Natalizumab efficacy on cognitive impairment in MS.

We report follow-up data on the efficacy of natalizumab therapy on neuropsychological impairment on an italian MS group of 39 patients at 1 year and of 11 patients at 2 years. Results show a significant reduction in relapse rate, in the number of impaired neuropsychological tests as well as in several single executive function and reasoning tests scores at 1 year. Improvement persisted at 2 years, including also memory and speed processing tasks. These data support the efficacy of natalizumab therapy in all the clinical domains, including cognitive deterioration, in multiple sclerosis patients.

Neuropsychological rehabilitation in adult multiple sclerosis.

Neuropsychological impairment affects 40-65% of multiple sclerosis patients, mainly involving speed in information processing, attention, executive functions and memory. Deterioration occurs over time independently from disability and seems to correlate particularly with magnetic resonance imaging (MRI) atrophy measures. Studies on therapies effective in controlling cognitive impairment are scanty. We found that intensive and specific training of attention, information processing and executive functions is significantly effective in ameliorating both neuropsychological treated functions and in reducing depression. Preliminary functional MRI data suggest that possible neural correlates of this neuropsychological training could be an exercise-induced activation of prefrontal and cingulate cortices.

Longitudinal serum neurofilament light chain (sNfL) concentration relates to cognitive function in multiple sclerosis patients.

BACKGROUND: Serum neurofilament light chain (sNfL) may be used as a biological marker of disease progression in multiple sclerosis (MS), although longitudinal studies correlating cognitive deficits to sNfL are limited. OBJECTIVE: To longitudinally investigate the relation between cognitive dysfunction, sNfL and MRI brain volume in a relapsing remitting MS patients. METHODS: 18 MS patients (9 males and 9 females, mean age 45 years, mean education 12.6 years) all prescribed with interferon beta 1a (44 mcg 3 times per week), are longitudinally evaluated by means of annual clinical exam with EDSS, neuropsychological evaluation with Brief repeatable battery (BRB) and Delis Kaplan Executive function test (DKEFS), dosage of sNfL (SIMOA) and MRI. RESULTS: Here are reported the results of 1 year follow-up. A significantly higher sNfL in MS compared to healthy controls and higher sNfL in patients with greater cognitive impairment were found. Cognitive Impairment Index, memory, executive function tests correlated with sNfL. Gray matter volume resulted unchanged at 1-year follow-up; a weak correlation between some tests' score and selective cortical brain areas was found. CONCLUSION: Our longitudinal pilot study confirms that sNfL are related to cognitive abilities, confirming data of other authors from retrospective studies.

Measurement of the sensitivity of different commercial assays in the diagnosis of CMV infection in pregnancy.

To evaluate the performance of different commercial assays for the detection of recent cytomegalovirus (CMV) in pregnancy, the sensitivity and specificity of assays for CMV-specific IgM antibodies were compared. Routine specimens from pregnant women were screened for CMV IgM using the Abbott AxSYM assay. Sera that were reactive according to AxSYM were further tested for IgM by other commercial assays. In selected IgM positive samples a CMV IgG avidity assay (Radim) and virus isolation from urine (shell vial) were also performed. The positivity rate for IgM anti-CMV by AxSYM was relatively high (140 out of 492, combining reactive and grayzone results). Only 26 of the 140 samples were positive for IgM according to Radim. The IgG avidity was low in 16 of the 43 samples tested, and the Radim and DiaSorin IgM assays were negative in 5 of them; 2 of the latter cases were also positive for viral isolation according to a shell vial method. There are differences in the sensitivity of the commercially available tests for CMV antibodies. CMV screening in pregnancy is performed as a first step by immunoassays and the choice of highly sensitive IgM test associated with further serological and virological methods could help to identify early primary infections.

Pharmacodynamics of peginterferon alpha-2a and peginterferon alpha-2b in interferon-naïve patients with chronic hepatitis C: a randomized, controlled study.

BACKGROUND: Peginterferon alpha-2a and alpha-2b, the two commercially available pegylated interferons, have different pharmacokinetic properties that produce differing abilities to suppress replication of the hepatitis C virus. AIM: To compare the pharmacodynamics of peginterferon alpha-2a and peginterferon alpha-2b in interferon-naive patients with chronic hepatitis C. METHODS: Patients were randomized to receive peginterferon alpha-2a, 180 microg (n = 10) or peginterferon alpha-2b 1.0 microg/kg (n = 12) once weekly. The enzymatic activity of 2'5'-oligoadenylate synthetase and levels of neopterin and beta(2)-microglobulin were measured at baseline and at 24, 48, 120 and 168 h. RESULTS: Oligoadenylate synthetase activity and serum neopterin and beta(2)-microglobulin concentrations did not differ significantly between the two patient groups at any time point, nor was there a significant correlation between the serum area under the concentration-time curve of either peginterferon and the area under the concentration-time curve for 2',5'-oligoadenylate synthetase, neopterin and beta(2)-microglobulin. The area under the concentration-time curves calculated for these three markers did not correlate with body mass index stratified at <25 and >or=25 kg/m(2) for either peginterferon. CONCLUSIONS: Despite pharmacokinetic differences between peginterferon alpha-2a and peginterferon alpha-2b, the pharmacodynamic profiles of the two formulations appear to be comparable.

A one-year study on the pharmacodynamic profile of interferon-beta1a in MS.

Interferon (IFN)-beta1a induction of neopterin and beta2-microglobulin (beta2-MG) were evaluated over 1 year in patients with MS. Neopterin and beta2-MG levels peaked 24 to 48 hours after weekly injections of IFNbeta1a over the entire study period. Predose levels of neopterin decreased significantly, consistent with a long-term decrease in IFNgamma expression and macrophage activation during IFNbeta-1a treatment. Predose levels of beta2-MG increased, the significance of which is as yet unclear.

P-glycoprotein expression affects the intracellular concentration and antiviral activity of the protease inhibitor saquinavir in a T cell line.

A number of ATP-binding cassette proteins, which function as cellular efflux pumps, are known to be expressed on the membranes of human cells, including CD4-positive lymphocytes. It has also been shown recently that most anti-HIV protease inhibitors (PIs) are first-rate substrates of one of these membrane transporters, P-glycoprotein (Pgp). These findings raise the question of whether Pgp expression could influence HIV replication and/or affect the action of PIs. To gain new insight into this, initially unexpected, phenomenon, a study was undertaken with the aims of investigating whether treatment with saquinavir (SQV) induces Pgp expression in primary or transformed human T cell lines and, primarily, establishing whether Pgp expression could modify both the uptake of SQV and its antiviral action. Pgp expression, mainly measured by reverse transcription-PCR, was found to be variably detectable in healthy individuals, and short or prolonged SQV treatment was unable to induce or increase the expression of Pgp in a lymphoblastoid cell line or in primary lymphocytes derived from these individuals. However, further experiments, performed in a cell line with high Pgp expression (CEM(VBL100) cells) and its parental cell line (CEM cells), demonstrated that over-expression of Pgp reduces the uptake of SQV This result is consistent with the finding that CEM(VBL100) cells are less sensitive to the antiviral activity of SQV, the ID50 value (100 microM) being significantly higher than the corresponding value in parental CEM cells (4 microM).

Immune complexed (IC) hepatitis C virus (HCV) in chronically and acutely HCV-infected patients.

In infected individuals, hepatitis C virus (HCV) exists in various forms of circulating particles which role in virus persistence and in HCV resistance to IFN therapy is still debated. Here, the proportion of HCV bound to immunoglobulin was determined in plasma of 107 chronically infected patients harbouring different HCV genotypes and, for comparison, of six patients with acute HCV infection. The results showed that, in spite of wide individual variability, chronically HCV-infected patients exhibited an extremely high proportion of immune complexed (IC) virus regardless of plasma HCV load and infecting genotype. Moreover, no significant association was found between baseline proportion of IC HCV and response to IFN treatment. Plasma samples collected within 2 weeks of treatment from 20 patients revealed a significant decline of mean IC HCV values relative to baseline that clearly paralleled the decay of total HCV load. In acutely infected patients, circulating HCV was not IC or IC at very low levels only in patients developing chronic HCV infection. Collectively, these findings strengthen the possibility that IC virus could play a critical role in the pathogenesis of HCV infection.

Expression of biomarkers of interferon type I in patients suffering from chronic diseases.

Interferons (IFNs) are used widely in the treatment of viral infections, tumours and neurological disorders. The aim of this study was to evaluate the endogenous expressions of various IFN-induced compounds [specifically: neopterin (NPT), beta2microglobulin (beta2mg) and 2-5 oligoadenylate synthetase (2-5 OAS)] in patients with various chronic diseases requiring treatment with IFN type I. The results showed that patients with such chronic diseases as hepatitis C virus-associated type II mixed cryoglobulinaemia (MC), chronic hepatitis C (CHC) and relapsing-remitting multiple sclerosis (RRMS) are characterized by different activations of the IFN system. Furthermore, the interindividual variability in baseline levels of IFN-induced biomarkers was higher in patients with chronic diseases than in healthy individuals. When levels of the above biomarkers were measured 24 h after the first injection of IFN in patients with CHC or RRMS, significant increases in expression levels of IFN-induced compounds were recorded but, again, there is a broad range of variability in the degree of increase. Further, a significant inverse correlation between baseline levels of NPT, beta2mg and 2-5 OAS activity and their relative increases after IFN administration was found in patients with CHC or RRMS. Together, the results are consistent with the observation that there is considerable interindividual heterogeneity in the clinical response to IFNs, which suggests that host factors other than disease markers must be taken into account in order to manage and optimize the IFN therapy.