HIV-associated progressive multifocal leukoencephalopathy. Current perspectives

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system, caused by the polyomavirus JC and occurring almost exclusively in the context of severe immune depression. AIDS represents the most common predisposing condition for PML development. Antiretroviral treatment has reduced PML incidence in HIV-infected subjects, but the disease remains a severe and life-threatening complication of AIDS, considering thus far the lack of an effective anti-JC virus (JCV) direct-acting antiviral drug. In the last decade, the use of monoclonal antibodies for treating immune-based diseases evidenced new predisposing conditions for PML development, promoting a renewed interest in PML pathogenesis. In this article, we review the current knowledge on JCV epidemiology and AIDS-associated PML incidence, JCV viral cycle, pathogenesis, and the interplay with HIV infection. We give an updated overview of diagnostic and prognostic tools available for PML diagnosis and describe past and current therapeutic approaches, including new strategies for PML cure

Diplomacy in the Time of Cholera

Turning everyday ordinary happenings into struggling moments for existence—from breathing to socializing—is how the Covid-19 pandemic will mark history. What we ask here is not how the ordinary becomes abnormal but how it becomes political and diplomatic. We argue that the spread of the Covid-19 virus, which is measured through virologic and epidemiological models, overlaps with feverous diplomatic and political activities taking place among big geopolitical powers. Yet, this is not new in history of health. The first encounters between diplomats and health professionals were elicited by the social and economic challenges caused, on a global scale, by the cholera epidemics of the nineteenth century. Indeed, health sciences and diplomacy have been historically co-produced. Such a historical perspective on science and health diplomacy facilitates our understanding of international institutions such as the World Health Organization as highly political and diplomatic endeavors. The Diplomatic Studies of Science, a new interdisciplinary research field underpinned by a historical perspective on science diplomacy, sheds light on the multiple factors contributing to the worsening of the global COVID-19 crisis we are facing nowadays

Effects of environmental and electric perturbations on the pKa of thioredoxin cysteine 35: a computational study

Here we present a theoretical-computational study dealing with the evaluation of the pKa of the Cysteine residues in Thioredoxin (TRX) and in its complex with the Thioredoxin-interacting protein (TXNIP). The free energy differences between the anionic and neutral form of the Cysteine 32 and 35 have been evaluated by means of the Perturbed Matrix Method with classical perturbations due to both the environment and an exogenous electric field as provided by Molecular Dynamics (MD) simulations. The evaluation of the free energies allowed us to show that the effect of the perturbing terms is to lower the pKa of Cysteine 32 and Cysteine 35 with respect to the free amino-acid. On the other hand, in the complex TRX-TXNIP, our data show an enhanced stabilization of the neutral reduced form of Cys 35. These results suggest that external electric stimuli higher than 0.02 V/nm can modulate the Cysteine pKa, which can be connected to the tight regulation of the TRX acting as an antioxidant agent

Reproductive disorders induced by Chlamydophila spp. infections in an italian mediterranean buffalo (bubalus bubalis) herd

The Italian Mediterranean Buffalo (Bubalus bubalis) has low fecundity and high incidence of abortion. Several studies have associated reproductive failure of water buffalo with viral infections but there is limited information on the role of chlamydial infections. To investigate the presence and the role of Chlamydiaceae in water buffalo a retrospective study was performed in a farm where, in the arch of 11 months, the pregnant heifers suffered an abortion rate of 36.8% in the 3rd and 5th month of pregnancy. Antibodies to Chlamydiaceae were detected in 57% of the aborted cows, while the rate of positivity was 0% in overtly healthy cows used as control. By a PCR assay 3 of 14 vaginal swabs from aborted animals tested positive for Chlamydophila agents and, additionally, 3 out of 7 aborted foetuses tested positive for Chlamydophila spp., with two being co-infections by Cp. abortus and Cp. pecorum and one being characterised as Cp. abortus. The presence of anti-Chlamydiaceae antibodies in 57% of the aborted animals and the detection of Chlamydophila agents in foetal organs and in vaginal swabs is consistent with the history of abortions (P<0.002) observed in the herd and may suggest a pathogenic role by Chlamydophila spp. in water buffalo

Molecular dynamics simulations reveal canonical conformations in different pMHC/TCR interactions

The major defense system against microbial pathogens in vertebrates is the adaptive immune response and represents an effective mechanism in cancer surveillance. T cells represent an essential component of this complex system. They can recognize myriads of antigens as short peptides (p) originated from the intracellular degradation of foreign proteins presented by major histocompatibility complex (MHC) proteins. The clonotypic T-cell antigen receptor (TCR) is specialized in recognizing pMHC and triggering T cells immune response. It is still unclear how TCR engagement to pMHC is translated into the intracellular signal that initiates T-cell immune response. Some work has suggested the possibility that pMHC binding induces in the TCR conformational changes transmitted to its companion CD3 subunits that govern signaling. The conformational changes would promote phosphorylation of the CD3 complex ζ chain that initiates signal propagation intracellularly. Here, we used all-atom molecular dynamics simulations (MDs) of 500 ns to analyze the conformational behavior of three TCRs (1G4, ILA1 and ILA1α1β1) interacting with the same MHC class I (HLA-A*02:01) bound to different peptides, and modelled in the presence of a lipid bilayer. Our data suggest a correlation between the conformations explored by the β-chain constant regions and the T-cell response experimentally determined. In particular, independently by the TCR type involved in the interaction, the TCR activation seems to be linked to a specific zone of the conformational space explored by the β-chain constant region. Moreover, TCR ligation restricts the conformational space the MHC class I groove

The burden of calcific aortic stenosis. what's behind

In Western countries, calcific aortic valve stenosis (CAS) is widely common, representing the third cause of death among cardiovascular diseases (CVD). The burden of CAS is high, with an increasing prevalence rate related to age. An efficient medical treatment, according to guidelines, lacks to prevent the development and to reduce the progression of CAS. In this context, due to the aging population and the lack of effective medical management, the prevalence is expected to double-triple within the next decades. In our review, we aim to provide an overview of the underlying mechanisms of pathogenesis and the current state of the art regarding pathophysiological insights and novel potential therapeutic targets

Oncological and functional outcome of conservative surgery for primary supraglottic cancer

The aim of this study was to verify the oncological and functional outcome of conservative surgical treatment of primary supraglottic squamous cell carcinoma (SGSCC) and related neck disease in order to verify the effectiveness of supraglottic laryngectomy (SL) and the validity of an "observation" policy in the control of clinically negative (NO) necks. Of a total of 252 consecutive patients affected by primary SGSCC seen between 1975 and 1990 at the Department of Otolaryngology of the University of Perugia (1975-1987) and the Catholic University of the Sacred Heart of Rome (1988-1990), a subset of 132 patients treated with classical SL was evaluated after presenting sufficient clinicopathological data and a follow-up period of at least 5 years. Tumors were staged according to the 1992 UICC TNM classification and grouped into stages I-II (n = 94) and III-IV (n = 38). Comprehensive neck dissections were performed only in the clinically positive (N+) necks (25/132 cases), while in the clinically NO ones (107/132 cases) an "observation" policy under strict follow-up conditions was adopted. After primary surgery, the 5-year relapse-free survival (RFS) was 74%. The RFS was 80% for T1-2 disease and 65% for T3. The RFS was 80% for stages I-II tumors and 71% for stages III-IV. The actual 5-year overall survival (OS) was 89% for T1-T2 tumors and 67% for T3 disease or 93% for stages I-II and 69% for stages III-IV. The OS was 89% for NO neck and 73% for N+. The 5-year-metastasis-free survival (MFS) was 83% for NO patients, 74% for N+, 84% for T1-T2 NO, 71% for T1-T2 N+, 81% for T3 NO and 68% for T3 N+. In all, SL was found to be highly effective in the management of primary SGSCC. In the presence of clinically NO neck "observation" under strict follow-up with therapeutic comprehensive neck dissection for delayed nodal recurrence, SL was suitable for controlling the neck cancer, as well as for salvaging recurrent disease. Bilateral elective, selective or functional neck dissection in every instance of supraglottic cancer was best performed only in those SGSCC patients who were more likely to have occult nodal disease on the basis of biological factors and imaging data

Functional Tricuspid Regurgitation: Behind the Scenes of a Long-Time Neglected Disease

Severe tricuspid valve regurgitation has been for a long time a neglected valve disease, which has only recently attracted an increasing interest due to the notable negative impact on the prognosis of patients with cardiovascular disease. It is estimated that around 90% of tricuspid regurgitation is diagnosed as "functional" and mostly secondary to a primary left-sided heart disease and, therefore, has been usually interpreted as a benign condition that did not require a surgical management. Nevertheless, the persistence of severe tricuspid regurgitation after left-sided surgical correction of a valve disease, particularly mitral valve surgery, has been associated to adverse outcomes, worsening of the quality of life, and a significant increase in mortality rate. Similar results have been found when the impact of isolated severe tricuspid regurgitation has been studied. Current knowledge is shifting the "functional" categorization toward a more complex and detailed pathophysiological classification, identifying various phenotypes with completely different etiology, natural history and, potentially, an invasive management. The aim of this review is to offer a comprehensive guide for clinicians and surgeons with a systematic description of "functional" tricuspid regurgitation subtypes, an analysis centered on the effectiveness of existing surgical techniques and a focus on the emergent percutaneous procedures. This latter may be an attractive alternative to a standard surgical approach in patients with high-operative risk or isolated tricuspid regurgitation.Copyright © 2022 Vinciguerra, Sitges, Luis Pomar, Romiti, Domenech-Ximenos, D'Abramo, Wretschko, Miraldi and Greco

Control of template positioning during de novo initiation of RNA synthesis by the bovine viral diarrhea virus NS5B polymerase

The RNA-dependent RNA polymerase of the hepatitis C virus and the bovine viral diarrhea virus (BVDV) is able to initiate RNA synthesis de novo in the absence of a primer. Previous crystallographic datahave pointed to the existence of a GTP-specific binding site (G-site) that is located in the vicinity of the active site of the BVDV enzyme. Here we have studied the functional role of the G-site and present evidence to show that specific GTP binding affects the positioning of the template during de novo initiation. Following the formation of the first phosphodiester bond, the polymerase translocates relative to the newly synthesized dinucleotide, which brings the 5′-end of the primer into the G-site, releasing the previously bound GTP. At this stage, the 3′-end of the template can remain opposite to the 5′-end of the primer or be repositioned to its original location before RNA synthesis proceeds. We show that the template can freely move between the two locations, and both complexes can isomerize to equilibrium. These data suggest that the bound GTP can stabilize the interaction between the 3′-end of the template and the priming nucleotide, preventing the template to overshoot and extend beyond the active site during de novo initiation. The hepatitis C virus enzyme utilizes a dinucleotide primer exclusively from the blunt end; the existence of a functionally equivalent G-site is therefore uncertain. For the BVDV polymerase we showed that de novo initiation is severely compromised by the T320A mutant that likely affects hydrogen bonding between the G-site and the guanine base. Dinucleotide-primed reactions are not influenced by this mutation, which supports the notion that the G-site is located in close proximity but not at the active site of the enzyme. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc