Despite a substantial body of research, we lack fundamental understanding of the pathophysiology of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) including pulmonary ...and cardiovascular outcomes, in part due to limitations of murine models. Most models use transgenic mice (K18) that express the human (h) angiotensin converting enzyme 2 ( ACE2 ), ACE2 knock-in (KI) mice, or mouse-adapted strains of SARS-CoV-2. Further, many SARS-CoV-2 variants produce fatal neurologic disease in K18 mice and most murine studies focus only on acute disease in the first 14 days post inoculation (dpi). To better enable understanding of both acute (<14 dpi) and post-acute (>14 dpi) infection phases, we describe the development and characterization of a novel non-lethal KI mouse that expresses both the ACE2 and transmembrane serine protease 2 ( TMPRSS2 ) genes (h ACE2 /h TMPRSS2 ). The human genes were engineered to replace the orthologous mouse gene loci but remain under control of their respective murine promoters, resulting in expression of ACE2 and TMPRSS2 instead of their murine counterparts. After intranasal inoculation with an omicron strain of SARS-CoV-2, h ACE2 /h TMPRSS2 KI mice transiently lost weight but recovered by 7 dpi. Infectious SARS-CoV-2 was detected in nasopharyngeal swabs 1-2 dpi and in lung tissues 2-6 dpi, peaking 4 dpi. These outcomes were similar to those in K18 mice that were inoculated in parallel. To determine the extent to which h ACE2/ h TMPRSS2 KI mice are suitable to model pulmonary and cardiovascular outcomes, physiological assessments measuring locomotion, behavior and reflexes, biomonitoring to measure cardiac activity and respiration, and micro computed tomography to assess lung function were conducted frequently to 6 months post inoculation. Male but not female SARS-CoV-2 inoculated h ACE2/ h TMPRSS2 KI mice showed a transient reduction in locomotion compared to control saline treated mice. No significant changes in respiration, oxygen saturation, heart rate variability, or conductivity were detected in SARS-CoV-2 inoculated mice of either sex. When re-inoculated 6 months after the first inoculation, h ACE2/ h TMPRSS2 KI became re-infected with disease signs similar to after the first inoculation. Together these data show that a newly generated h ACE2/ h TMPRSS2 KI mouse can be used to study mild COVID-19.
To compare the current recommended dose of pentosan polysulfate sodium (PPS) with doses two to three times higher.
We evaluated three dosages (300, 600, and 900 mg) of PPS in a randomized, ...double-blind, double-dummy, parallel-group, multicenter, 32-week study. Adults (n = 380) with a diagnosis of interstitial cystitis (IC) as determined by a positive cystoscopic examination combined with bladder pain and urgency or a history of IC symptoms for at least 6 months were enrolled. Participants completed the Patient’s Overall Rating of Symptom Index (PORIS) and the O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI) at baseline (ICSI only) and during follow-up visits at 4, 8, 12, 16, 24, and 32 weeks.
Mean ICSI scores improved significantly during the 32 weeks for all dosages (baseline 11.2, 11.9, and 11.9 to endpoint 8.2, 8.1, 8.6 for 300, 600, and 900 mg, respectively;
P <0.001) but the response to treatment was not dose dependent (no statistically significant difference in response among the three dosages). At baseline, 3.2%, 62.2%, and 34.6% reported mild, moderate, and severe symptoms, respectively, as assessed by the ICSI. At study end, 27.5%, 56.9%, and 15.7% reported mild, moderate, and severe symptoms, respectively. The PORIS scores improved within 4 weeks with 15.8% to 21.1% of all patients classified as responders (50% or greater improvement on PORIS). At 32 weeks, 49.6%, 49.6%, and 45.2% of all patients were responders at a dose of 300, 600, and 900 mg, respectively. Most adverse events were mild and resolved without intervention.
For all three dosages of PPS, a clinically significant but similar response was demonstrated. The duration of therapy appears to be more important than the dosage.
Extreme Responses to Climate Change in Antarctic Lakes Quayle, Wendy C.; Peck, Lloyd S.; Peat, Helen ...
Science (American Association for the Advancement of Science),
01/2002, Letnik:
295, Številka:
5555
Journal Article
Recenzirano
Quayle et al report data for maritime Antarctic lakes showing extremely fast physical ecosystem change, combined with the ecological responses to that change. Nutrient levels at some sites exhibit ...order of magnitude increases per decade.
Data from the Third National Health and Nutrition Examination Survey, phase 2 (1991 to 1994), indicate that among hypertensive individuals in the United States, 53.6% are treated and only 27.4% are ...controlled to goal levels. We sought to determine whether poor hypertension control is due to lack of systolic or diastolic blood pressure control, or both. We studied Framingham Heart Study participants examined between 1990 and 1995 and determined rates of control to systolic goal (<140 mm Hg), diastolic goal (<90 mm Hg), or both (systolic <140 and diastolic <90 mm Hg). Of 1959 hypertensive subjects (mean age 66 years, 54% women), 32.7% were controlled to systolic goal, 82.9% were controlled to diastolic goal, and only 29.0% were controlled to both. Among the 1189 subjects who were receiving antihypertensive therapy (60.7% of all hypertensive subjects), 49.0% were controlled to systolic goal, 89.7% were controlled to diastolic goal, and only 47.8% were controlled to both. Thus, poor systolic blood pressure control was overwhelmingly responsible for poor rates of overall control to goal. Covariates associated with lack of systolic control in treated subjects included older age (OR for age 61 to 75 years, 2.43, 95% CI 1.79 to 3.29; OR for age >75 years, 4.34, 95% CI 3.10 to 6.09), left ventricular hypertrophy (OR 1.63, 95% CI 1.04 to 2.54), and obesity (OR for body mass index >/=30 versus <25 kg/m(2), 1.49, 95% CI 1.08 to 2.06). In this community-based sample of middle-aged and older subjects, overall rates of hypertension control were remarkably similar to those in the Third National Health and Nutrition Examination Survey. Poor blood pressure control was overwhelmingly due to lack of systolic control, even among treated subjects. Therefore, clinicians and policymakers should place greater emphasis on the achievement of goal systolic levels in all hypertensive patients, especially those who are older or obese or have target organ damage.
A key component of reperfusion of myocardial infarction is an immediate inflammatory response, which enhances tissue repair. Matrix turnover is crucial to tissue repair, and matrix metalloproteinases ...(MMPs) are key enzymes involved in matrix degradation. The hypothesis tested is that one inflammation-based effector of tissue repair is the secretion and activation of MMP-9 by infiltrating neutrophils.
Cardiac lymph and tissue were assayed for atent and active MMP-2 and MMP-9 by zymography and immunochemistry. Dual-labeling immunofluorescence determined the cellular source of MMP-9 protein. Isolated canine neutrophils were incubated with preischemic and postischemic cardiac lymph in the presence and absence of collagen-fibronectin pads, and the supernatants were assayed for latent and active MMP-9. MMP-9 increased during the first hours of reperfusion in both lymph supernatants and myocardial extracts, and this increase was of neutrophil origin. MMP-9 in the cardiac lymph remained latent but was activatable. In contrast, MMP-9 in the myocardium was in both latent and active forms. In situ zymography demonstrated that activated MMP-9 surrounded the infiltrated neutrophils. When postischemic cardiac lymph was incubated with neutrophils in vitro, MMP-9 secretion and activation occurred only in the presence of a collagen-fibronectin substrate; preischemic cardiac lymph did not induce significant secretion or activation.
Infiltrating neutrophils are an early source of MMP-9 after reperfusion, and a portion of MMP-9 in the myocardium is active. Infiltrating neutrophils may localize MMP-9 activation by secreting MMP-9 and as a source of activating proteases.
Functional limitations and physical disabilities associated with aging and chronic disease are major concerns for human societies and expeditious development of function-promoting therapies is a ...public health priority.
Expert panel discussion.
The remarkable success of Operation Warp Speed for the rapid development of COVID-19 vaccines, COVID-19 therapeutics, and of oncology drug development programs over the past decade have taught us that complex public health problems such as the development of function-promoting therapies will require collaboration among many stakeholders, including academic investigators, the National Institutes of Health, professional societies, patients and patient advocacy organizations, the pharmaceutical and biotechnology industry, and the U.S. Food and Drug Administration.
There was agreement that the success of well designed, adequately powered clinical trials will require careful definitions of indication/s, study population, and patient-important endpoints that can be reliably measured using validated instruments, commensurate resource allocation, and versatile organizational structures such as those used in Operation Warp Speed.
Aim The prevalence of abdominal wall herniation at the site of a previous temporary stoma is uncertain. This cohort study investigated the frequency of radiological abnormalities at the site of a ...closed diverting loop ileostomy.
Method All patients in whom an ileostomy was raised and later closed during a 5‐year period formed the study group. When colorectal cancer surveillance computed tomography (CT) was undertaken the images were scrutinized and graded as to defined anatomical abnormalities.
Results One hundred and seventy‐nine patients had an ileostomy, of which 92 were diverting. Fifty‐nine (64%) were closed at various intervals (median time to closure 6 (2–22) months and 43 underwent a surveillance CT at 1–3 (median 2) years. At 1 year an abnormality (atrophy or defect) at the site of closure was seen in 16 (37%) CT scans. These were more frequent with increasing duration of follow‐up. One asymptomatic hernia was detected at 2 years but there was no deterioration in the abdominal wall at 3 years when compared with that at 2 years.
Conclusion Abnormalities in the abdominal wall at the site of a closed diverting ileostomy are common but true herniation is unusual. The routine use of prophylactic mesh at ileostomy closure may be unnecessary.
Reasons for Vaping Among U.S. 12th Graders Evans-Polce, Rebecca J.; Patrick, Megan E.; Lanza, Stephanie T. ...
Journal of adolescent health,
04/2018, Letnik:
62, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Vaping has recently increased in popularity among adolescents. Little is known about heterogeneity of vapers, particularly in terms of why they vape. Identifying major subgroups of adolescent vapers ...by reasons for vaping is important to understand adolescent vaping behavior and to identify those most at risk for other substance use.
Monitoring Future data from 2015 and 2016 were used in a latent class analysis to identify subgroups of 12th graders based on their endorsement of 10 potential reasons for vaping. Multinomial regression with a latent class outcome was used to predict class membership.
Three distinct classes of vapers were identified: adolescents who were (1) Vaping to Experiment (29.4%), (2) Vaping to Replace Cigarettes (7.3%), and (3) Vaping for Taste + Entertainment (63.4%). Vaping only flavors was associated with lower odds of membership and cigarette use was associated with higher odds of membership in the Vaping to Replace Cigarettes subgroup, and marijuana was associated with lower odds of membership in the Vaping to Experiment subgroup, compared with the Vaping for Taste + Entertainment subgroup.
This study identified multiple subgroups of vapers based on reasons for vaping. Whereas a small subgroup vaped for reasons related to cigarette use, most adolescent vapers reported vaping for reasons unrelated to cigarette use. There were considerable differences in primary reasons for vaping and risk for traditional cigarette and other substance use, suggesting different intervention strategies may be needed for different subgroups of vapers.
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