine the host's viral coreceptor tropism. Emerging therapies targeting CXCR4, the other HIV coreceptor, have shown promise in decreasing plasma concentrations of HIV-1 RNA. Long-term studies with both targets are required to explore the critical issues of efficacy and immunologic safety, as the function of these coreceptors is linked to host chemokine pathways.