Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC)

Cryoglobulinemic vasculitis (CV) or mixed cryoglobulinemic syndrome (MCS) is a systemic small-vessel vasculitis characterized by the proliferation of B-cell clones producing pathogenic immune complexes, called cryoglobulins. It is often secondary to hepatitis C virus (HCV), autoimmune diseases, and hematological malignancies. CV usually has a mild benign clinical course, but severe organ damage and life-threatening manifestations can occur. Recently, evidence in favor of rituximab (RTX), an anti-CD 20 monoclonal antibody, is emerging in CV: nevertheless, questions upon the safety of this therapeutic approach, especially in HCV patients, are still being issued and universally accepted recommendations that can help physicians in MCS treatment are lacking. A Consensus Committee provided a prioritized list of research questions to perform a systematic literature review (SLR). A search was made in Medline, Embase, and Cochrane library, updated to August 2021. Of 1227 article abstracts evaluated, 27 studies were included in the SLR, of which one SLR, 4 RCTs, and 22 observational studies. Seventeen recommendations for the management of mixed cryoglobulinemia with rituximab from the Italian Study Group of Cryoglobulinemia (GISC) were developed to give a valuable tool to the physician approaching RTX treatment in CV

Hepatitis C virus genotypes in patients with essential mixed cryoglobulinemia

We studied 54 patients with essential mixed cryoglobulinaemia (EMC), (23 males, 31 females) mean age 61 years (range 28-77). Forty-one (76%) had type II cryoglobulinaemia and 13 (24%) type III. Antibodies to HCV were detectable by second-generation ELISA in 49 patients (91%) with confirmed or indeterminate RIBA results. HCV RNA was detected by RT PCR using 5' UTR nested primers; HCV genotypes 1a, 1b, 2 and 3a were identified by genotype-specific core-region nested primers. All patients (49) with antibodies to HCV in their serum were HCV-RNA positive; 27 (55.1%) had HCV subtype 1b and 21 (42.8%) type 2. In one patient the HCV genotype could not be determined. The genotype distribution was not different from that found in patients with chronic hepatitis C without cryoglobulinaemia. However, the presence of HCV subtype 1b correlated significantly with signs of chronic hepatitis and presence of peripheral neuropathy. Severity of disease tended to be worse in patients infected with HCV subtype 1b, but this was mainly due to liver disease. HCV genotypes may influence the clinical expression and, in particular, the severity of liver involvement in patients with EMC. Extent and severity of EMC disease in general may also be affected by the different HCV genotypes. These findings may have therapeutical implications, since the different HCV genotypes respond differently to interferon treatment

Histological and immunological features of primary Kaposi's sarcoma: evaluation before and after chemotherapy

Forty-one patients with primary Kaposi's sarcoma (KS) have been evaluated clinically, histologically and immunologically at the time of diagnosis. There was no correlation between histological and immunological features. Moreover, the disease did not appear to be related to particular HLA phenotypes. The T4/T8 ratio was augmented. Leu 7+ cells were also significantly increased. The last 15 patients who received chemotherapy were recently reevaluated after treatment and an increase in B lymphocytes was observed. We also observed that spindle-shaped cells (SSC), which appear later in the histopathological course of the disease, disappear first during chemotherapy, concomitantly with the increase in B cells. We conclude that the course of the disease appears to be controlled by the host's immune response, though there is no clear correlation between histological and immunological evolution. Several immunological features differentiating it from AIDS associated KS have been found

Cryoglobulinaemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease. GISC. Italian Group for the Study of Cryoglobulinaemias

In a multi-centre retrospective study, we compared clinical and laboratory data in 913 patients with cryoglobulinaemias, divided as: (i) essential cryoglobulinaemias; (ii) cryoglobulinaemias secondary to connective tissue diseases (CTD), lymphoproliferative or other haematological diseases (LPD), chronic liver diseases (CLD), and 'other diseases'. Purpura was the commonest presenting feature in all groups and was more common in essential cryoglobulinaemias (p3% (p<0.0001), C4<15mg/dl (p<0.001), HBsAg prevalence (p<0.01) and purpura (p<0.05). Despite the high prevalence of HCV markers in all groups, the role of HCV in essential cryoglobulinaemia is not well defined; HBV seems to play only a marginal role