Consultas neurológicas e diagnósticos em um grande hospital universitário dedicado a COVID-19

Background: More than one-third of COVID-19 patients present neurological symptomsranging from anosmia to stroke and encephalopathy. Furthermore, pre-existingneurological conditions may require special treatment and may be associated with worseoutcomes. Notwithstanding, the role of neurologists in COVID-19 is probablyunderrecognized. Objective: The aim of this study was to report the reasons forrequesting neurological consultations by internists and intensivists in a COVID-19-dedicated hospital. Methods: This retrospective study was carried out at Hospital dasClínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil, a 900-bedCOVID-19 dedicated center (including 300 intensive care unit beds). COVID-19 diagnosiswas confirmed by SARS-CoV-2-RT-PCR in nasal swabs. All inpatient neurologyconsultations between March 23rd and May 23rd, 2020 were analyzed. Neurologistsperformed the neurological exam, assessed all available data to diagnose theneurological condition, and requested additional tests deemed necessary. Difficultdiagnoses were established in consensus meetings. After diagnosis, neurologists wereinvolved in the treatment. Results: Neurological consultations were requested for 89 outof 1,208 (7.4%) inpatient COVID admissions during that period. Main neurologicaldiagnoses included: encephalopathy (44.4%), stroke (16.7%), previous neurologicaldiseases (9.0%), seizures (9.0%), neuromuscular disorders (5.6%), other acute brainlesions (3.4%), and other mild nonspecific symptoms (11.2%). Conclusions: Mostneurological consultations in a COVID-19-dedicated hospital were requested for severeconditions that could have an impact on the outcome. First-line doctors should be able torecognize neurological symptoms; neurologists are important members of the medicalteam in COVID-19 hospital care.Introdução: Mais de um terço dos pacientes com COVID-19 apresentam sintomasneurológicos que variam de anosmia a AVC e encefalopatia. Além disso, doençasneurológicas prévias podem exigir tratamento especial e estar associadas a pioresdesfechos. Não obstante, o papel dos neurologistas na COVID-19 é provavelmentepouco reconhecido. Objetivo: O objetivo deste estudo foi relatar os motivos para solicitarconsultas neurológicas por clínicos e intensivistas em um hospital dedicado à COVID-19. Métodos: Estudo retrospectivo realizado no Hospital das Clínicas da Faculdade deMedicina da Universidade de São Paulo, Brasil, um centro dedicado à COVID-19 com900 leitos (incluindo 300 leitos para unidades de terapia intensiva). O diagnóstico deCOVID-19 foi confirmado por SARS-CoV-2-RT-PCR em swabs nasais. Todas asinterconsultas de neurologia hospitalar entre 23 de março e 23 de maio de 2020 foramanalisadas. Os neurologistas realizaram o exame neurológico, avaliaram todos os dadosdisponíveis para diagnosticar a patologia neurológica e solicitaram exames adicionaisconforme necessidade. Diagnósticos difíceis foram estabelecidos em reuniões deconsenso. Após o diagnóstico, os neurologistas participaram da condução dos casos.Resultados: Foram solicitadas consultas neurológicas para 89 de 1.208 (7,4%) empacientes internados por COVID-19 durante o período. Os principais diagnósticosneurológicos incluíram: encefalopatia (44,4%), acidente vascular cerebral (16,7%),doenças neurológicas prévias (9,0%), crises epilépticas (9,0%), transtornosneuromusculares (5,6%), outras lesões encefálicas agudas (3,4%) e outros sintomasleves inespecíficos (11,2%). Conclusões: A maioria das consultas neurológicas em umhospital dedicado à COVID-19 foi solicitada para condições graves que poderiam afetaro desfecho clínico. Os médicos na linha de frente devem ser capazes de reconhecersintomas neurológicos. Os neurologistas são membros importantes da equipe médica noatendimento hospitalar à COVID-19

New insights into the synergism of nucleoside analogs with radiotherapy

Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells

The Horizontal Constitutions

The goal of this paper is to describe the “horizontalization” of state/national constitutions in a scenario of globalizing law, where the Supranational World Order Legislative Policy Modelling (WOLPM) is dramatically redesigning the traditional hierarchy of legal sources, whose top were with state–national constitutions. The current scenario is radically different and state/national constitutions are no longer frameworks for law-making; rather they are part of a larger frame, but rather framed in a different framework. This new framework is vertically shorter and horizontally much longer, as transnational and supranational treaties are shifting the sovereignty is going more and more supranational and global; as a consequence, a condition of interdependence is emerging, which shapes a non-reversible network of networks. This horizontalization process evolves the innovative power of the legislative function in the global law system; this system is the one which can proactively support an innovation policy viable to the key challenges of our times. Furthermore, this power shift leverages and increases the quality of democracy: by a dramatical downsizing of the meso and the micro organizational Wiliamson’s costs -which can also facilitate a direct link between the macro and the psycho-social levels- an evolution seems to be emerging from different peoples to one People (eg: from the EU member states peoples to the EU people). A better comprehension of this evolution is based upon two theoretical grounds. On one side, Lawrence Friedman’s works about the globalization of culture and technology, which is also recombining social, political and religious traditions in the globalized law making process. On the other side the Luhmann-Teubner’s vision based on the concept of Law System (just one and global all over the planet); in this case, a Global Law System is implies two evolutive directions: a vertical direction, which means increasing law production at the top of this System; and a horizontal direction, consisting of structural couplings with local juridical social systems. These couplings can also show conflictual features. As a matter of fact, as Teubner points out, there is a crisis in traditional constitutionalism, that is caused by transnationalization. As a matter of fact, traditional constitutionalism is Nation-state based and hardly can it accept supranational sovereignties. Furthermore, tendencies are strong among social systems, to put themselves outside the state and to engender individual or institutional autonomy. In order to foresee the possible outcome of this trend, the best theoretical tool is the system/environment distinction. This notions draws a neat distinction between a more and more formalized and unified global world order (through supranational treaties as mentioned above) and a more and more turbulent and noisy environment, consisting of strong protests. According to systemic theory, irritation and resonance might make the law system oscillate, nevertheless the noisy environment has no construction function

A Synthetic Lethal Screen Reveals Enhanced Sensitivity to ATR Inhibitor Treatment in Mantle Cell Lymphoma with ATM Loss-of-function

Mechanisms to maintain genomic integrity are essential for cells to remain viable. Not surprisingly, disruption of key DNA damage response (DDR) pathway factors, such as ataxia telangiectasia-mutated (ATM)/ATM- and RAD3-related (ATR) results in loss of genomic integrity. Here, a synthetic lethal siRNA-screening approach not only confirmed ATM but identified additional replication checkpoint proteins, when ablated, enhanced ATR inhibitor (ATRi) response in a high-content g-H2AX assay. Cancers with inactivating ATM mutations exhibit impaired DNA double-stranded break repair (DSB) and rely on compensatory repair pathways for survival. Therefore, impairing ATR activity may selectively sensitize cancer cells to killing. ATR inhibition in an ATM-deficient context results in phosphorylation of DNA-dependent protein kinase catalytic subunits (DNA-PKcs) and leads to induction of g-H2AX. Using both in vitro and in vivo models, ATR inhibition enhanced efficacy in ATM loss-of-function mantle cell lymphoma (MCL) compared to ATM wild-type cancer cells. In summary, single agent ATR inhibitors have therapeutic utility in the treatment of cancers, like MCL, in which ATM function has been lost. Implications: These data suggest that single agent ATR inhibitors have therapeutic utility and that ATR utilizes a complex and coordinated set of proteins to maintain genomic stability which could be further exploite