Nitric oxide dosed in short bursts at high concentrations may protect against Covid 19.

It has long been suggested that NO may inhibit an early stage in viral replication. Furthermore, in vitro tests have shown that NO inhibits the replication cycle of severe acute respiratory syndrome coronavirus. Despite smoking being listed as a risk factor to contract Covid-19, only a low proportion of the smokers suffered from SARS-corona infection in China 2003, and from Covid-19 in China, Europe and the US. We hypothesize, that the intermittent bursts of high NO concentration in cigarette smoke may be a mechanism in protecting against the virus. Mainstream smoke from cigarettes contains NO at peak concentrations of between about 250 ppm and 1350 ppm in each puff as compared to medicinal use of no more than 80 to a maximum of 160 ppm. The diffusion of NO through the cell wall to reach the virus should be significantly more effective at the very high NO concentration in the smoke, according to classic laws of physics. The only oxide of nitrogen in the mainstream smoke is NO, and the NO2 concentration that is inhaled is very low or undetectable, and methemoglobin levels are lower in smokers than non-smokers, reasonably explained by the breaths of air in between the puffs that wash out the NO. Specialized iNO machines can now be developed to provide the drug intermittently in short bursts at high concentration dose, which would then provide both a preventative drug for those at high risk, as well as an effective treatment, without the health hazards associated with smoking.

Predictive Analysis of Mechanistic Triggers and Mitigation Strategies for Pathological Scarring in Skin Wounds.

Wound fibrosis (i.e., excessive scar formation) is a medical problem of increasing prevalence, with poorly understood mechanistic triggers and limited therapeutic options. In this study, we employed an integrated approach that combines computational predictions with new experimental studies in mice to identify plausible mechanistic triggers of pathological scarring in skin wounds. We developed a computational model that predicts the time courses for six essential cell types, 18 essential molecular mediators, and collagen, which are involved in inflammation and proliferation during wound healing. By performing global sensitivity analyses using thousands of model-simulated wound-healing scenarios, we identified five key processes (among the 90 modeled processes) whose dysregulation may lead to pathological scarring in wounds. By modulating a subset of these key processes, we simulated fibrosis in wounds. Moreover, among the 18 modeled molecular mediators, we identified TGF-ß and the matrix metalloproteinases as therapeutic targets whose modulation may reduce fibrosis. The model predicted that simultaneous modulation of TGF-ß and matrix metalloproteinases would be more effective in treating excessive scarring than modulation of either therapeutic target alone. Our model was validated with previously published and newly generated experimental data, and suggested new in vivo experiments.

Pro-migratory and TGF-ß-activating functions of αvß6 integrin in pancreatic cancer are differentially regulated via an Eps8-dependent GTPase switch.

The integrin αvß6 is up-regulated in numerous carcinomas, where expression commonly correlates with poor prognosis. αvß6 promotes tumour invasion, partly through regulation of proteases and cell migration, and is also the principal mechanism by which epithelial cells activate TGF-ß1; this latter function complicates therapeutic targeting of αvß6, since TGF-ß1 has both tumour-promoting and -suppressive effects. It is unclear how these different αvß6 functions are linked; both require actin cytoskeletal reorganization, and it is suggested that tractive forces generated during cell migration activate TGF-ß1 by exerting mechanical tension on the ECM-bound latent complex. We examined the functional relationship between cell invasion and TGF-ß1 activation in pancreatic ductal adenocarcinoma (PDAC) cells, and confirmed that both processes are αvß6-dependent. Surprisingly, we found that cellular functions could be biased towards either motility or TGF-ß1 activation depending on the presence or absence of epidermal growth factor receptor pathway substrate 8 (Eps8), a regulator of actin remodelling, endocytosis, and GTPase activation. Similar to αvß6, we found that Eps8 was up-regulated in >70% of PDACs. In complex with Abi1/Sos1, Eps8 regulated αvß6-dependent cell migration through activation of Rac1. Down-regulation of Eps8, Sos1 or Rac1 suppressed cell movement, while simultaneously increasing αvß6-dependent TGF-ß1 activation. This latter effect was modulated through increased cell tension, regulated by Rho activation. Thus, the Eps8/Abi1/Sos1 tricomplex acts as a key molecular switch altering the balance between Rac1 and Rho activation; its presence or absence in PDAC cells modulates αvß6-dependent functions, resulting in a pro-migratory (Rac1-dependent) or a pro-TGF-ß1 activation (Rho-dependent) functional phenotype, respectively. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Ventricular fibrillation cardiac arrest produces a chronic striatal hyperdopaminergic state that is worsened by methylphenidate treatment.

Cardiac arrest survival rates have improved with modern resuscitation techniques, but many survivors experience impairments associated with hypoxic-ischemic brain injury (HIBI). Currently, little is understood about chronic changes in striatal dopamine (DA) systems after HIBI. Given the common empiric clinical use of DA enhancing agents in neurorehabilitation, investigation evaluating dopaminergic alterations after cardiac arrest (CA) is necessary to optimize rehabilitation approaches. We hypothesized that striatal DA neurotransmission would be altered chronically after ventricular fibrillation cardiac arrest (VF-CA). Fast-scan cyclic voltammetry was used with median forebrain bundle (MFB) maximal electrical stimulations (60Hz, 10s) in rats to characterize presynaptic components of DA neurotransmission in the dorsal striatum (D-Str) and nucleus accumbens 14 days after a 5-min VF-CA when compared to Sham or Naïve. VF-CA increased D-Str-evoked overflow [DA], total [DA] released, and initial DA release rate versus controls, despite also increasing maximal velocity of DA reuptake (Vmax ). Methylphenidate (10 mg/kg), a DA transporter inhibitor, was administered to VF-CA and Shams after establishing a baseline, pre-drug 60 Hz, 5 s stimulation response. Methylphenidate increased initial evoked overflow [DA] more-so in VF-CA versus Sham and reduced D-Str Vmax in VF-CA but not Shams; these findings are consistent with upregulated striatal DA transporter in VF-CA versus Sham. Our work demonstrates that 5-min VF-CA increases electrically stimulated DA release with concomitant upregulation of DA reuptake 2 weeks after brief VF-CA insult. Future work should elucidate how CA insult duration, time after insult, and insult type influence striatal DA neurotransmission and related cognitive and motor functions.

Missed Opportunities for Chlamydia Screening in Title X Family Planning Clinics.

BACKGROUND: Annual chlamydia (CT) screening is recommended for women younger than 25 years, yet less than half of young women seeking health care are screened annually. We analyzed Title X family planning service data from the Northwest United States to assess factors associated with missed opportunities for CT screening. Our primary hypothesis was screening coverage is higher during annual preventive health visits compared to other visit types. Study objectives were: (1) identify gaps in screening coverage by patient demographics, visit characteristics, and clinic measures; and (2) examine the association between visit type and CT screening by controlling for other covariates and stratifying by state. METHODS: Calendar year 2011 Title X visit records (n = 180,856) were aggregated to the patient level (n = 112,926) to assess CT screening coverage by all characteristics. Screening variation was explored by bivariate and multivariate Poisson regression. Adjusted models for each state estimated association between comprehensive examination and screening controlling for confounders. RESULTS: Clinic and visit characteristics were associated with CT screening. Coverage ranged from 45% in Washington to 80% in Alaska. Only 34% of patients visited for a routine comprehensive examination. Visit type was associated with screening; 75% of patients who had a comprehensive examination were screened versus 34% of those without a comprehensive examination (unadjusted PR, 2.18; 95% confidence interval, 2.16-2.21). The association between comprehensive examination and CT screening varied significantly by state (interaction term, P < 0.001). CONCLUSIONS: Missed screening opportunities are common among women who access brief appointments for specific needs but do not seek routine preventive care, particularly in some states. Structural interventions may help address these systematically missed opportunities.

Wound healing in Mac-1 deficient mice.

Mac-1 (CD11b/CD18) is a macrophage receptor that plays several critical roles in macrophage recruitment and activation. Because macrophages are essential for proper wound healing, the impact of Mac-1 deficiency on wound healing is of significant interest. Prior studies have shown that Mac-1-/- mice exhibit deficits in healing, including delayed wound closure in scalp and ear wounds. This study examined whether Mac-1 deficiency influences wound healing in small excisional and incisional skin wounds. Three millimeter diameter full thickness excisional wounds and incisional wounds were prepared on the dorsal skin of Mac-1 deficient (Mac-1-/- ) and wild type (WT) mice, and wound healing outcomes were examined. Mac-1 deficient mice exhibited a normal rate of wound closure, generally normal levels of total collagen, and nearly normal synthesis and distribution of collagens I and III. In incisional wounds, wound breaking strength was similar for Mac-1-/- and WT mice. Wounds of Mac-1 deficient mice displayed normal total macrophage content, although macrophage phenotype markers were skewed as compared to WT. Interestingly, amounts of TGF-ß1 and its downstream signaling molecules, SMAD2 and SMAD3, were significantly decreased in the wounds of Mac-1 deficient mice compared to WT. The results suggest that Mac-1 deficiency has little impact on the healing of small excisional and incisional wounds. Moreover, the findings demonstrate that the effect of single genetic deficiencies on wound healing may markedly differ among wound models. These conclusions have implications for the interpretation of the many prior studies that utilize a single model system to examine wound healing outcomes in genetically deficient mice.

Age of Childhood Onset in Type 1 Diabetes and Functional Brain Connectivity in Midlife.

OBJECTIVES: The development of Type 1 diabetes mellitus (T1DM) within the first 7 years of life has been linked to poorer cognitive performance. Adults with T1DM have altered functional brain connectivity, but no studies have examined whether earlier age of T1DM onset is associated with functional connectivity later in life. Accordingly, we tested the relationship between age of onset and resting state functional connectivity in a cohort of middle-aged adults with childhood-onset T1DM. METHODS: Participants were from a subsample of the Pittsburgh Epidemiology of Diabetes Complications cohort and included 66 adults (mean age = 47.54 years, 32 men). Resting state blood oxygen level-dependent activity was used to calculate mean connectivity for eight functional brain networks. A multivariate analysis of variance examined associations between age of onset and network connectivity. Diffusion tensor and fluid-attenuated inversion recovery images were analyzed to identify microstructural alterations and white-matter hyperintensity volumes. RESULTS: Later childhood onset of T1DM was associated with lower connectivity (F(8,57) = 2.40, p = .026). A significant interaction was present for current age such that an inverse association with age of onset for functional connectivity was present in older individuals (F(8,55) = 2.88, p = .035). Lower connectivity was associated with older age, increased white-matter hyperintensity volume, and lower microstructural integrity. CONCLUSIONS: Diagnosis of T1DM later in childhood may be associated with lower brain functional connectivity, particularly in those surviving into older ages. These alterations may be an early marker for subsequent cognitive decrements. Future studies are warranted to understand the pathways underlying these associations.

Generation of purified nitric oxide from liquid N2O4 for the treatment of pulmonary hypertension in hypoxemic swine.

Inhaled nitric oxide (NO) selectively dilates pulmonary blood vessels, reduces pulmonary vascular resistance (PVR), and enhances ventilation-perfusion matching. However, existing modes of delivery for the treatment of chronic pulmonary hypertension are limited due to the bulk and heft of large tanks of compressed gas. We present a novel system for the generation of inhaled NO that is based on the initial heat-induced evaporation of liquid N2O4 into gas phase NO2 followed by the room temperature reduction to NO by an antioxidant, ascorbic acid cartridge just prior to inhalation. The biologic effects of NO generated from liquid N2O4 were compared with the effects of NO gas, on increased mean pulmonary artery pressure (mPAP) and PVR in a hypoxemic (FiO2 15%) swine model of pulmonary hypertension. We showed that NO concentration varied directly with the fixed cross sectional flow of the outflow aperture when studied at temperatures of 45, 47.5 and 50°C and was independent of the rate of heating. Liquid N2O4-sourced NO at 1, 5, and 20 ppm significantly reduced the elevated mPAP and PVR induced by experimental hypoxemia and was biologically indistinguishable from gas source NO in this model. These experiments show that it is feasible to generate highly purified NO gas from small volumes of liquid N2O4 at concentrations sufficient to lower mPAP and PVR in hypoxemic swine, and suggest that a miniaturized ambulatory system designed to generate biologically active NO from liquid N2O4 is achievable.

Type 2 diabetes and cognitive impairment: contributions from neuroimaging.

Type 2 diabetes mellitus (T2D) and Alzheimer disease (AD) are major public health burdens associated with aging. As the age of the population rapidly increases, a sheer increase in the incidence of these diseases is expected. Research has identified T2D as a risk factor for cognitive impairment and potentially AD, but the neurobiological pathways that are affected are only beginning to be understood. The rapid advances in neuroimaging in the past decade have added significant understanding to how T2D affects brain structure and function and possibly lead to AD. This article provides a review of studies that have utilized structural and functional neuroimaging to identify neural pathways that link T2D to impaired cognitive performance and potentially AD. A primary focus of this article is the potential for neuroimaging to assist in understanding the mechanistic pathways that may provide translational opportunities for clinical intervention.

Tumor-stromal interactions in pancreatic cancer.

Pancreatic adenocarcinoma has one of the worse prognoses of any cancer with a 5-year survival of only 3%. Pancreatic cancer displays one of the most prominent stromal reactions of all tumors and it is evident that this is a key contributing factor to disease outcome. The tumor microenvironment of pancreatic cancer harbors a wide spectrum of cell types and a complex network of mechanisms which all serve to promote tumor progression. It is clear that the symbiotic relationship between pancreatic cancer cells and stellate cells is the chief factor creating this unique tumor milieu. Pancreatic stellate cells play critical roles in evasion of cancer cell apoptosis, invasion and metastases, angiogenesis, and promotion of an immunosuppressive environment, all key hallmarks of malignancy. Existing treatments for pancreatic cancer focus on targeting the cancer cells rather than the whole tumor, of which cancer cells represent a small proportion. It is now increasingly evident that research targeted towards the interactions between these cell types, ideally at an early stage of tumor development, is imperative in order to propel the way forward to more effective treatments.

Long-term trends in Chlamydia trachomatis infections and related outcomes in a U.S. managed care population.

BACKGROUND: Given recent increasing case rates of Chlamydia trachomatis infection, we evaluated trends in chlamydia rates and related health outcomes in women and men aged 15 to 44 years who were enrolled in a Pacific Northwest health plan. METHODS: We identified chlamydia, pelvic inflammatory disease (PID), ectopic pregnancy, and male urethritis cases occurring annually during 1997-2007 using computerized health plan databases, calculating rates per 100,000 person-years (py) by gender and 5-year age groups. We also calculated annual chlamydia testing rates. RESULTS: In women, chlamydia testing rates increased by approximately 23% (220 tests per 1000 py in 1997 to 270 tests per 1000 in 2007). Chlamydia diagnosis rates rose from 449 cases/100,000 py in 1997 to 806/100,000 in 2007, a 79% increase (P = 0.01). Increases were greatest during 2005-2007, also the period of major conversion to nucleic acid amplification test. PID rates in this interval declined steadily from 823 cases/100,000 py to 473/100,000 (P < 0.01). Ectopic pregnancy rates remained unchanged. In men, chlamydia testing rates increased nearly 3.5-fold, from 12 to 42 tests per 1000 py. Chlamydia rates for men also rose significantly throughout the study interval (from 91 cases/100,000 py to 218/100,000; P < 0.01) as did urethritis diagnosis rates (P < 0.01). CONCLUSION: Between 1997 and 2007, annual health plan chlamydia rates increased significantly for both women and men. These trends may be due in part to increased testing rates and increased use of more sensitive tests, but they likely do not explain the increased urethritis rates. During this same interval, we observed steady declines in PID rates, consistent with other national data sources.

A life with prosopagnosia.

The author gives an anecdotal account of his life with developmental prosopagnosia (DP). He was not formally diagnosed until the age of 53 and has evolved a complicated strategy for recognizing people based on non-facial physical features and context. He describes his experiences through infancy, school, university life and courtship, work and family life. He believes that he has lived a full and successful life despite DP but that some aspects of his social and work life were impaired by face-blindness. In his experience people react positively and helpfully if the consequences of DP are explained to them, and this improves social interactions and communications.

Improving outpatient services: the Southampton IBD virtual clinic.

The follow-up of inflammatory bowel disease (IBD) patients is challenging due to the relapsing remitting nature of the diseases, the wide spectrum of severity and complexity as well as the need for monitoring of long-term complications and drug treatments. Conventional outpatient follow-up lacks flexibility for patients and there are competing pressures for clinic time. Alternative follow-up pathways include telephone clinics, self-management programmes or discharging patients. The IBD virtual clinic (VC) is a further option. Patients with an established diagnosis for >2 years, who have been stable for >1 year, do not have primary sclerosing cholangitis and who give their consent, are entered into the VC system. Two months before their annual follow-up is due patients are sent blood test forms and a simple questionnaire with an information sheet. If they meet any of the criteria on the questionnaire, they are asked to contact the IBD specialist nursing team to discuss their situation. The blood test results and the patient's database entry are reviewed to ensure that they are not due surveillance investigations. The patients and their GPs then receive a letter informing them of their management plan. We currently follow-up 20% of the Southampton IBD cohort using the VC. The VC system is an innovative, efficient and patient-responsive method for following up mild to moderate IBD. It is well liked by patients but is dependent on a well-maintained database with good integration of IT systems and requires both clerical and IBD nurse specialist support.

Converting data into information.

Improving healthcare in the 21st century will depend on how well vast amounts of data are mined. However, converting data contained in multiple hospital and clinical databases into information that can be used for clinical decision support is a complex task. The process involves a combination of cultural and technological steps that are time-consuming and resource-intensive. The authors describe one hospital's long journey toward becoming a data-driven organization.

Refractive outcomes following bilateral implantation of a diffractive toric intraocular lens in a multisurgeon hospital setting.

OBJECTIVE: To assess residual postoperative refractive astigmatism following bilateral implantation of a trifocal toric intraocular lens (IOL) in a real-world multisurgeon setting. DESIGN: Prospective multisurgeon study (6 surgeons at 2 sites). METHODS: Bilateral implantation of a trifocal toric IOL (AcrySof PanOptix IOL; Alcon Vision LLC, Fort Worth, TX, USA) was performed in 140 eyes of 70 patients. Patients were assessed on day 1 and 3 months postoperatively. The primary outcome measure was residual astigmatism. Secondary endpoints included absolute prediction error, IOL rotation, binocular uncorrected and distance-corrected visual acuities at near (40 cm), intermediate (60 cm), and distance (6 m) and spectacle independence evaluated with the validated Intraocular Lens Satisfaction questionnaire. RESULTS: Mean preoperative cylinder was 1.25 ± 0.72 D and was 0.39 ± 0.28 D at 3 months postoperatively. At 3 months postoperatively, mean residual astigmatism was 0.39 ± 0.28 D (range, 0-1.25 D), and 118 eyes (84.3%) had postoperative astigmatism of 0.5 D or less. Mean absolute prediction error was 0.25 ± 0.21 D (range, 0-1.13 D), and 124 eyes (88.6%) had absolute prediction error of 0.5 D or less. At 3 months postoperatively, mean absolute rotation was 2.0 ± 2.7 degrees compared with baseline (range, 0-15 degrees), and 133 IOLs (95.0%) were within 5 degrees of the implanted axis. Additionally, 55 patients (79%) reported never or rarely using spectacles at near, 66 (94%) at intermediate, and 67 (96%) at distance. CONCLUSIONS: The results of this study demonstrate that implantation with the PanOptix toric IOL can provide excellent refractive and visual outcomes with minimal residual astigmatism.

Use of ultra pure nitric oxide generated by the reduction of nitrogen dioxide to reverse pulmonary hypertension in hypoxemic swine.

Inhaled nitric oxide (NO) has the capacity to selectively dilate pulmonary blood vessels, and thus enhance the matching of ventilation and perfusion, improve oxygenation and decrease pulmonary hypertension. However, existing approaches for the administration of inhaled NO are associated with the co-delivery of potentially toxic concentrations of nitrogen dioxide (NO2) due to the oxidation of NO in oxygen rich environments. We tested the ability of a novel methodology for generating highly purified NO through the reduction of NO2 by ascorbic acid to reverse pulmonary hypertension. In vitro testing demonstrated that the NO output of the novel device is ultrapure and free of NO2. An in vivo hypoxemic swine model of pulmonary hypertension was used to examine the dose response to NO in terms of pulmonary pressures and pulmonary vascular resistance. Pulmonary hypertension was induced by lowering inspired oxygen to 15% prior to treatment with inhaled ultra purified NO (1, 5, 20, and 80PPM). Hypoxemia increased mean pulmonary artery pressures and pulmonary vascular resistance. Inhaled ultra purified NO doses (down to 1PPM) show a marked reduction of hypoxemia-induced pulmonary vascular resistance. These experiments demonstrate a simple and robust method to generate purified inhaled NO that is devoid of NO2 and capable of reversing hypoxemia induced pulmonary hypertension.

Chlamydia trachomatis infection among women reporting sexual activity with women screened in Family Planning Clinics in the Pacific Northwest, 1997 to 2005.

OBJECTIVES: We sought to define Chlamydia trachomatis positivity among women who report sexual activity with women, a population for which sparse data on this infection are available and for whom health disparities including challenged access to comprehensive sexual and reproductive health services, have been reported. METHODS: We analyzed data from 9358 family planning clinic visits with C trachomatis tests among women aged 15 to 24 years who reported sexual activity within the past year exclusively with women (WSW) or with men and women (WSMW), in the Region X Infertility Prevention Project. Characteristics were compared with women who reported sexual activity exclusively with men (WSM). Results. C trachomatis positivity among both WSW and WSMW was 7.1%, compared with 5.3% among WSM. Behavioral risks were more commonly reported by WSW and WSMW, compared with reports by WSM. Risks for C trachomatis positivity were comparable across groups and included younger age, non-White race, behavioral risks, and clinical signs. CONCLUSIONS: Higher C trachomatis positivity among women reporting same-sex sexual behavior supports investigation into potential explanatory factors, including sexual behaviors, biological susceptibility, routine C trachomatis screening disparities, sexual identity disclosure, and sexual network assessment.