Constituents in rosemary have shown a variety of pharmacological activities for cancer chemoprevention and therapy in in vitro and in vivo models. In order to further explore the chemopreventive ...properties of crude extracts of rosemary (Rosmarinus officinalis L), we studied its anti-proliferative property on several human cancer cell lines and its antioxidant and anti-inflammatory properties in vitro in a mouse RAW 264.7 macrophage/monocyte cell line. Our study shows that crude ethanolic rosemary extract (RO) has differential anti-proliferative effects on human leukemia and breast carcinoma cells. The 50% inhibitory concentration (IC50) was estimated at 1/700, 1/400, 1/150 and 1/500 dilutions, for the HL60, K562, MCF7 and MDA-MB-468 cells, respectively. Non-cytotoxic concentrations of RO at 1/1000 dilution minimally induced HL60 cell differentiation into granulocyte lineage at 9.5+/-2.2% compared to 2.8+/-0.8% in the untreated control (p<0.001), and did not induce HL60 cell differentiation into monocyte/macrophage lineage. The 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid (Trolox) equivalent antioxidant capacity assay showed that RO has substantial antioxidant activity with RO at 1/10 and 1/5 dilutions having 8.1 and 12.6 microM Trolox equivalents, respectively. RO at non-cytotoxic 1/2000 and 1/1000 dilutions did not affect nitric oxide (NO) production by non-stimulated RAW 264.7 cells. However, at the same dilutions RO significantly reduced NO production by lipopolysaccharide (LPS)-activated cells in a dose-dependent manner from 32.6+/-2.3 microM in the LPS-activated cells to 19.2+/-2.2 microM (p<0.01), and 7.7+/-1.2 microM (p<0.001), respectively. RT-PCR analyses showed that RAW 264.7 cells treated with 1/1000 and 1/500 dilutions for 5 h did not affect TNFalpha, IL-1beta, iNOS and COX-2 mRNA expression in these cells when compared to the untreated controls, nor did the 1/1000 dilution of RO affect TNFalpha, IL-1beta, iNOS and COX-2 mRNA expression in the LPS-activated cells. At 1/500 dilution, RO significantly reduced IL-1beta (p<0.01) and COX-2 (p<0.05) mRNA expression and non-significantly reduced TNFalpha and iNOS mRNA expression in the LPS-activated cells. In view of the chemopreventive potentials, further studies are needed to explore other biological properties of this popular spice used by many cultures in the world.
Abstract
Background
Long-term incidences and baseline determinants of functional cure (hepatitis B surface antigen HBsAg seroclearance) during entecavir (ETV) or tenofovir disoproxil fumarate (TDF) ...treatment are incompletely understood.
Methods
This is an international multicenter cohort study of treatment-naive patients with chronic hepatitis B who started ETV or TDF treatment without baseline cancer. Patients were observed for HBsAg seroclearance until death or loss to follow-up. We calculated the incidences and explored the baseline determinants of HBsAg seroclearance using competing risk regression.
Results
The analysis included 4769 patients (median age, 50 years; 69.05% male), with a median follow-up of 5.16 years (26 614.47 person-years). HBsAg clearance occurred in 58 patients, yielding a 10-year cumulative incidence of 2.11% (95% confidence interval, 1.54%–2.88%) and an annual rate of 0.22% (.17%–.28%). Baseline predictors included low-level viremia with hepatitis B virus DNA <2000 IU/mL (adjusted subdistribution hazard ratio, 3.14 95% confidence interval, 1.80–5.49), elevated serum alanine aminotransferase >200 U/L (3.68 2.07–6.53), serum bilirubin (1.11 per mg/dL; 1.06–1.17 mg/dL), and fatty liver (1.84 1.03–3.29).
Conclusion
HBsAg seroclearance rarely occurs in patients with chronic hepatitis B treated with ETV or TDF and is associated with low-level viremia, alanine aminotransferase flare, bilirubin level, and fatty liver.
Functional cure of hepatitis B virus infection rarely occurred at an average annual rate of 0.22% during first-line oral antiviral treatment, with higher chances observed in patients with low-level viremia, high-level aminotransferase flare, elevation of serum bilirubin, and fatty liver.
Key points
Controversy exists about the physiological mechanism(s) underlying decreases in cardiac output after immediate clamping of the umbilical cord at birth.
To define these mechanisms, the four ...major determinants of ventricular output (afterload, preload, heart rate and contractility) were measured concurrently in fetal lambs at 15 s intervals over a 2 min period after cord clamping and before ventilation following delivery.
After cord clamping, right (but not left) ventricular output fell by 20% in the initial 30 s, due to increased afterload associated with higher arterial blood pressures, but both outputs then halved over 45 s, due to a falling heart rate and deteriorating ventricular contractility accompanying rapid declines in arterial oxygenation to asphyxial levels.
Ventricular outputs subsequently plateaued from 75 to 120 s, associated with rebound rises in ventricular contractility accompanying asphyxia‐induced surges in circulating catecholamines.
These findings provide a physiological basis for the clinical recommendation that effective ventilation should occur within 60 s after immediate cord clamping.
Controversy exists about the physiological mechanism(s) underlying large decreases in cardiac output after immediate clamping of the umbilical cord at birth. To define these mechanisms, anaesthetized preterm fetal lambs (127(1)d, n = 12) were instrumented with flow probes and catheters in major central arteries, and a left ventricular (LV) micromanometer‐conductance catheter. Following immediate cord clamping at delivery, haemodynamics, LV and right ventricular (RV) outputs, and LV contractility were measured at 15 s intervals during a 2 min non‐ventilatory period, with aortic blood gases and circulating catecholamine (noradrenaline and adrenaline) concentrations measured at 30 s intervals. After cord clamping, (1) RV (but not LV) output fell by 20% in the initial 30 s, due to a reduced stroke volume associated with increased arterial blood pressures, (2) both outputs then halved over the next 45 s, associated with falls in heart rate, arterial blood pressures and ventricular contractility accompanying a rapid decline in arterial oxygenation to asphyxial levels, (3) reduced outputs subsequently plateaued from 75 to 120 s, associated with rebound rises in blood pressures and ventricular contractility accompanying exponential surges in circulating catecholamines. These findings are consistent with a time‐dependent decline of ventricular outputs after immediate cord clamping, which comprised (1) an initial, minor fall in RV output related to altered loading conditions, (2) ensuing large decreases in both LV and RV outputs related to the combination of bradycardia and ventricular dysfunction during emergence of an asphyxial state, and (3) subsequent stabilization of reduced LV and RV outputs during ongoing asphyxia, supported by cardiovascular stimulatory effects of marked sympathoadrenal activation.
Key points
Controversy exists about the physiological mechanism(s) underlying decreases in cardiac output after immediate clamping of the umbilical cord at birth.
To define these mechanisms, the four major determinants of ventricular output (afterload, preload, heart rate and contractility) were measured concurrently in fetal lambs at 15 s intervals over a 2 min period after cord clamping and before ventilation following delivery.
After cord clamping, right (but not left) ventricular output fell by 20% in the initial 30 s, due to increased afterload associated with higher arterial blood pressures, but both outputs then halved over 45 s, due to a falling heart rate and deteriorating ventricular contractility accompanying rapid declines in arterial oxygenation to asphyxial levels.
Ventricular outputs subsequently plateaued from 75 to 120 s, associated with rebound rises in ventricular contractility accompanying asphyxia‐induced surges in circulating catecholamines.
These findings provide a physiological basis for the clinical recommendation that effective ventilation should occur within 60 s after immediate cord clamping.
Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing ...factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.
Experimental animal data show that protection against severe acute respiratory syndrome coronavirus (SARS-CoV) infection with human monoclonal antibodies (mAbs) is feasible. For an effective immune ...prophylaxis in humans, broad coverage of different strains of SARS-CoV and control of potential neutralization escape variants will be required. Combinations of virus-neutralizing, noncompeting mAbs may have these properties.
Human mAb CR3014 has been shown to completely prevent lung pathology and abolish pharyngeal shedding of SARS-CoV in infected ferrets. We generated in vitro SARS-CoV variants escaping neutralization by CR3014, which all had a single P462L mutation in the glycoprotein spike (S) of the escape virus. In vitro experiments confirmed that binding of CR3014 to a recombinant S fragment (amino acid residues 318-510) harboring this mutation was abolished. We therefore screened an antibody-phage library derived from blood of a convalescent SARS patient for antibodies complementary to CR3014. A novel mAb, CR3022, was identified that neutralized CR3014 escape viruses, did not compete with CR3014 for binding to recombinant S1 fragments, and bound to S1 fragments derived from the civet cat SARS-CoV-like strain SZ3. No escape variants could be generated with CR3022. The mixture of both mAbs showed neutralization of SARS-CoV in a synergistic fashion by recognizing different epitopes on the receptor-binding domain. Dose reduction indices of 4.5 and 20.5 were observed for CR3014 and CR3022, respectively, at 100% neutralization. Because enhancement of SARS-CoV infection by subneutralizing antibody concentrations is of concern, we show here that anti-SARS-CoV antibodies do not convert the abortive infection of primary human macrophages by SARS-CoV into a productive one.
The combination of two noncompeting human mAbs CR3014 and CR3022 potentially controls immune escape and extends the breadth of protection. At the same time, synergy between CR3014 and CR3022 may allow for a lower total antibody dose to be administered for passive immune prophylaxis of SARS-CoV infection.
Purpose
The COVID-19 pandemic forced many surgeons to adopt “virtual medicine” practices, defined as telehealth services for patient care and online platforms for continuing medical education. The ...purpose of this study was to assess spine surgeon reliance on virtual medicine during the pandemic and to discuss the future of virtual medicine in spine surgery.
Methods
A comprehensive survey addressing demographic data and virtual medicine practices was distributed to spine surgeons worldwide between March 27, 2020, and April 4, 2020.
Results
902 spine surgeons representing seven global regions responded. 35.6% of surgeons were identified as “high telehealth users,” conducting more than half of clinic visits virtually. Predictors of high telehealth utilization included working in an academic practice (OR = 1.68,
p
= 0.0015) and practicing in Europe/North America (OR 3.42,
p
< 0.0001). 80.1% of all surgeons were interested in online education. Dedicating more than 25% of one’s practice to teaching (OR = 1.89,
p
= 0.037) predicted increased interest in online education. 26.2% of respondents were identified as “virtual medicine surgeons,” defined as surgeons with both high telehealth usage and increased interest in online education. Living in Europe/North America and practicing in an academic practice increased odds of being a virtual medicine surgeon by 2.28 (
p
= 0.002) and 1.15 (
p
= 0.0082), respectively. 93.8% of surgeons reported interest in a centralized platform facilitating surgeon-to-surgeon communication.
Conclusion
COVID-19 has changed spine surgery by triggering rapid adoption of virtual medicine practices. The demonstrated global interest in virtual medicine suggests that it may become part of the “new normal” for surgeons in the post-pandemic era.
Wave reflection from the site of aortic coarctation produces a reflected backward compression wave (BCW) that raises left ventricular (LV) afterload. However, not all reflected wave power will ...propagate back to the LV. This study investigated the hypothesis that the BCW is partially transmitted into supra-aortic vessels as a forward wave and explored the consequences of this phenomenon for cerebral and LV haemodynamic load. In eight sheep, high fidelity pressure and flow were measured in the aortic trunk (AoT) and brachiocephalic trunk (BCT, the single supra-aortic vessel present in sheep) at baseline and during two levels of proximal descending aortic constriction. Wave power analysis showed that aortic constriction produced not only a BCW in the AoT, but also a second forward compression wave (
FCW
2
)
in the BCT that augmented pressure and flow after the initial forward compression wave (
FCW
1
)
. Mathematical analysis and a one-dimensional model of the human systemic arteries and aortic coarctation suggested that the relative transmission of waves into supra-aortic vessels versus the aorta was determined by the relative admittances of these vessels. Reducing supra-aortic admittance (1) increased pressure and flow pulsatility in cerebral arteries, (2) produced carotid and middle cerebral arterial flow waveforms with an older adult phenotype, (3) promoted transmission of reflected wave power towards the LV and (4) substantially increased mid- to late-systolic myocardial stress, which may promote LV hypertrophy. These findings suggest that wave transmission into supra-aortic branches has an important impact on both cerebral hemodynamics and LV load in aortic coarctation.
This study addressed the impact on mental health and wellbeing in relation to views of the self, the world, and the future during the early stage of the global novel coronavirus (COVID-19) pandemic ...outbreak. An online survey battery included the 21-item Depression Anxiety and Stress Scale (DASS-21), Subjective Happiness Scale, Self-Compassion Scale, Adult Hope Scale, and two specifically-written items measuring the valence quality and quantity of the impact of the pandemic. A total of 345 Hong Kong residents (54% females) responded; 17.1%, 24.7%, and 19.7% reported elevated levels of depression, anxiety, and stress, respectively. The prevalence of these issues was lower in this Hong Kong sample than reported in other COVID-19 studies, possibly due to the past experience of the severe acute respiratory syndrome (SARS) outbreak in Hong Kong in promoting the voluntary wearing of masks in public places and introducing social distancing measures during the early first wave of the pandemic. Correlational analyses showed associations between positive views about the self (higher self-compassion), the world (higher positive valence), and the future (more hope) and better mental health and psychological wellbeing (fewer depression, anxiety, and stress symptoms; more happiness). Regression analyses indicated a differential predicting power of the three views on the four selected mental health and psychological wellbeing indicators. Intervention programs to alleviate distress and/or promote better wellbeing should be matched to the specific problems encountered by the sufferers.
Entry of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and its envelope fusion with host cell membrane are controlled by a series of complex molecular mechanisms, largely dependent on the ...viral envelope glycoprotein Spike (S). There are still many unknowns on the implication of cellular factors that regulate the entry process.
We performed a yeast two-hybrid screen using as bait the carboxy-terminal endodomain of S, which faces the cytosol during and after opening of the fusion pore at early stages of the virus life cycle. Here we show that the ezrin membrane-actin linker interacts with S endodomain through the F1 lobe of its FERM domain and that both the eight carboxy-terminal amino-acids and a membrane-proximal cysteine cluster of S endodomain are important for this interaction in vitro. Interestingly, we found that ezrin is present at the site of entry of S-pseudotyped lentiviral particles in Vero E6 cells. Targeting ezrin function by small interfering RNA increased S-mediated entry of pseudotyped particles in epithelial cells. Furthermore, deletion of the eight carboxy-terminal amino acids of S enhanced S-pseudotyped particles infection. Expression of the ezrin dominant negative FERM domain enhanced cell susceptibility to infection by SARS-CoV and S-pseudotyped particles and potentiated S-dependent membrane fusion.
Ezrin interacts with SARS-CoV S endodomain and limits virus entry and fusion. Our data present a novel mechanism involving a cellular factor in the regulation of S-dependent early events of infection.
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