Association of chronic inflammation and perceived stress with abnormal functional connectivity in brain areas involved with interoception in hepatitis C patients.

BACKGROUND: Sickness behavioral changes elicited by inflammation may become prolonged and dysfunctional in patients with chronic disease, such as chronic hepatitis C (CHC). Neuroimaging studies show that the basal ganglia and insula are sensitive to systemic inflammation. AIM: To elucidate the clinical and neurobiological aspects of prolonged illnesses in patients with CHC. METHODS: Thirty-five CHC patients not treated with interferon-α or other antiviral therapy, and 30 control subjects matched for age and sex, were evaluated for perceived stress (perceived stress scale; PSS), depression (PHQ-9), fatigue and irritability through a visual analog scale (VAS), as well as serum levels of interleukin-6 (IL-6), prostaglandin E2 (PGE2) and oxidative stress markers. Functional MRI was performed, measuring resting-state functional connectivity using a region-of-interest (seed)-based approach focusing on the bilateral insula, subgenual anterior cingulate cortex and bilateral putamen. Between-group differences in functional connectivity patterns were assessed with two-sample t-tests, while the associations between symptoms, inflammatory markers and functional connectivity patterns were analyzed with multiple regression analyses. RESULTS: CHC patients had higher PSS, PHQ-9 and VAS scores for fatigue and irritability, as well as increased IL-6 levels, PGE2 concentrations and antioxidant system activation compared to controls. PSS scores positively correlated with functional connectivity between the right anterior insula and right putamen, whereas PHQ-9 scores correlated with functional connectivity between most of the seeds and the right anterior insula. PGE2 (positively) and IL-6 (negatively) correlated with functional connectivity between the right anterior insula and right caudate nucleus and between the right ventral putamen and right putamen/globus pallidus. PGE2 and PSS scores accounted for 46% of the variance in functional connectivity between the anterior insula and putamen. CONCLUSIONS: CHC patients exhibited increased perceived stress and depressive symptoms, which were associated with changes in inflammatory marker levels and in functional connectivity between the insula and putamen, areas involved in interoceptive integration, emotional awareness, and orientation of motivational state.

A body, a dog, and a fistful of scats.

Dogs and coyotes are the most frequently reported canids responsible for scavenging human remains. We present the case of a 90-year-old woman whose mummified body was found in her home showing partial destruction of the thorax and extremities and absence of the cranium. The victim lived with a beagle dog whose dead body was also found, along with abundant scats throughout the house. Scavenging by the decedent's pet was the proposed hypothesis for the partial dismemberment and consumption of her body. Forensic analysis revealed that the victim died as a result of an accidental fracture of the proximal femoral epiphysis. Bone exam showed signs of canine scavenging on certain bones. Macroscopic and histological analyses of the dog feces revealed the presence of small bone fragments within scats. All the collected data supported the hypothesis that the decedent's pet fed on the victim following her death. The current case illustrates that forensic anthropology has much more to offer than personal identification and determining the manner of death. Systematic search and examination of scat deposits recovered from the scene may be very useful in the medicolegal investigation, identifying the origin of body mutilation and particularly the animal responsible for any scavenging.

Serotonin and interleukin-6: the role of genetic polymorphisms in IFN-induced neuropsychiatric symptoms.

BACKGROUND: Cytokines and serotonin neurotransmission may play an important role on the development of psychopathological symptoms during interferon (IFN) treatment. The aim of the present study was to investigate the association between IFN-induced depression, anxiety and fatigue and functional genetic variants at the interleukin-6 gene (IL-6) and serotonin transporter gene (SERT). METHODS: 385 consecutive Caucasian outpatients with chronic hepatitis C initiating treatment with IFN-alpha and ribavirin were included. All patients were interviewed at baseline using the Structured Clinical Interview for DSM-IV (SCID-I) and those with a current major depressive disorder or anxiety disorder before starting treatment were excluded. Depression and anxiety were assessed at baseline during the treatment (at 4, 12, 24 and 48 weeks) using the Hospital Anxiety and Depression Scale and fatigue was evaluated using a visual analogue scale. The 5-HTTLPR region of SERT gene and the functional polymorphism located at the promoter region of IL-6 gene (rs1800795) were genotyped. RESULTS: Genotypic distribution was in the Hardy-Weinberg equilibrium for SERT (p=0.41) and for IL-6 (p=0.72) polymorphisms. At baseline we found only a significant effect of IL-6 polymorphism on fatigue symptoms. During antiviral treatment we reported that subjects with CC genotype (IL-6) presented significantly lower changes from baseline in IFN-induced depression (p=0.005) and IFN-induced anxiety (p=0.004). We did not find statistically significant differences on depression (p=0.21) or anxiety (p=0.15) between SS/SL and LL genotypes of SERT. CONCLUSIONS: Genetic variations in the IL-6 gene increase the risk of IFN-induced depression and anxiety. The IL-6 polymorphism was associated with fatigue rates in patients with chronic hepatitis C before treatment. Our study confirms the role of inflammatory mechanisms in IFN-induced psychopathological symptoms.

Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Depression is one of the main reasons for treatment withdrawal and failure in chronic hepatitis C patients treated with interferon. Antidepressants are useful for its treatment, but whether they can also be used for prevention has yet to be established. METHOD: To evaluate the efficacy and safety of escitalopram for preventing interferon alfa-2a-induced depression, we conducted an investigator-initiated multicenter, randomized, double-blind, placebo-controlled trial in 133 chronic hepatitis C patients without baseline mental disorders who were randomly assigned to receive escitalopram or placebo during the first 12 weeks of treatment. Primary efficacy outcomes were the development of DSM-IV major depression and scores on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hospital Anxiety and Depression Scale (HADS). Primary safety end points were biochemical and virological responses. Patients were recruited between March 2005 and July 2006. RESULTS: Rates of major depression were low (5.4%) and did not differ between placebo (3.2%) and escitalopram (7.6%). MADRS and HADS scores significantly increased during treatment (P < .001 and P = .028, respectively), but there were no differences between treatment groups. Sustained virological response was achieved by 69.2% of patients, 70.4% in the placebo group and 67.9% in the escitalopram group. CONCLUSIONS: Findings do not support the use of an antidepressant to prevent interferon-induced depression during the first 12 weeks of treatment in chronic hepatitis C patients at low psychiatric risk. Future studies should be directed to subpopulations of patients at high psychiatric risk. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00166296.

Differences in virological response to pegylated interferon and ribavirin between hepatitis C virus (HCV)-monoinfected and HCV-HIV-coinfected patients.

BACKGROUND: Suboptimal doses of ribavirin have been suggested to explain the diminished efficacy of pegylated interferon (PEG-IFN) plus ribavirin in hepatitis C virus (HCV)-HIV-coinfected patients. METHODS: A cohort of 104 coinfected patients and an age-, sex- and genotype-matched cohort of HCV-monoinfected patients (n = 104) were compared. All patients received PEG-IFN-alpha2a 180 microg/week plus ribavirin 800-1,200 mg daily (HCV genotype 2/3 patients received 800 mg daily and those with genotype 1/4 received 1,000-1,200 mg daily) for 48 weeks (24 weeks for monoinfected patients with genotypes 2/3). HCV RNA levels were determined qualitatively at weeks 4, 12, 24, 48 and 72 and quantified monthly until week 12. RESULTS: The coinfected cohort had more advanced liver disease and lower body weight. HCV genotype 1 patients coinfected with HIV showed higher levels of HCV RNA than monoinfected patients. A significantly higher proportion of coinfected patients interrupted the prescribed treatment period prematurely (84% versus 98%). During the first 12 weeks, smaller decreases in HCV RNA levels were observed in coinfected patients. Among patients with HCV genotype 1, coinfected patients achieved lower rates of early virological response (64% versus 87%), end-of-treatment response (47.3% versus 80%) and sustained virological response (SVR; 27.3% versus 56.4%), but not rapid virological response (RVR). HCV-HIV-coinfected patients with HCV genotype 2/3 achieved significantly lower rates of RVR (52% versus 88%). Multivariate analysis identified RVR, gender and liver fibrosis as independent predictors of SVR. CONCLUSIONS: Differences in efficacy of PEG-IFN-alpha2a plus ribavirin treatment between HCV-HIV-coinfected and HCV-monoinfected patients were maintained despite optimized ribavirin dose.