Search

Oral HPV infection is the main risk factor for the development of oropharyngeal carcinoma. Men who have sex with men (MSM), especially if living with HIV (PLWH), are at increased risk of infection and consequently of cancer development. Aim of this study is to evaluate the impact of nonavalent vaccine on oral HPV infection in a cohort of MSM and transgender women (TGW). This prospective study included all MSM and TGW who started nonavalent HPV vaccination from May 2019 to September 2021. Oral rinse was collected before each vaccine administration and after six months of follow up. Descriptive statistics were used. Kaplan Meier probability curves and Cox regression models for HPV acquisition and clearance were calculated. The analysis included 211 individuals (202 MSM and 9 TGW). PLWH were 138 (65.4%). Baseline oral rinse was positive in 30 subjects (14.2%). Positivity rate did not change over time (p = 0.742), even when restricting the analysis only to high-risk genotypes (p = 0.575) and to genotypes covered by vaccine (p = 0.894). The risk to acquire HPV infection was 12.8% at one year and 33.4% at two years after vaccination. The probability to clear the infection was 67.6% at one year and 87.9% at two years. HIV infection had no impact on vaccine efficacy. Age above 45 years was the only factor associated to HPV acquisition (aHR 4.06, 95% CI 1.03-15.98, p = 0.045). Prevalence of oral HPV infection was higher in PLWH, but HIV had no impact on viral clearance or acquisition after vaccination., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: In this study, we compared the performance of a self-administered point-of-care test (POCT) for anal human papillomavirus (HPV) screening with laboratory gold-standard test in pre-exposure prophylaxis (PrEP) users and evaluated its feasibility., Methods: We enrolled PrEP users from a local community-based PrEP service. Each participant self-collected an anal swab to test anal HPV with a PCR POCT capable of detecting 14 high-risk HPV genotypes. Anonymous questionnaires on self-sampling feasibility were completed. Participants were then referred to local clinics to undergo standard viral genotyping. Concordance between POCT and gold-standard test was measured with absolute agreement and Cohen's kappa. Receiver operating characteristic (ROC) curves were used to calculate POCT sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)., Results: 179 subjects got a valid POCT result, most of them men (98.3%) and men who have sex with men (90.4%). 68.2% tested positive for at least one high-risk HPV genotype on POCT. 150 feasibility questionnaires were collected: 92.7% of compilers found the self-swab easy to perform. For 178 subjects, a gold-standard test valid result was also available: 77% tested positive for at least one high-risk HPV genotype. The median time elapsed between the two tests was 9.8 months, due to COVID-19-related service interruptions. Agreement between POCT and gold-standard test was 79.3% (Cohen's kappa=0.49). POCT showed a sensitivity of 81.0%, a specificity of 73.8%, a PPV of 91.0% and an NPV of 54.4%., Conclusions: POCT showed a moderate agreement with gold-standard test and a discrete sensitivity and specificity, suggesting that it could be a useful and feasible additional tool for HPV screening, especially in low-resource and community-based settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aflatoxin M1 (AFM1) is a well-known carcinogenic compound that may contaminate milk and dairy products. Thus, with the regulation 1881/2006, the European Union established a concentration limit for AFM1 in milk and insisted on the importance of defining enrichment factors (EFs) for cheese. In 2019, the Italian Ministry of Health proposed four different EFs based on cheese's moisture content on a fat-free basis (MMFB) for bovine dairy products. This study aimed to define the EFs of cheese with different MFFB. The milk used for cheesemaking was naturally contaminated with different AFM1 concentrations. Results showed that all the EF average values from this study were lower than those of the Italian Ministry of Health. Hence, the current EFs might need to be reconsidered for a better categorization of AFM1 risk in cheese., Competing Interests: Conflict of interest: the authors declare no potential conflict of interest., (©Copyright: the Author(s).)

HCV infection could have extrahepatic manifestations due to an aberrant immune response. HCV/HIV co-infection increases such persistent immune activation. Aim of the present study is to describe the evolution of inflammatory markers used in clinical practice, mixed cryoglobulinemia (MC) and autoantibody reactivity in co-infected individuals who achieved sustained virological response (SVR) after DAA treatment. This prospective, observational study included all HIV/HCV co-infected subjects who started any DAA regimen from 2015 to 2020. Samples for laboratory measurements (ferritin, C reactive protein, C3 and C4 fractions, rheumatoid factor, MC, anti-thyroglobulin Ab, anti-thyroid peroxidase Ab, ANCA, ASMA, anti-LKM, anti-DNA, AMA, ANA, T CD4+ and CD8+ cell count, and CD4/CD8 ratio) were collected at baseline, after 4 weeks, at end of treatment, and at SVR12. The analysis included 129 individuals: 51.9% with a F0-F3 fibrosis and 48.1% with liver cirrhosis. Cryocrit, C3 fraction, and rheumatoid factor significantly improved at week 4; ferritin, anti-thyroglobulin Ab, and C4 fraction at EOT; total leukocytes count at SVR12. MC positivity decreased from 72.8% to 35.8% (p < .001). T CD4+ cell slightly increased at SVR12, but with an increase also in CD8+ resulting in stable CD4/CD8 ratio. Autoantibody reactivity did not change significantly. ANA rods and rings positivity increased from 14.8% to 28.6% (p = .099): they were observed in three subjects without exposure to RBV. DAA therapy may lead to improvement in inflammatory markers and MC clearance but without significant changes in autoantibodies reactivity and CD4/CD8 ratio over a follow up of 12 weeks., (© 2023 John Wiley & Sons Ltd.)

Objectives: Human papillomavirus (HPV) is the most common STI and is associated with a wide range of diseases from anogenital warts to malignancies. Anal HPV infection is considerably more common in men who have sex with men (MSM) living with HIV. Aims of the present study are to (i) describe the prevalence of anal HPV infection in MSM who started pre-exposure prophylaxis (PrEP) and (ii) analyse factors associated with anal infection from genotypes that would be covered by nonavalent vaccination., Methods: This monocentric, cross-sectional study included all subjects who started PrEP from May 2018 to November 2021. PrEP candidates underwent full behavioural and clinical evaluation, including digital anal rectal examination and swabbing for HPV determination. Descriptive statistics, Mann-Whitney U test for continuous and χ 2 tests for categorical variables were adopted. Unadjusted and adjusted regression analyses were performed to assess factors associated with positive anal swabs and to the presence of genotypes covered by the nonavalent vaccination., Results: The analysis included 288 subjects: anal swabs tested positive in 87.2% of cases, 79.2% of the subjects had a high-risk genotype (mainly 16), whereas 67.4% had a genotype covered by nonavalent vaccine. Sexual role was the only factor associated with anal HPV infection. Use of recreational drugs and a diagnosis of ≥2 STIs correlated with the presence of genotypes that would have been covered by vaccine, while previous vaccination had a protective role., Conclusions: PrEP candidates showed a high prevalence of anal HPV infection, especially due to high-risk genotypes, comparable to what has been reported in MSM living with HIV., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Severe liver fibrosis (LF) is associated with poor long-term liver-related outcomes in people living with HIV (PLWH). The study aimed to explore the prevalence and predictors of LF and the concordance between different non-invasive methods for the estimation of LF in HIV-infected individuals without hepatitis virus infection. We enrolled PLWH with HIV-1-RNA <50 copies/mL for >12 months, excluding individuals with viral hepatitis. LF was assessed by transient elastography (TE) (significant >6.65 kPa), fibrosis-4 (FIB-4) (significant >2.67), and AST-to-platelet ratio index (APRI) (significant >1.5). We included 234 individuals (67% males, median age 49 years, median time from HIV diagnosis 11 years, 38% treated with integrase strand transfer inhibitors). In terms of the TE, 13% had ≥F2 stage; FIB-4 score was >1.5 in 7%; and APRI > 0.5 in 4%. Higher body mass index, diabetes mellitus, detectable baseline HIV-1 RNA and longer atazanavir exposure were associated with higher liver stiffness as per TE. Predictors of higher APRI score were CDC C stage and longer exposure to tenofovir alafenamide, while HBcAb positivity and longer exposure to tenofovir alafenamide were associated to higher FIB-4 scores. Qualitative agreement was poor between FIB-4/TE and between APRI/TE by non-parametric Spearman correlation and kappa statistic. In our study, in the group of PLWH without viral hepatitis, different non-invasive methods were discordant in predicting liver fibrosis.

SARS-CoV2 infection is a systemic disease that may involve multiple organs, including the central nervous system (CNS). Aims of our study are to describe prevalence and clinical features of neurological manifestations, mortality and hospital discharge in subjects hospitalized with COVID-19. All individuals admitted for to our hospital COVID-19 were retrospectively included. Patients were classified according to the symptoms at hospital entry in (1) isolated respiratory, (2) combined respiratory and neurologic, (3) isolated neurologic and (4) stroke manifestations. Descriptive statistics and nonparametric tests to compare the groups were calculated. Kaplan Meier probability curves and multivariable Cox regression models for survival and hospital discharge were applied. The analysis included 901 patients: 42.6% showed a severe or critical disease with an overall mortality of 21.2%. At least one neurological symptom or disease was observed in 30.2% of subjects ranging from dysgeusia/anosmia (9.1%) to postinfective diseases (0.8%). Patients with respiratory symptoms experienced a more severe disease and a higher in-hospital mortality compared to those who showed only neurologic symptoms. Kaplan Meier estimates displayed a statistically significant different survival among groups (p = 0.003): subjects with stroke had the worst. After adjusting for risk factors such as age, sex and comorbidity, individuals with isolated neurologic manifestations exhibited a better survival (aHR 0.398, 95% CI [0.206, 0.769], p = 0.006). Neurologic manifestations in COVID-19 are common but heterogeneous and mortality in subjects with isolated neurologic manifestations seems lower than in those with respiratory symptoms., (© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

In routine clinical practice, hepatitis C virus-infected patients can prematurely discontinue the prescribed regimen for several reasons. The aim of our study was to investigate sustained virological response (SVR12) rates in patients who prematurely discontinued directly acting antiviral (DAA) regimens and to assess the shortest effective duration of DAA able to lead to SVR12. We retrospectively collected the SVR rates of patients, registered in the NAVIGATORE-Lombardia Network database from January 2015, who discontinued DAAs before the predefined end of treatment. Overall, we included 365 patients, males were the majority (213, 58.4%), mean age was 60.5 years, and 53 (14.5%) patients were HIV-co-infected. Liver cirrhosis was observed in 251 (68.8%) subjects, and the most represented genotypes were 1b (n = 168, 46%) and 3 (n = 59, 16.2%). DAA was discontinued a median of 1 (IQR 1-4) weeks before the predefined EOT, with 164 (44.9%) patients stopping DAAs at least 2 weeks before the planned schedule. In patients with F0-F3 liver fibrosis, lower rates of SVR12 were observed in patients treated for <4 weeks: 50% (n = 2/4) vs. 99.1% (n = 109/110) for ≥4 weeks, p = 0.003. In patients with liver cirrhosis, lower rates of SVR12 were observed in patients treated <8 weeks: 83.3% (n = 25/30) vs. 94.6% (n = 209/221) for ≥8 weeks, p = 0.038. Despite premature discontinuation of DAA, high SVR12 rates were observed in a real-life setting for treatment lasting at least 4 weeks in patients with liver fibrosis F0-F3 and 8 weeks in those with liver cirrhosis. On this basis, feasibility of reducing DAA treatment duration should be explored in randomized clinical trials., (© 2020 John Wiley & Sons Ltd.)

Since SARS-CoV-2-based disease (COVID-19) spreads as a pandemic, the necessity of a highly sensitive molecular diagnosis that can drastically reduce false negatives reverse transcription PCR (rtPCR) results, raises as a major clinical need. Here we evaluated the performance of a ddPCR-based assay to quantify SARS-CoV-2 titer in 55 suspected COVID-19 cases with negative rtPCR results thanks to in-house ddPCR assay (targeting RdRp and host RNaseP). Samples were collected at ASST-GOM Niguarda between February and May 2020 at hospital admission. Clinical and imaging data were obtained for clinical staging and definition of disease severity. Patients were mainly female (45.5%) with a median age of 73 (57-84) years. ddPCR-based assay detected SARS-CoV-2 genome in nasopharyngeal samples of 19 (34.5%) patients (median viral-load: 128 copies/mL, IQR: 72-345). In 15 of them (78.9%), chest CT showed a classical COVID-19 bilateral interstitial pneumonia; 14 patients (73.7%) showed severe COVID-19 manifestations. ddPCR did not identify any trace of SARS-CoV-2 genome in the respiratory samples of the remaining 36 patients. The serological assay performed in a subgroup of 34 patients at the later stage of illness (from 3 days to 90 days after) confirmed the presence of SARS-CoV-2 antibodies in all patients tested positive for SARS-CoV-2 in ddPCR (100%). Contrariwise, negative tests were observed in 95.0% ddPCR negative patients (P<0.001). Thanks to a ddPCR-based assay, we achieved a rapid and accurate SARS-CoV-2 diagnosis in rtPCR-negative respiratory samples of individuals with COVID-19 suspect, allowing the rapid taking care and correct management of these patients., Competing Interests: The authors have declared that no competing interests exist.

Background & Aims: In the direct-acting antiviral era, treatment of genotype-3 HCV (HCV-GT3) is still challenging. Real-life comparisons between recommended regimens, sofosbuvir (SOF)+daclatasvir (DAC), SOF/velpatasvir (VEL), glecaprevir/pibrentasvir (GLE/PIB), are scarce. We aimed at filling this data gap., Methods: Sustained virological response 12 weeks after treatment completion (SVR12) was assessed for all HCV-GT3 patients consecutively treated within the Lombardia web-based Navigatore HCV-Network; differences in SVR12 across regimens were evaluated by logistic regression., Results: Of the 2082 subjects with HCV-GT3, 1544 were evaluable for comparisons between regimens: SOF + DAC (1023, 66.2%), SOF/VEL (369, 23.9%), GLE/PIB (152, 9.8%). Patients treated with former regimens were more frequently male, cirrhotic, HIV-positive, pretreated, used ribavirin in their regimen, and had lower baseline HCV-RNA. SVR12 was similar across groups: 94.8% in SOF + DAC, 97.6% in SOF/VEL, 96.7% in GLE/PIB (P = .065). At univariate analysis, SVR12 was associated with female gender (97.9% vs 94.8%, P = .007) and lower median pretreatment Log 10 HCV-RNA (5.87 vs 6.20, P = .001). At multivariate logistic regression analysis, treatment with SOF/VEL was associated with a higher likelihood of SVR12 than SOF + DAC, but only in the absence of ribavirin (98% vs 90.3%). Female gender and lower pretreatment HCV-RNA were independently associated with SVR12., Conclusions: In a large real-life setting of HCV-GT3-infected patients with a high proportion of cirrhosis, the success rate was remarkable. The slight advantage of SOF/VEL on SOF + DAC was significant only without ribavirin. The current prescription shift towards novel regimens (ie SOF/VEL and GLE/PIB) in easier-to-treat patients allows ribavirin-free and shorter schedules without mining SVR12 in this <> genotype., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: The efficacy and safety of glecaprevir/pibrentasvir (G/P) for patients infected with hepatitis C virus (HCV) have only been investigated in clinical trials, with no real-world data currently available. The aim of our study was to investigate the effectiveness and safety of G/P in a real-world setting., Methods: All patients with HCV consecutively starting G/P between October 2017 and January 2018 within the NAVIGATORE-Lombardia Network were analyzed. G/P was administered according to drug label (8, 12 or 16 weeks). Fibrosis was staged either histologically or by liver stiffness measurement. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks after the end of treatment., Results: A total of 723 patients (50% males) were treated with G/P, 89% for 8 weeks. The median age of our cohort was 58 years, with a median body mass index of 23.9 kg/m 2 , and median liver stiffness measurement of 6.1 kPa; 84% were F0-2 and 16% were interferon-experienced. Median HCV-RNA was 1,102,600 IU/ml, and 49% of patients had HCV genotype 1 (32% 1b), 28% genotype 2, 10% genotype 3 and 13% genotype 4. The median estimated glomerular filtration rate was 90.2 ml/min, platelet count 209x10 3 /mm 3 and albumin 4.3 g/dl. The SVR rates were 94% in intention-to-treat and 99.3% in per protocol analysis (8-week vs. 12 or 16-week: 99.2% vs. 100%). Five patients failed therapy because of post-treatment relapse; a post-treatment NS5A resistance-associated substitution was detected in 1 case. SVR rates were lower in males (p = 0.002) and in HCV genotype-3 (p = 0.046) patients treated for 8 weeks, but independent of treatment duration, fibrosis stage, baseline HCV-RNA, HIV co-infection, chronic kidney disease stage and viral kinetics. Mild adverse events were reported in 8.3% of the patients, and 0.7% of them prematurely withdrew treatment. Three patients died of drug-unrelated causes., Conclusions: In a large real-world cohort of Italian patients, we confirmed the excellent effectiveness and safety of G/P administered for 8, 12 or 16 weeks., Lay Summary: A large number of patients with hepatitis C virus have been treated with glecaprevir/pibrentasvir (G/P) within the NAVIGATORE-Lombardia Network, in Italy. This is the first real-world study evaluating effectiveness and safety of G/P in patients with hepatitis C virus treated according to international recommendations. This study demonstrated excellent effectiveness (with sustained virological response rates of 99.3%) and safety profiles., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The role of anti-HCV direct-acting agents (DAAs) is well described in HCV-related lymphoproliferative disorders, whereas few data are available on their use in other malignancies, such as aggressive T-cell lymphomas requiring autologous stem cell transplantation (ASCT). We describe two oncologic cirrhotic patients treated with DAAs who underwent ASCT achieving cure for both diseases. Co-administration of sofosbuvir with cisplatin led an unexpected severe kidney impairment that did not resolve 30 weeks after drug exposure. The optimal timing of DAA administration in the ASCT setting has yet to be defined: our experience shows that co-administration is feasible, but requires close monitoring for adverse events.

Background: This study aimed to investigate the efficacy and safety of a 12-month treatment with Phyllanthus niruri in subjects with chronic hepatitis B virus (HBV) infection., Patients and Methods: A placebo-controlled, parallel-group double-blind trial was performed. Clinical assessments took place at baseline and at 1, 3, 9, and 12 months after the treatment start and 6 months after treatment end., Results: In the first 2 years, 50 eligible subjects with chronic HBV accepted to participate. Of those, 47 completed all the study-related visits (6% drop-out rate): 24 of the 26 (92%) allocated to the Phyllanthus group and 23 of the 24 (96%) allocated to the placebo group completed the study. No statistically significant differences in viral load were found between the intervention and placebo groups after 12 months and no subjects showed HBsAg clearance. With regards to safety, there were no changes in renal function parameters in both groups after 12 months and no serious adverse events occurred due to the treatment. The study was stopped at the end of the second year because there was no apparent benefit of the treatment., Conclusion: This study does not support the use of Phyllanthus niruri for the treatment of chronic hepatitis B., (© 2018 S. Karger GmbH, Freiburg.)

Chronic infection with hepatitis C virus (HCV) may lead to B cell activation and transformation into non-Hodgkin lymphoma (NHL). Molecular mechanisms of B cell transformation by HCV are poorly understood. One of the most common lymphoproliferative disorders in HCV-infected patients is splenic marginal zone lymphoma (SMZL). A case of a 42-years old man, affected by HCV-related SMZL, effectively treated with an IFN-free, NS3-NS4A inhibitor-based regimen, is hereby described. The patient was treated for 16 weeks with faldaprevir, deleobuvir, and ribavirin, achieving a very rapid viral eradication without relevant toxicities. A rapid haematologic response was noted as well, with a statistically significant correlation between viral decay and lymphocyte improvement (coefficient r = 0.55, p = 0.042). The viral clearance led to SMZL cure, even without the use of IFN. Thus, the causative role, played by HCV in SMZL development, is once again reinforced, whereby the antiviral, rather than the anti-proliferative activity of IFN is indirectly proven. A regimen including DAAs should be considered when treating a HCV-related extra-hepatic disease., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

In the era of Directly Acting anti HCV Antivirals treatment of hepatitis C is successful in the majority of persons treated. However, treatment of persons with HIV or who inject drugs remains challenging because of special issues: drug-drug interactions with antiretroviral, psychiatric and drug substitution therapies, treatment adherence, impact of treatment on HIV disease course or on risk of bacterial infections. Sofosbuvir induced sustained virologic response in 91% of 23 HIV/HCV coinfected persons treated in combination with ribavirin and pegylated interferon, in 83% of 497 treated in combination with ribavirin and in all 50 patients infected with HCV GT1 treated in combination with ledipasvir and ribavirin. The rates of efficacy in HCV-HIV coinfected were almost the same as those observed in HCV monoinfected suggesting that the efficacy of sofosbuvir is not reduced by HIV coinfection. There are no data on the efficacy of sofosbuvir in injection drugs users. The pangenotypic activity, the high barrier to resistance, the modest potential for drug-drug interactions makes sofosbuvir a reference drug for the treatment of these two special populations., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. All rights reserved.)

Activation of the nuclear factor κB/c-Rel can increase neuronal resilience to pathological noxae by regulating the expression of pro-survival manganese superoxide dismutase (MnSOD, now known as SOD2) and Bcl-xL genes. We show here that c-Rel-deficient (c-rel(-/-)) mice developed a Parkinson's disease-like neuropathology with ageing. At 18 months of age, c-rel(-/-) mice exhibited a significant loss of dopaminergic neurons in the substantia nigra pars compacta, as assessed by tyrosine hydroxylase-immunoreactivity and Nissl staining. Nigral degeneration was accompanied by a significant loss of dopaminergic terminals and a significant reduction of dopamine and homovanillic acid levels in the striatum. Mice deficient of the c-Rel factor exhibited a marked immunoreactivity for fibrillary α-synuclein in the substantia nigra pars compacta as well as increased expression of divalent metal transporter 1 (DMT1) and iron staining in both the substantia nigra pars compacta and striatum. Aged c-rel(-/-) mouse brain were characterized by increased microglial reactivity in the basal ganglia, but no astrocytic reaction. In addition, c-rel(-/-) mice showed age-dependent deficits in locomotor and total activity and various gait-related deficits during a catwalk analysis that were reminiscent of bradykinesia and muscle rigidity. Both locomotor and gait-related deficits recovered in c-rel(-/-) mice treated with l-3,4-dihydroxyphenylalanine. These data suggest that c-Rel may act as a regulator of the substantia nigra pars compacta resilience to ageing and that aged c-rel(-/-) mice may be a suitable model of Parkinson's disease.

Background: The functioning of the nervous system depends upon the specificity of its synaptic contacts. The mechanisms triggering the expression of the appropriate receptors on postsynaptic membrane and the role of the presynaptic partner in the differentiation of postsynaptic structures are little known., Methods and Findings: To address these questions we cocultured murine primary muscle cells with several glutamatergic neurons, either cortical, cerebellar or hippocampal. Immunofluorescence and electrophysiology analyses revealed that functional excitatory synaptic contacts were formed between glutamatergic neurons and muscle cells. Moreover, immunoprecipitation and immunofluorescence experiments showed that typical anchoring proteins of central excitatory synapses coimmunoprecipitate and colocalize with rapsyn, the acetylcholine receptor anchoring protein at the neuromuscular junction., Conclusions: These results support an important role of the presynaptic partner in the induction and differentiation of the postsynaptic structures.

The relationship between β-amyloid (Aβ) and tau is not fully understood, though it is proposed that in the pathogenesis of Alzheimer's disease (AD) Aβ accumulation precedes and promotes tau hyperphosphorylation via activation of glycogen synthase kinase-3beta (GSK-3β). Both events contribute to learning and memory impairments. Modulation of γ-secretase activity has proved to reduce the Aβ burden and cognitive deficits in mouse models of AD, but its ability in reducing the tau pathology remains elusive. Chronic treatments with two γ-secretase modulators, ibuprofen and CHF5074, disclosed higher activity of CHF5074 in ameliorating brain plaque deposition and spatial memory deficits in transgenic mice expressing human amyloid precursor protein (hAPP) with Swedish and London mutations (APP(SL) mice). The aim of our study was to investigate in APP(SL) mice the effect of the two compounds on the accumulation of native hyperphosphorylated tau as well as on the GSK-3β signaling. CHF5074 was more effective than ibuprofen in reducing tau pathology, though both compounds decreased the GSK-3β level and increased the GSK-3β inhibitory phosphorylation near to the non-Tg values. The inhibition of GSK-3β appeared to be secondary to the reduction of Aβ generation as, differently from LiCl, CHF5074 reproduced its effect in hAPP-overexpressing neuroglioma cells, but not in wild-type primary neurons. Our data show that the novel γ-secretase modulator CHF5074 can fully reverse β-amyloid-associated tau pathology, thus representing a promising therapeutic agent for AD.

After denervation of adult rat abdominal muscles, the postsynaptic apparatus of neuromuscular junctions (NMJs) retains its original architecture and clustering of acetylcholine receptors (AChRs). When descending fibers of the spinal cord are surgically diverted to this muscle by a nerve grafting procedure, supraspinal glutamatergic neurons can innervate muscle fibers and restore motor function; the newly formed NMJs switch from a cholinergic to a glutamatergic-type synapse. We show here that regenerating nerve endings contact the fibers in an area occupied by cholinergic endplates. These NMJs are morphologically indistinguishable from those in controls, but they differ in the subunit composition of AChRs. Moreover, by immunofluorescence and immunoelectron microscopy, new NMJs express glutamatergic synapse markers. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 partially colocalizes with AChRs, and vesicular glutamate transporter 2 is localized in the presynaptic compartment. Immunoprecipitation analysis of membranes from reinnervated muscle showed that AMPA receptor subunits GluR1 and GluR2 coimmunoprecipitate with rapsyn, the AChR-anchoring protein at the NMJ. Taken together, these results indicate that cholinergic endplates can be targeted by new glutamatergic projections and that the clustering of AMPA receptors occurs there.

Nuclear factor-kappaB (NF-kappaB) is a dimeric transcription factor composed of five members, p50, RelA/p65, c-Rel, RelB, and p52 that can diversely combine to form the active transcriptional dimer. NF-kappaB controls the expression of genes that regulate a broad range of biological processes in the central nervous system such as synaptic plasticity, neurogenesis, and differentiation. Although NF-kappaB is essential for neuron survival and its activation may protect neurons against oxidative-stresses or ischemia-induced neurodegeneration, NF-kappaB activation can contribute to inflammatory reactions and apoptotic cell death after brain injury and stroke. It was proposed that the death or survival of neurons might depend on the cell type and the timing of NF-kappaB activation. We here discuss recent evidence suggesting that within the same neuronal cell, activation of diverse NF-kappaB dimers drives opposite effects on neuronal survival. Unbalanced activation of NF-kappaB p50/RelA dimer over c-Rel-containing complexes contributes to cell death secondary to the ischemic insult. While p50/RelA acts as transcriptional inducer of Bcl-2 family proapoptotic Bim and Noxa genes, c-Rel dimers specifically promote transcription of antiapototic Bcl-xL gene. Changes in the nuclear content of c-Rel dimers strongly affect the threshold of neuron vulnerability to ischemic insult and agents, likewise leptin, activating a NF-kappaB/c-Rel-dependent transcription elicit neuroprotection in animal models of brain ischemia.

HIV and HCV share common transmission pathways, but HCV is more efficiently transmitted through blood than with sexual exposure. Thus HCV coinfection is frequent in HIV seropositives, mainly in those with history of injection drug use and/or transfusion. HIV coinfection increases HCV replication rate, the rate of HCV vertical transmission and accelerates the course of hepatitis C towards cirrhosis and hepatocellular carcinoma. The evidence of an effect of HCV on HIV disease progression is less convincing. The results of several studies suggest that HCV coinfection does not hasten the progression of HIV infection towards AIDS. However two recent studies showed that HCV coinfection is independently associated with a lower restoration of CD4 counts during combination antiretroviral treatment. However this finding should be confirmed by additional studies.