Effective antiretroviral therapy reduces degradation of tryptophan in patients with HIV-1 infection

Antiretroviral therapy (ART) has a significant impact on HIV-1 RNA levels, the CD4 cell count, and immune activation. We examined whether these changes are associated with a change in the rate of tryptophan degradation (expressed as the kynurenine to tryptophan ratio, kyn/trp) as an estimate for the activity of interferon-gamma inducible enzyme indoleamine (, )-dioxygenase (IDO). Plasma levels of tryptophan, kynurenine, and neopterin were measured pretherapy and 6 months postinitiation of therapy in 45 patients with HIV-1 RNA levels of less than 1000 copies/ml 6 months after initiation of ART. Before ART, the patients had decreased tryptophan and increased kynurenine concentrations compared to healthy controls. During ART, average tryptophan levels increased; in the same time kynurenine and kyn/trp decreased (P < 0.001), although not to normal levels. Since pretherapy tryptophan concentrations correlated inversely with neopterin, and kynurenine correlated with viral load and neopterin but not with CD4 cell count, the data support the view that HIV production may induce immune activation and consequently tryptophan is degraded at a higher rate. In agreement, kyn/trp positively correlated with neopterin (r(s) = 0.60, P < 0.001), with virus load (r(s) = 0.37, P = 0.013), and very weakly with CD4(+) cells counts (r(s) = 0.30, P = 0.049). The change in the kyn/trp ratio during ART correlated more strongly with the change in neopterin levels (r(s) = 0.49, P = 0.001) than with the change in HIV RNA levels and weakly with the CD4 cell count. The data underscore the fact that both neopterin production and tryptophan degradation are triggered by immune activation. Tryptophan degradation is increased in HIV infection and partially reversed under ART. The data agree with the concept that immune activation is the common background of IDO activation which may be an important factor underlying T-cell hyporesponsiveness.     

Computerized Digital Imaging Techniques Provided by Digital X-ray Radiogrammetry as New Diagnostic Tool in Rheumatoid Arthritis

Purpose Our study evaluates digital x-ray radiogrammetry (DXR) and Radiogrammetry Kit (RK) as a new diagnostic method for the measurement of disease-related osteoporosis including quantification of joint space narrowing dependent on the severity of rheumatoid arthritis (RA). Materials and Methods A total of 172 unselected patients with RA underwent computerized measurements of bone mineral density (BMD) and metacarpal index (MCI) by DXR, as well as a semiautomated measurement of joint space distances at the metacarpal–phalangeal articulation (JSD-MCP 2–5), both were analyzed from plain radiographs of the nondominant hand. Results Correlations between DXR-BMD and DXR-MCI vs. parameters of RK were all significant (0.34 < R < 0.61; p < 0.01). An expected negative association was observed between RK parameters and the different scoring methods (−0.27 < R < −0.59). The maximum relative decrease in BMD vs. MCI as measured by DXR between the highest and lowest RA severity group was −27.7% vs. −27.5% (p < 0.01) for the modified Larsen Score, whereas the minimal value of relative DXR-BMD and DXR-MCI reduction could be documented for the Sharp Erosion Score (−20.8% vs. −26.8%; p < 0.01). The relative reduction of mean JSD-MCP using RK significantly varied from −25.0% (Sharp Erosion Score) to −41.2% (modified Larsen Score). In addition, an excellent reproducibility of DXR and RK could be verified. Conclusion DXR in combination with RK could be a promising, widely available diagnostic tool to supplement the different scoring methods of RA with quantitative data, allowing an earlier and improved diagnosis and more precision in determining disease progression.     

Effect of lipid lowering diet on low density lipoprotein receptor activity in freshly isolated peripheral blood mononuclear cells

The effect of lipid lowering diet on low density lipoprotein (LDL) receptor activity has been studied in freshly isolated peripheral blood mononuclear cells (PBMCs) from 16 hypercholesterolemic male subjects during a three weeks' dietary intervention trial. The participants were randomized to an intervention group or to a control group. The subjects in the intervention group had a non-significantly larger increase in LDL receptor activity, determined as degradation of 125I-LDL at 37 degrees C, than the control group (49.7 +/- 18.1 and 35.4 +/- 21.2 ng/mg, respectively). Irrespective of assignment to the intervention group or control group, the eight subjects with the largest reduction in total serum cholesterol had significantly larger absolute and percentage increases in LDL receptor activity than the eight subjects with the smallest reduction in total serum cholesterol (p less than 0.05). Thus, it appears that the cholesterol reduction that can be achieved in humans by dietary intervention results in a small increase in LDL receptor activity in freshly isolated PBMCs.     

Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium

BACKGROUND: Venous thromboembolism is a leading cause of morbidity and mortality during pregnancy and the puerperium. However, the role of mutations in the prothrombin and factor V genes and other thrombophilic abnormalities as risk factors for thromboembolism in women during pregnancy and the pueperium is not known. METHODS: In a study of 119 women with a history of venous thromboembolism during pregnancy and the puerperium and 233 age-matched normal women, we measured the activity of antithrombin, protein C, protein S, and lupus anticoagulant. We also performed genetic analyses to detect the G1691A mutation in the factor V gene (factor V Leiden), the G20210A mutation in the prothrombin gene, and the C677T mutation in the methylenetetrahydrofolate reductase gene. Blood samples were obtained at least three months post partum or after the cessation of lactation. RESULTS: Among the women with a history of venous thromboembolism, the prevalence of factor V Leiden was 43.7 percent, as compared with 7.7 percent among the normal women (relative risk of venous thromboembolism, 9.3; 95 percent confidence interval, 5.1 to 16.9); that of the G20210A prothrombin-gene mutation, 16.9 percent as compared with 1.3 percent (relative risk, 15.2; 95 percent confidence interval, 4.2 to 52.6); and that of both factor V Leiden and the G20210A prothrombin-gene mutation 9.3 percent as compared with 0 (estimated odds ratio, 107). Assuming an overall risk of 1 in 1500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2 percent, among carriers of the G20210A prothrombin-gene mutation, 0.5 percent, and among carriers of both defects, 4.6 percent, as calculated in a multivariate analysis. CONCLUSIONS: The G20210A prothrombin-gene mutation and factor V Leiden individually are associated with an increased risk of venous thromboembolism during pregnancy and the puerperium, and the risk among women with both mutations is disproportionately higher than that among women with only one mutation.     

Strategic control and medial frontal negativity: beyond errors and response conflict

Errors in timed choice tasks typically produce an error-related negativity (ERN) in the event-related potential (ERP). The error specificity of the ERN has been challenged by studies showing a correct response negativity (CRN). Forty-five participants engaged in a flanker task in which both compatibility between flankers and target and the probability of compatible flankers were manipulated. Correct responses elicited a CRN, the amplitude of which increased with the degree of mismatch between the presence of conflict and conflict probability, even on low-conflict (compatible) trials. The fronto-central N2 component was larger on high-conflict (incompatible) correct response trials. However, in contrast to some recent accounts, this N2 was largest for highly probable stimuli. These findings suggest revision to models of the effects of conflict on response-related negativity to account for strategic adjustments made in preparation for the response.     

Obsessive-compulsive bipolar comorbidity: focus on children and adolescents

BACKGROUND: Growing evidence documents the frequent co-morbidity between Obsessive Compulsive Disorder (OCD) and Bipolar Disorder (BP) in adults. The aim of the present study is to explore some clinical aspects of this interface in children and adolescents, as it appears in a setting of routine clinical practice. METHOD: The sample comprised 102 consecutively referred children and adolescents, both inpatients and outpatients, with BP, OCD or co-morbid BP-OCD during a 3-year period. The mean age was 14.2 (SD=3.2); 65 (63.7%) were males. Diagnoses and clinical features were collected by means of structured interview according to DSM-IV (DICA-R) and a rating scale for OCD (CY-BOCS). Clinical outcome was evaluated prospectively by means of clinical global impression (CGI) as part of routine clinical care, throughout the follow-up. RESULTS: Thirty-seven (36.3%) patients (21 males and 16 females) were diagnosed as BP, 35 (34.3%) patients (26 males and 9 females) were diagnosed as OCD and 30 (29.4%) patients (18 males and 12 females) were diagnosed as BP-OCD. BP II, was more frequent in the BP-OCD than in BP. When OCD was co-morbid with BP, age of onset was significantly earlier than in the 'pure' OCD patients. On the contrary, age of onset of BP was not affected by co-morbid OCD. According to CGI baseline scores, OCD patients were significantly less impaired than BP-OCD and BP patients, while the severity of the symptomatology was similar in the last two groups. Severity scores at the end of the follow-up were significantly higher in BP-OCD patients than in OCD patients. Patients with pure BP showed lower rates of panic disorder-agoraphobia than BP-OCD patients and higher rates of ADHD-conduct disorder. Pure OCD patients showed lower rates of ADHD and higher rates of Generalized Anxiety Disorder. The number of obsessions did not differentiate the two groups, whereas pure OCD patients showed significantly more compulsions. 'Other' obsessions-e.g., existential, philosophical, odd and/or superstitious-were significantly more frequent in BP-OCD than in pure OCD patients. Ordering compulsions were significantly more frequent in pure OCD patients. LIMITATIONS: Possible low reliability of children's and their parents' recall of past episodes of mental disorder. CONCLUSIONS: In a tertiary care center, co-morbidity between OCD and BP is a significant clinical problem affecting a large number of patients. The correct identification of OCD-bipolar co-morbidity has relevant clinical implications as far as other concomitant disorders, symptomatological features, course, complications, and treatment management and outcome are concerned.     

Antigenic sites of coxsackie A9 virus inducing neutralizing monoclonal antibodies protective in mice

A panel of murine IgG monoclonal antibodies (MAbs) was produced against coxsackievirus A9 (CAV9). Fifty-nine MAbs reactive in ELISA with purified CAV9 were identified. Eighteen of them could efficiently inhibit infection by CAV9 but not coxsackieviruses B. Neutralization-resistant CAV9 variants to four different MAbs were isolated and tested for resistance to neutralization by other MAbs of the panel. Three groups of reactivity including 10, 7, and 1 MAbs were thus identified. Sequencing of neutralization-escape virus mutants showed that neutralization by one MAb group was affected by change of VP3 amino acids 62 or 69. For the second group of reactivity, mutations included amino acids 154 or 165 of VP2. The only MAb of the third group selected for a change at residue 70 of VP2. Protection studies in a newborn mouse model of myositis suggested that either epitopes in VP2 or in VP3 mediate protection from CAV9 infection in vivo.     

“High spinal” dysrhaphism

Summary High spinal (cervical and upper thoracic) dysrhaphism usually involves either a meningocele or a dermal sinus tract. These high spinal lesions can have a complex intradural anatomy at the level of the lesion (as this case reports) and are associated with an increased incidence of lower spinal occult dysrhaphic anomalies. It is therefore recommended that patients with high spinal dysrhaphism undergo radiological evaluation of the entire spine to identify those patients with intradural anomalies, define the anatomy for surgery, and investigate the lower spine for associated occult anomalies.