Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder

Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (P<0.02), insula (P<0.001), primary visual cortex (P<0.05), locus coeruleus (P<0.04), thalamus (P<0.01), and at the trend level in inferior frontal gyrus (P=0.07). All regions except fusiform were moderated by childhood trauma. Amygdala–calcarine (P=0.01) and amygdala–thalamus (P=0.06) functional connectivity selectively increased in PTSD patients for high-intensity stimuli after conditioning. In contrast, amygdala–ventromedial prefrontal cortex (P=0.04) connectivity selectively increased in trauma-exposed controls compared with PTSD patients for low-intensity stimuli after conditioning, representing safety learning. In summary, fear generalization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma.     

Left ventricular pseudoaneurysm after mitral valve replacement

Development of left ventricular pseudoaneurysm is a rare complication of mitral valve surgery and requires urgent surgical intervention. We describe a case of pseudoaneurysm of membranous septum following repeat mitral valve replacement with the use of multimodality imaging.     

Chronic hepatitis C in Latinos: natural history, treatment eligibility, acceptance, and outcomes

OBJECTIVES: The natural history of chronic hepatitis C and treatment response are different between blacks and Caucasians, but little comparable data is available about Latinos. METHODS: A cross-sectional secondary analysis to investigate differences between 421 anti-HCV-positive, treatment-na?ve, HCV-viremic Latinos and 2,510 Caucasians in 24 VA medical centers enrolled in a prospective study. RESULTS: Latinos were infected at a younger age and were less likely to have blood contact during combat, surgery, and needle stick injury, but were more frequently HIV coinfected (20.4%vs 3.9%, p < 0.0001) and prior HAV infection (39.9%vs 26.4%, p= 0.0001). Latinos were more likely to be treatment candidates, but less likely to actually initiate treatment. Liver histology (123 Latinos, 743 Caucasians) showed no difference in fibrosis or fibrosis rate, but steatosis (54.7%vs 43.2%, p= 0.038) was more common in Latinos. Eighty-eight Latinos and 481 Caucasians were subsequently treated with interferon-ribavirin: body mass index (BMI), duration of infection, baseline tests, liver histology and genotype distribution were similar. Compared with Caucasians, Latinos discontinued treatment prematurely more often (39.8%vs 28.9%, p= 0.043) and tended to have lower sustained virological response (SVR) rates (14.8%vs 22.5%, p= 0.10). Multivariate analysis found Latino race and history of recent alcohol use to be associated with early treatment discontinuation, whereas genotype and viral load but not ethnicity to be associated with SVR. CONCLUSIONS: Latinos were infected younger, more frequently HIV coinfected, more likely to meet criteria for antiviral therapy yet less likely to initiate treatment and had a trend toward lower SVR rates than Caucasians, but not in severity of liver disease. Latino ethnicity was associated with early discontinuation but not as an independent predictor of SVR.     

Modulation of the enzymic activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase by multiple kinase systems involving reversible phosphorylation: a review

This report summarizes the current concepts regarding the in vitro and in vivo modulation of the enzymic activity of HMG-CoA reductase and mevalonate formation in rat and human liver, as well as in cultured fibroblasts from normal and familial hypercholesterolemic subjects. Three separate mechanisms for the short-term modulation of hepatic HMG-CoA reductase activity by covalent phosphorylation have been described. These mechanisms involved three separate specific kinase systems including reductase kinase, protein kinase C, and a Ca+2, calmodulin-dependent kinase. The conceptual schemes presented in this report will provide a basis for future research as well as an overview for improved understanding of the complex and multifaceted short-term regulation of this key enzyme in the biosynthetic pathways of mevalonate, ubiquinones, dolichols, isopentenyl-tRNAs, and cholesterol.     

Model to predict mortality in critically ill adults with acute kidney injury

Summary

Background and objectives

Acute kidney injury (AKI) requiring dialysis is associated with high mortality. Most prognostic tools used to describe case complexity and to project patient outcome lack predictive accuracy when applied in patients with AKI. In this study, we developed an AKI-specific predictive model for 60-day mortality and compared the model to the performance of two generic (Sequential Organ Failure Assessment [SOFA] and Acute Physiology and Chronic Health Evaluation II [APACHE II]) scores, and a disease specific (Cleveland Clinic [CCF]) score.

Design, setting, participants, & measurements

Data from 1122 subjects enrolled in the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network study; a multicenter randomized trial of intensive versus less intensive renal support in critically ill patients with AKI conducted between November 2003 and July 2007 at 27 VA- and university-affiliated centers.

Results

The 60-day mortality was 53%. Twenty-one independent predictors of 60-day mortality were identified. The logistic regression model exhibited good discrimination, with an area under the receiver operating characteristic (ROC) curve of 0.85 (0.83 to 0.88), and a derived integer risk score yielded a value of 0.80 (0.77 to 0.83). Existing scoring systems, including APACHE II, SOFA, and CCF, when applied to our cohort, showed relatively poor discrimination, reflected by areas under the ROC curve of 0.68 (0.64 to 0.71), 0.69 (0.66 to 0.73), and 0.65 (0.62 to 0.69), respectively.

Conclusions

Our new risk model outperformed existing generic and disease-specific scoring systems in predicting 60-day mortality in critically ill patients with AKI. The current model requires external validation before it can be applied to other patient populations.     

Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7-1 (CD80) and only a subset express B7-2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7-1 and B7-2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.     

National multicenter study of HIV testing and HIV seropositivity in patients with chronic hepatitis C virus infection

BACKGROUND: Although HIV testing is recommended for persons with hepatitis C virus (HCV) infection who are at risk for HIV, little is known about HIV testing in this population. METHODS: Data were prospectively collected in 4364 HCV-infected patients at 24 Veterans Affairs medical centers across the United States, including demographics, risk factors for HIV infection, and self-reported information on HIV testing. RESULTS: Overall, 76.8% had been tested for HIV at least once, 14.8% were never tested, 6.6% did not know if they were tested, and 1.8% declined to answer. Multivariable analysis identified injection drug use, needlestick injury, sex with a same-sex partner, a greater number of lifetime sexual partners, and sex with an injection drug user as factors that were independently associated with HIV testing. At least one risk factor for HIV infection was present in 84.5% of the 646 patients who were never HIV tested. Among the 3350 subjects who were tested for HIV, 8.4% were positive, 88.3% were negative, 2.4% did not know the results of their test, and 0.9% declined to answer. Multivariable analysis identified African American and Hispanic race/ethnicity, income < or = 10,000 dollars, sex with a same-sex partner, and sex with an injection drug user as the only variables that were independently associated with HIV seropositivity. CONCLUSIONS: Although a substantial proportion of HCV-infected patients have been tested for HIV, missed opportunities for early diagnosis of HIV infection exist. Public health strategies to improve HIV testing among patients with chronic HCV infection are needed.