HOCl Rapidly Kills Corona, Flu, and Herpes to Prevent Aerosol Spread.

The COVID-19 pandemic has escalated the risk of SARS-CoV-2 transmission in the dental practice, especially as droplet-aerosol particles are generated by high-speed instruments. This has heightened awareness of other orally transmitted viruses, including influenza and herpes simplex virus 1 (HSV1), which are capable of threatening life and impairing health. While current disinfection procedures commonly use surface wipe-downs to reduce viral transmission, they are not fully effective. Consequently, this provides the opportunity for a spectrum of emitted viruses to reside airborne for hours and upon surfaces for days. The objective of this study was to develop an experimental platform to identify a safe and effective virucide with the ability to rapidly destroy oral viruses transported within droplets and aerosols. Our test method employed mixing viruses and virucides in a fine-mist bottle atomizer to mimic the generation of oral droplet-aerosols. The results revealed that human betacoronavirus OC43 (related to SARS-CoV-2), human influenza virus (H1N1), and HSV1 from atomizer-produced droplet-aerosols were each fully destroyed by only 100 ppm of hypochlorous acid (HOCl) within 30 s, which was the shortest time point of exposure to the virucide. Importantly, 100 ppm HOCl introduced into the oral cavity is known to be safe for humans. In conclusion, this frontline approach establishes the potential of using 100 ppm HOCl in waterlines to continuously irrigate the oral cavity during dental procedures to expeditiously destroy harmful viruses transmitted within aerosols and droplets to protect practitioners, staff, and other patients.

Bevacizumab use and risk of cardiovascular adverse events among elderly patients with colorectal cancer receiving chemotherapy: a population-based study.

BACKGROUND: Cardiovascular risk attributable to bevacizumab (Avastin(®), BEV) for treatment of metastatic colorectal cancer (CRC) remains unclear. We conducted a population-based cohort study to assess the safety of BEV use among patients aged ≥ 65. PATIENTS AND METHODS: We identified CRC patients diagnosed from 2005 to 2007 who received chemotherapy and were followed until 31 December 2009. Outcomes were 3-year risk of arterial thromboembolic events (ATEs), cardiomyopathy or congestive heart failure (CM/CHF), and cardiac death (CD) after chemotherapy initiation. We fitted Cox-proportional hazards (PHs) models with inverse-probability-of-treatment-weights and calculated hazard ratios (HRs) for the risk of adverse events. RESULTS: We identified 6803 CRC patients (median age: 73 years). Those with cardiac comorbidity were less likely to receive BEV (P < 0.0001). BEV is associated with an elevated risk of ATEs (HR = 1.82, 95% CI = 1.20-2.76, P < 0.001; rate difference: 3.5 additional cases/1000 person-years). We observed no association between BEV and CD or CM/CHF. CONCLUSIONS: In general practice, the cardiovascular risk of BEV in elderly CRC is modest. The observed ATEs risk is lower than reported in clinical trials, which may be due to careful patient selection. Our findings may facilitate clinical decision-making of BEV use in elderly patients.

Time- and dose-dependent effects of corticotropin releasing factor on cerebral glucose metabolism in rats.

The time course and the relation to dose of locomotor activity and of the regional cerebral metabolic rates for glucose (rCMRglc) were measured in freely moving Sprague-Dawley rats after intracerebroventricular administration of ovine corticotropin releasing factor (oCRF). Motor activity was determined using a familiar photocage cell. rCMRglc was measured, using the quantitative autoradiographic [(14)C]2-deoxyglucose procedure, in 73 brain regions at 10, 30, 90 and 180 min after administration of oCRF 10 microg and at 90 min after oCRF 0.1, 1 and 100 microg. oCRF 10 microg increased motor activity in a sustained fashion and increased rCMRglc with different time courses throughout brain regions. In cerebellar regions rCMRglc increases peaked at 90 min and were sustained up to 180 min. In non-cerebellar regions rCMRglc increases peaked at 90 min but declined thereafter. At lower doses (0.1 and 1 microg) oCRF increased rCMRglc in fewer brain regions (1 and 5 regions affected, average increases 1% and 7%) including cerebellar areas and brainstem sensory nuclei and decreased rCMRglc in medial prefrontal cortex. At the highest dose (100 microg) oCRF induced large and widespread rCMRglc increases in cerebellar, brainstem, hypothalamic, limbic and neocortical areas (40 brain regions affected, average increase 32%). The findings indicate that cerebellar areas and brainstem nuclei are highly sensitive to oCRF and may mediate oCRF autonomic and behavioral effects.

Neither B cells nor T cells are required for CNS demyelination in mice persistently infected with MHV-A59.

Murine hepatitis virus A59 infection of the central nervous system (CNS) results in CNS demyelination in susceptible strains of mice. In infected B-cell-deficient mice, demyelination not only occurred but was also more severe than in parental C57BL/6 animals. This increase may be due to the persistence of virus in the CNS in the absence of B cells. In mice lacking antibody receptors or complement pathway activity, virus did not persist yet demyelination was similar to parental mice. In infected RAG1(-/-) mice, moderately sized, typical demyelinating lesions were identified. Therefore, demyelination can occur in the absence of B and T cells.

Murine hepatitis virus--a model for virus-induced CNS demyelination.

Most murine hepatitis virus (MHV) strains, as their name suggests, infect the liver. However, several murine strains are tropic for the central nervous system (CNS) and cause encephalitis with subsequent CNS demyelination. The CNS demyelination shares pathological similarities with human CNS demyelinating diseases such as multiple sclerosis (MS). These viruses are, therefore, used to study the role of the immune system in viral clearance from the CNS, in CNS demyelination, and in remyelination. Nevertheless, it is still unclear exactly how MHV induces demyelination and to what extent the immune system plays a role in this pathology. Here we review this field in the context of the immune response to MHV in the liver and the CNS focusing on studies that have been published in the past 5 years.

Clinical correlates of estrogen replacement therapy use and duration of use among medicaid recipients.

Estrogen replacement therapy (ERT) is used not only for the short-term control of menopausal symptoms but long-term for disease prevention. This study examined the influence of selected clinical conditions on the use of ERT and the duration of ERT use among women enrolled in a state Medicaid program. We identified 60,531 women, aged >/=45 years, who were enrolled in Maryland Medicaid continuously for at least 2 of 3 years. ERT use was determined through prescription claims submitted for reimbursement. The presence or risk of selected clinical conditions (e.g., osteoporosis, heart disease, estrogen-sensitive cancers) was determined by screening Medicaid claims files for related diagnoses, procedures, or prescription claims. Multiple logistic regression was used to model ERT use, and proportional hazards regression was used to model duration of use. Fourteen percent of these women filled an ERT prescription, with use varying by age, race, and place of residence. Oral dosage forms were the most popular (80.8%), followed by vaginal cream or ring (22.2%), and transdermal patch (7.3%). In adjusted models, osteoporosis, heart disease, hypertension, hyperlipidemia, diabetes, ovarian cancer, and thromboembolic disease were positively associated and dementia and breast cancer were negatively associated with ERT use. None of these medical conditions predicted the duration of estrogen therapy. Use of ERT was very low among these women despite coverage of prescription medications, and the presence of clinical indications had no influence on the length of therapy among these women despite known benefits for long-term preventive therapy.

Multiple regions of the murine coronavirus spike glycoprotein influence neurovirulence.

The spike (S) glycoprotein of mouse hepatitis virus (MHV) is a major determinant of neurovirulence. Using targeted recombination we previously demonstrated that the S gene of the highly neurovirulent MHV-4 conferred a dramatic increase in neurovirulence to the mildly neurovirulent MHV-A59. To identify the genetic determinants of neurovirulence within the MHV-4 spike, we generated isogenic recombinant viruses containing various MHV-4/MHV-A59 chimeric spike genes, and studied their phenotypes in vivo. The MHV-4/MHV-A59 chimeric spike genes consisted of either reciprocal exchanges between the S1 and S2 spike subunits, or smaller exchanges specifically in the hypervariable region (HVR) of S1. The chimeric spike gene containing recombinants all exhibited efficient replication in vitro, yet many were severely attenuated for virulence in vivo. Furthermore, these attenuated recombinants exhibited decreased titers of infectious virus in the brain relative to the parental recombinant viruses containing the full-length MHV-4 or MHV-A59 spike genes. This is the first report that compares the neurovirulence and pathogenesis of isogenic viruses with defined alterations in the MHV spike protein. From these studies, it appears that the interactions of multiple regions of the MHV spike, including the HVR, act in concert to allow for efficient infection of and virulence in the murine central nervous system.

Antibody is required for clearance of infectious murine hepatitis virus A59 from the central nervous system, but not the liver.

Intracerebral inoculation with mouse hepatitis virus strain A59 results in viral replication in the CNS and liver. To investigate whether B cells are important for controlling mouse hepatitis virus strain A59 infection, we infected muMT mice who lack membrane-bound IgM and therefore mature B lymphocytes. Infectious virus peaked and was cleared from the livers of muMT and wild-type mice. However, while virus was cleared from the CNS of wild-type mice, virus persisted in the CNS of muMT mice. To determine how B cells mediate viral clearance, we first assessed CD4(+) T cell activation in the absence of B cells as APC. CD4(+) T cells express wild-type levels of CD69 after infection in muMT mice. IFN-gamma production in response to viral Ag in muMT mice was also normal during acute infection, but was decreased 31 days postinfection compared with that in wild-type mice. The role of Ab in viral clearance was also assessed. In wild-type mice plasma cells appeared in the CNS around the time that virus is cleared. The muMT mice that received A59-specific Ab had decreased virus, while mice with B cells deficient in Ab secretion did not clear virus from the CNS. Viral persistence was not detected in FcR or complement knockout mice. These data suggest that clearance of infectious mouse hepatitis virus strain A59 from the CNS requires Ab production and perhaps B cell support of T cells; however, virus is cleared from the liver without the involvement of Abs or B cells.

Murine coronavirus spike protein determines the ability of the virus to replicate in the liver and cause hepatitis.

Recombinant mouse hepatitis viruses (MHV) differing only in the spike gene, containing A59, MHV-4, and MHV-2 spike genes in the background of the A59 genome, were compared for their ability to replicate in the liver and induce hepatitis in weanling C57BL/6 mice infected with 500 PFU of each virus by intrahepatic injection. Penn98-1, expressing the MHV-2 spike gene, replicated to high titer in the liver, similar to MHV-2, and induced severe hepatitis with extensive hepatocellular necrosis. S(A59)R13, expressing the A59 spike gene, replicated to a somewhat lower titer and induced moderate to severe hepatitis with zonal necrosis, similar to MHV-A59. S4R21, expressing the MHV-4 spike gene, replicated to a minimal extent and induced few if any pathological changes, similar to MHV-4. Thus, the extent of replication and the degree of hepatitis in the liver induced by these recombinant viruses were determined largely by the spike protein.

Pathogenesis of fusion deficient recombinant mouse hepatitis viruses.

In this study we have demonstrated that recombinant viruses carrying the amino acid mutations Q1067H, Q1094H, and L1114R were unable to induce fusion at neutral pH, replicated more efficiently in L2 cells, and that infection was delayed by ammonium chloride. These results suggest that the R120/R121 recombinants most likely use the endosomal pathway to enter cells. In this sense they are similar to the pH-dependent MHV-4 variant OBLV60. We were able to observe an attenuated virulence in vivo, despite the fact that our R120/R121 recombinants replicated to comparable (IC) or higher (IN) titers than the S4R29 recombinant in the brain. Preliminary results showed that the level of inflammation observed in infected mice is consistent with the attenuated virulence, but they cannot be explained by the high titers of replication.

Seizure models: anticonvulsant effects of ECT and rTMS.

1. A variety of enzymes, peptides, neurotrophic factors and their receptors show complex cascades of alterations with amygdala-kindled seizure progression; some represent compensatory adaptations that could become new targets of therapeutics. 2. Non-convulsant brain stimulation with repetitive transcranial magnetic stimulation (rTMS) may be able to engage some of the neuro-adaptive effects of ECT without the necessity of inducing a seizure. 3. Data from preclinical and clinical studies raise the possibility that non-convulsant stimulation achieved by high or low frequency rTMS may be able to alter neurotransmitters, neuropeptides, and neurotrophic factors, leading to frequency- and region-dependent changes in neural excitability. 4. Individual depressed patients show differential responses to two weeks high vs. low frequency rTMS, as revealed by the inverse correlation of degree of improvement in depression achieved by these two frequencies. 5. Preliminary data from rTMS and positron emission tomography (PET) studies reveal moderately sustained differential effects of rTMS frequency on regional cerebral neural activity in depressed patients. 6. These data suggest the possibility that an individual's level of baseline rCBF or rCMRglu on PET would help predict which rTMS frequency might be the most appropriate treatment for their depression.