First Phase Of Disease Research Articles

New Therapeutic Options in Mild Moderate COVID-19 Outpatients.

Background: In recent years, the therapeutic options for COVID have significantly improved; however, the therapies are expensive with restricted access to drugs, and expeditious and difficult to manage at home. We investigated the effect of pidotimod in preventing hospitalization in patients with mild-moderate COVID-19. Methods: A total of 1231 patients between January and June 2021 were screened. A total of 184 patients with mild-moderate COVID-19 were enrolled and divided into two groups: group-A (97) had undergone therapy with pidotimod 800 mg bid for 7−10 days and group-B (87) had other therapies. We excluded those who had undergone complete vaccination course, monoclonal anti-spike/antivirals or the co-administration of pidotimod-steroid. The primary outcome chosen was the emergency room, hospitalization, and deaths for COVID-related causes; the secondary outcome chosen was the duration of COVID-19 illness. Results: A total of 34 patients (18.5%) required hospital treatment, 11 in group-A and 23 in group-B (11.3% vs. 26.4%, p = 0.008). The median disease duration in group-A was 21 days (IQR 17−27) vs. 23 (IQR 20−31) in group-B (p = 0.005). Patients in the pidotimod group had higher SpO2 in the walking test (IQR 96−99% vs. IQR 93−98%, p = 0.01) and a lower need for steroid rescue therapy (11.5% vs. 60.9%, p < 0.001). Conclusions: In the first phase of disease, pidotimod can represent an effective, low-cost, weapon, without restrictions of use, that is able to prevent a second aggressive phase and promote faster virological recovery.

Aspirin or Ticagrelor in Staphylococcus aureus Infective Endocarditis: Where Do We Stand?

Infective endocarditis is a challenging disease with a high mortality and morbidity rate. Antibiotic prophylaxis is currently recommended in high-risk infective endocarditis patients. However, the use of antibiotics faces the challenge of a low efficacy and contributes further to the emerging infection rate by antibiotic-resistant strains, emphasizing the need for new therapeutic strategies. Platelets are essential in the initial phase of infective endocarditis, acting as first-line immune responders. During the first phase of disease, bacteria can interact with platelets and counteract platelet antimicrobial activities. Mechanistic in vitro and animal studies on the effect of aspirin on bacteria-platelet interactions and the prevention of vegetation development showed promising results. However, data from clinical studies on the outcome of infective endocarditis patients who were receiving medically indicated aspirin therapy remain controversial. Therefore, the benefit of antiplatelet agents in infective endocarditis prevention has been questioned. Besides aspirin, it has been discovered that the platelet P2Y12 receptor antagonist ticagrelor has antibacterial properties in addition to its potent antiplatelet activity. Furthermore, a recent study in mice and a case report remarkably indicated the ability of this drug to eradicate Staphylococcus aureus bacteremia. This review will focus on current knowledge on antibacterial activity of ticagrelor, compared to aspirin, pointing out main unanswered questions. The goal is to provide food for thought as to whether a prior ticagrelor therapy might be beneficial for the prevention of infective endocarditis.

Contribution of STAT1 to innate and adaptive immunity during type I interferon-mediated lethal virus infection.

Signal transducers and activators of transcription (STAT) 1 is critical for cellular responses to type I interferons (IFN-Is), with the capacity to determine the outcome of viral infection. We previously showed that while wildtype (WT) mice develop mild disease and survive infection with lymphocytic choriomeningitis virus (LCMV), LCMV infection of STAT1-deficient mice results in a lethal wasting disease that is dependent on IFN-I and CD4+ cells. IFN-Is are considered to act as a bridge between innate and adaptive immunity. Here, we determined the relative contribution of STAT1 on innate and adaptive immunity during LCMV infection. We show that STAT1 deficiency results in a biphasic disease following LCMV infection. The initial, innate immunity-driven phase of disease was characterized by rapid weight loss, thrombocytopenia, systemic cytokine and chemokine responses and leukocyte infiltration of infected organs. In the absence of an adaptive immune response, this first phase of disease largely resolved resulting in survival of the infected host. However, in the presence of adaptive immunity, the disease progressed into a second phase with continued cytokine and chemokine production, persistent leukocyte extravasation into infected tissues and ultimately, host death. Overall, our findings demonstrate the key contribution of STAT1 in modulating innate and adaptive immunity during type I interferon-mediated lethal virus infection.

Reconstituting Corticostriatal Network on-a-Chip Reveals the Contribution of the Presynaptic Compartment to Huntington’s Disease

Huntington's disease (HD), a devastating neurodegenerative disorder, strongly affects the corticostriatal network, but the contribution of pre- and postsynaptic neurons in the first phases of disease is unclear due to difficulties performing early subcellular investigations invivo. Here, we have developed an on-a-chip approach to reconstitute an HD corticostriatal network invitro, using microfluidic devices compatible with subcellular resolution. We observed major defects in the different compartments of the corticostriatal circuit, from presynaptic dynamics to synaptic structure and transmission and to postsynaptic traffic and signaling, that correlate with altered global synchrony of the network. Importantly, the genetic status of the presynaptic compartment was necessary and sufficient to alter or restore the circuit. This highlights an important weight for the presynaptic compartment in HD that has to be considered for future therapies. This disease-on-a-chip microfluidic platform is thus a physiologically relevant invitro system for investigating pathogenic mechanisms and for identifying drugs.

The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosis

BackgroundIncreased relapse rates in multiple sclerosis (MS) as a consequence of peripheral immune system activation, owing to infection for example, have been widely reported, but the mechanism remains unclear. Acute brain injury models can be exacerbated by augmenting the hepatic acute phase response (APR). Here, we explored the contribution of the hepatic APR to relapse in two rodent models of MS.MethodsMice with MOG-CFA-induced chronic relapsing experimental autoimmune encephalitis (CR-EAE) were killed before, during and after the first phase of disease, and the brain and liver chemokine, cytokine and acute phase protein (APP) mRNA expression profile was determined. During remission, the APR was reactivated with an intraperitoneal lipopolysaccharide (LPS) and clinical score was monitored throughout. To explore the downstream mediators, CXCL-1, which is induced as part of the APR, was injected into animals with a focal, cytokine/MOG-induced EAE lesion (fEAE) and the cellularity of the lesions was assessed.ResultsCompared to CFA control, in a rodent CR-EAE model, an hepatic APR preceded clinical signs and central cytokine production in the initial phase of disease. Compared to administration in naïve animals, an LPS challenge during the asymptomatic remission phase of CR-EAE rodents provoked relapse and resulted in the increased and extended expression of specific peripheral hepatic chemokines. CXCL-1 and several other APPs were markedly elevated. A single intravenous administration of the highly induced chemokine, CXCL-1, was found to be sufficient to reactivate the lesions by increasing microglial activation and the recruitment of T cells in fEAE lesions.ConclusionsThe APR plays a contributing role to the pathology seen in models of chronic brain injury and in translating the effects of peripheral immune system stimulation secondary to trauma or infection into central pathology and behavioural signs. Further elucidation of the exact mechanisms in this process will inform development of more effective, selective therapies in MS that, by suppressing the hepatic chemokine response, may prevent relapse.

PARP-1 inhibition prevents CNS migration of dendritic cells during EAE, suppressing the encephalitogenic response and relapse severity

Background: Pharmacological inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) are currently evaluated in clinical trials for various malignancies but, interestingly, also proved of remarkable efficacy in preclinical models of autoimmune disorders including experimental autoimmune encephalomyelitis (EAE). Objectives: The objectives of the study were to determine molecular mechanisms underlying suppression of the encephalitogenic response by these drugs; likewise, whether clinically-relevant post-treatment paradigms with PARP-1 inhibitors could prevent EAE relapses. Methods: Adopted both in vitro techniques (bone marrow-derived cultured DC) as well as in vivo models of chronic or relapsing–remitting (RR) EAE. Results: We report that two structurally unrelated PARP-1 inhibitors negatively regulated NFκB activation, as well as maturation, cytokine production and APC function of cultured mouse bone marrow-derived dendritic cells (DCs). PARP-1 inhibitors also reduced the number and APC function of DCs migrating in the draining lymph nodes of ovalbumin-immunized mice. In C57Bl mice with chronic EAE or SJL mice with RR EAE, pharmacological inhibition of PARP-1 reduced CNS DC migration and demyelination as well as neurological impairment to an extent similar to that achieved with the potent immunosuppressant cyclosporine A. Remarkably, PARP-1 inhibitors injected after the first phase of disease reduced relapse incidence and severity, as well as the spinal cord number of autoreactive Th17 cells. Under this clinically-relevant treatment paradigm, PARP inhibitors also suppressed epitope spreading of the encephalitogenic response. Conclusions: Overall, data underscore the potential relevance of PARP-1 inhibitors to MS therapy and suppression of autoimmunity.

Leprous neuropathy: a clinical and neurophysiological study

Leprosy is one of the most common treatable causes of neuropathy in the world. Peripheral nerves and skin are commonly affected. We reported the clinical features and electrophysiological findings in 46 patients with leprosy. The aim of our study was to evaluate the nature of damage in the nerve fibres, especially in the first phase of disease. Forty‐six patients (mean age: 44.8 ± 17.8) with diagnosed leprosy were studied by neurological examination and nerve conduction studies (NCS). Twenty‐eight patients were examined for a mean period of 34.8 months. The number of tests for patients varied from 1 to 13 controls. Amplitude of sensory and motor action potentials (SNAP and MAP), sensory‐motor conduction velocity of median, ulnar, tibialis, peroneal and sural nerves were evaluated. Abnormalities were found in 282 of 647 nerves investigated (37.56%), sensory nerve abnormalities being more frequent than motor (50.16% 29.45). Of 282 nerves with neurophysiological abnormalities, 123 were clinically asymptomatic (43.62%). A statistically significant correlation between duration of disease and number of electrophysiological abnormalities was demonstrated. In 19 nerves partial “conduction‐block”(reduction of cMAP &gt; 50% in the proximal response) was individuated. The first electrophysiological alteration, suggesting segmental demyelination, was detected in 41 nerves of 21 patients (33.3 %). According to this view, our data support the hypothesis that leprosy induces a neuropathy of demyelinating nature in the first phase.

Is there a role for microorganisms in the pathogenesis of sarcoidosis?

Sarcoidosis is a granulomatous disease that has the immunopathological features of being antigen-driven. It is a complex disease that appears to arise from the interaction of one or more triggers with an immunologically predisposed host. Previous reports of familial clustering and varying prevalence of sarcoidosis in different populations could reflect differences in ethnic predisposition or differences in local environmental exposures. This review focuses specifically on these areas that have been the subjects of intensive investigation recently. Specific focus is provided on the issue of an infective trigger and highlights popular candidates. It is concluded that microbes are a likely trigger (but not as an infection) in a genetically predisposed individual and that this initial event culminates in the sarcoidosis granulomatous response.

Survival models with two phases and length biased sampling

A survival model is presented in which all patients go through a first phase of disease; some then die and the remainder progress to a second phase of disease. The data observed are the path taken and the total sojourn time in the system but not the time, if ever, at which the second phase is entered. The sojourn time in each phase is assumed to be exponentially distributed with possibly different rates for the two phases. Themodel describes serious diseases that progress through one or two phases, and can be extended to multiple phases. The model is extended to account for several length-biased sampling situations. Censoring is considered in all models. Maximum like lihood estimates for the parameters involved exist, are consistent and are a symptotically normal. One of the proposed models is applied to data from the Veterans Administration involving a study of coronary arterial occlusive disease.