Skin reaction in antiviral therapy for chronic hepatitis C: a role for polyethylene glycol interferon?

In the past decade, different modalities of antiviral therapy have been adopted aimed at eradicating hepatitis C virus infection. Initially, interferon was used in monotherapy, then interferon combined with ribavirin and amantadine. Recently, interferon has been conjugated with polyethylene glycol to allow optimization of its pharmacokinetic properties and to improve its antiviral activity. This study focused on the characteristics of the skin reactions that we observed in 27 patients with na?ve hepatitis C who received polyethylene glycol interferon-ribavirin-amantadine or polyethylene glycol interferon-ribavirin and in 10 previous non-responders to interferon monotherapy who were retreated with triple therapy. In 9 patients (7 on triple therapy) dermatitis-like lesions were observed, and in 5 the severity of the lesions necessitated withdrawal from therapy.     

Environmental modulation of the interoceptive effects of amphetamine in the rat

The aim of the present study was to investigate the effect of environmental novelty on amphetamine discrimination. Two groups of rats (home group and novelty group) were trained to perform water-reinforced operant behavior in cages equipped with two levers and a retractable liquid dipper (0.1cc cup). The experimental procedures for the two groups were identical except for the fact that home rats were housed and tested in the operant cages whereas novelty rats were transferred daily to these cages for the testing sessions (25min). The rats were trained to discriminate one of two doses of amphetamine (0.25 and 0.5mg/kg) from saline. Saline and amphetamine were administered intraperitoneally immediately before each daily session according to a semi-random schedule for a total of 50 sessions. Reinforcements were delivered according to a fixed ratio that was increased daily from 2 to 30. Successful drug discrimination was achieved when activity on the appropriate lever before the first reinforcement was greater than 80% of total activity, on at least seven out of eight consecutive sessions. When training was conducted with 0.25mg/kg of amphetamine, no home rat acquired drug discrimination whereas 56% of novelty rats reached criterion. When training was conducted with 0.5mg/kg of amphetamine, drug discrimination was achieved by 50% of home rat versus 86% of novelty rats. These findings indicate that environmental novelty can alter the ability of amphetamine to produce interoceptive cues.     

Benign focal epilepsy with onset in infancy in a patient with 18q-syndrome

Case report The 18q-syndrome is sometimes associated with epilepsy. We report a child with a 18q deletion who showed the typical manifestations of the syndrome. In addition, she had benign focal epilepsy with onset in infancy characterized by complex partial seizures with a frequency from 1 to 20 per day. This type of epilepsy is a rare condition and this is the first report of benign focal epilepsy with onset in infancy in a child with 18q-syndrome. The EEGs performed during sleep showed low-voltage spikes over the fronto-central region of the left hemisphere. The magnetic resonance imaging of the brain was normal.Conclusion In conclusion, benign focal epilepsy with onset in infancy could be a condition associated with 18q-syndrome.     

Association after linkage analysis indicates that homozygosity for the 46C-->T polymorphism in the F12 gene is a genetic risk factor for venous thrombosis

In a family-based study called GAIT (Genetic Analysis of Idiopathic Thrombophilia) that included a genome-wide scan we demonstrated that a polymorphism (46C-->T) in the F12 locus jointly influences variability of plasma (Factor XII) FXII levels and susceptibility to thrombotic disease. It then became germane to determine the prevalence of the 46C-->T polymorphism and its relative risk of thrombotic disease. We followed up evidence for genetic linkage with a case-control study, including 250 unrelated consecutive Spanish patients suffering from venous thrombotic disease and 250 Spanish subjects matched for sex and age as a controls. We measured FXII levels and genotyped the 46C-->T polymorphism, as well as a number of classical risk factors for thrombotic disease.We confirmed that individuals with different genotypes for this polymorphism showed significant differences in their FXII levels. Most importantly, the mutated T allele in the homozygous state (genotype T/T) was associated with an increased risk of thrombosis (adjusted OR of 4.82; 95% CI 1.5-15.6), suggesting that the polymorphism itself is an independent risk factor for venous thromboembolism. This study confirms that the 46C-->T polymorphism is a genetic risk factor for venous thrombosis in the Spanish population. In addition, our results confirm that a genome-wide scan coupled with a classical case-control association study is an extremely valuable approach to identify DNA variants that affect complex diseases.     

Impaired fear processing in right mesial temporal sclerosis: a fMRI study

Lesion and neuroimaging studies have demonstrated that the mesial temporal lobe is crucial for recognizing emotions from facial expressions. In humans, bilateral amygdala damage is followed by impaired recognition of facial expressions of fear. To evaluate the influence of unilateral mesial temporal lobe damage we examined recognition of facial expressions and functional magnetic resonance (fMRI) brain activation associated with incidental processing of fearful faces in thirteen mesial temporal lobe epilepsy (MTLE) patients (eight with right MTLE, five with left MTLE). We also examined the effect of early versus later damage, comparing subjects with hippocampal-amygdalar sclerosis (MTS) and seizures occurring before five years of age to epilepsy patients with late onset seizures. Fourteen healthy volunteers participated as controls. Neuropsychological testing demonstrated that the ability of right MTLE patients to recognize fearful facial expressions is impaired. Patients with early onset of seizures were the most severely impaired. This deficit was associated with defective activation of a neural network involved in the processing of fearful expressions, which in controls and left MTLE included the left inferior frontal cortex and several occipito-temporal structures of both hemispheres.     

Effects of aminoguanidine and cyclooxygenase inhibitors on nitric oxide and prostaglandin production, and nitric oxide synthase and cyclooxygenase expression induced by lipopolysaccharide in the estrogenized rat uterus

BACKGROUND/OBJECTIVE: The aim of our study was first to investigate if there exists an interaction between nitric oxide (NO) and prostaglandin (PG) generation in the estrogenized rat uterus challenged by lipopolysaccharide (LPS), and, secondly, which isoforms of nitric oxide synthase (NOS) and cyclooxygenase (COX) participate in this process. METHODS: To study the effect of LPS and to characterize the isoenzymes involved in the process, specific inhibitors of iNOS (aminoguanidine) and COX-II (meloxicam, nimesulide) and non-specific of COX (indomethacin) were injected intraperitoneally to determine their effect on NO and PG production, and on NOS and COX expression induced by LPS in estrogenized rat uterus. NO production was measured by arginine-citrulline conversion assay and PGE(2)/PGF(2alpha,)by radioconversion. Enzyme expression was evaluated by Western blot analysis. RESULTS: The present work shows that iNOS inhibitor, aminoguanidine, reduced NO and PGE(2)/PGF(2alpha) production induced by LPS injection. Aminoguanidine exerts its effect over the PG metabolism by inhibiting COX-II activity and expression. On the other hand, both indomethacin, a non-selective PG inhibitor, and meloxicam, a COX-II inhibitor, stimulated NO production and reduced PGE(2)/PGF(2alpha) generation. Indomethacin also reduced COX-II and iNOS expression. CONCLUSION: These results indicate that in the estrogenized rat uterus challenged with LPS, PG and NO interact affecting each other's metabolic pathways. The above findings indicate that the interaction between NOS and COX might be important in the regulation of physiopathologic events during pregnancy.     

IL-10 inhibits nitric oxide synthesis in murine uterus

OBJECTIVES: Recent reports point to a role for the nitric oxide/nitric oxide synthase (NO/NOS) system in implantation. It has been suggested that inducible NOS expressed at peri-implantation would lead to enhanced NO production, which could promote the attachment of the blastocyst. Short-term administration of NO donors during the pre-implantation period reduced the pregnancy rate in a dose-dependent manner. Thus, it is thought that optimal levels of NO are critical for embryo implantation, so regulation of NOS must be crucial. Taking this into consideration, interleukin-10 (IL-10), synthesized and secreted by the embryo, could be modulating NOS during implantation. In this study we have investigated the in vitro effect of IL-10 on NOS in the uterus. METHODS: To determine the effect of IL-10, slices of uterus from estrogenized mice were pre-incubated for 60 min with different concentrations of IL-10 and NOS activity was measured. RESULTS: IL-10 (50 and 100 ng/ml in vitro) diminished NOS activity. The in vivo administration of lipopolysaccharide (LPS; 8 mg/kg) significantly increased the conversion of arginine into citrulline. This effect was abolished after 60 min of preincubation with IL-10 (100 ng/ml). The stimulatory effect of LPS and estrogen on NOS activity is exerted on the Ca-independent isoform and IL-10 in vitro abolished this increase. We observed that the uterus of pregnant mice on day 5 of gestation synthesized NO. This production was significantly inhibited by preincubation with IL-10 (100 ng/ml). CONCLUSIONS: This report demonstrates that IL-10 is capable of inhibiting NO synthesis in estrogenized, LPS-treated and pregnant rat uterus.     

Language of dyspnea in panic disorder

Dyspnea is a key symptom in panic attacks. This study investigated different types of dyspnea induced by the 35% CO2 challenge test given to patients with panic disorder (PD). The types of dyspnea provide room for possible conjectures on neurophysiological pathways involved in the experience of breathing discomfort in PD and in the panic-respiration connection. Factor analysis applied to the Dyspnea Questionnaire identified three main factors: breathing effort, sense of suffocation, and rapid breath. Factor scores for breathing effort and sense of suffocation significantly discriminated between patients who did and those who did not report CO2-induced panic attacks. Factor scores for breathing effort significantly discriminated between patients whose reaction resembled their unexpected panic attacks and those whose reaction did not. A dissociation between an increased central respiratory command and a decreased mechanical efficiency of the respiratory response in patients with PD may underlie the breathing effort factor during the CO2 challenge. The sense of suffocation factor was found to be linked to chemosensitivity. Although involved in CO2 reactivity, it may not be a central factor in unexpected panic attacks.     

Update on Creutzfeldt-Jakob disease

PURPOSE OF REVIEW: Prion diseases are transmissible fatal neurodegenerative disorders in which infectivity is associated with the accumulation of PrP(Sc), a disease-related isoform of normal cellular prion protein. The recent emergence of variant Creutzfeldt-Jakob disease has led to major public health concerns, and the need for the development of effective treatments. As PrP(Sc) is associated both with pathology and infectivity, therapeutic approaches to date have largely aimed at preventing its accumulation, but this strategy has produced only modest results in animal models. The link between PrP(Sc) and neurotoxicity is unclear, and alternative pathological processes need to be considered. Here we focus on the latest progress in therapeutic strategies and potential mechanisms of prion neurotoxicity. RECENT FINDINGS: Passive immunisation with anti-prion protein antibodies prevents peripheral prion replication and blocks progression to clinical disease in peripherally infected mice. A new approach, in which neuronal cellular prion protein is depleted in mice with established neuroinvasive prion infection, prevents the onset of clinical disease, blocks neuronal cell loss and reverses early spongiform pathology. This dramatic protective effect occurs despite the continued build-up of extraneuronal PrP(Sc) and continued replication of prion infectivity, effectively producing a sub-clinical state. SUMMARY: New insights into the mechanisms of neurotoxicity in prion diseases support the concept that PrP(Sc) itself is not directly neurotoxic. They suggest that neuronal prion propagation results in the production of a toxic intermediate or depletion of a key constituent. Prevention of the formation of such a species rather than PrP(Sc) accumulation itself is a clear target for prion therapeutics.     

Comorbidity: alcohol use and other psychiatric disorders

Alcohol related disorders often coexist with other psychiatric disorders and its incidence is increasing in last decades. Studies show that patients with comorbidity, specially those with severe psychiatric disorders, have higher rates of suicide, relapse, money spent in treatment, homeless and they use more medical service. Their evaluation must be meticulous because the differential diagnosis become complicated without a long period of alcohol withdrawal. These patients have a worse prognostic and their treatment is more difficult. Most of studies in this area have indicated that the integration of psychosocial and pharmacological techniques is more effective. The long term treatment must focus in the reduction of symptoms, improvement of social and familiar functioning, coping skills and relapse prevention.