Recently Published Documents
Objectives: Olfactory dysfunction is a major comorbidity observed in patients with multiple sclerosis, yet different prevalence rates are reported for it. Therefore, we have designed this systematic review to estimate the pooled prevalence of olfactory dysfunction in patients with MS. To our knowledge, this is the first systematic review and meta-analysis on the prevalence of olfactory dysfunction in MS patients. Method: We searched PubMed, Scopus, EMBASE, Web of Science, ProQuest, and gray literature including references from the identified studies, review studies, and conference abstracts which were published up to January 2021. Articles that were relevant to our topic and could provide information regarding the prevalence of olfactory dysfunction, or the scores of smell threshold, discrimination, or identification (TDI scores) among MS patients and healthy individuals were included; however, articles published before 1990 and after the end of 2020 were excluded. Results: The literature search found 1630 articles. After eliminating duplicates, 897 articles remained. two abstract conference papers were included for final analysis. A total of 1099 MS cases and 299 MS patients with olfactory dysfunction were included in the analysis. The pooled prevalence of olfactory dysfunction in the included studies was 27.2%. (95% CI: [19.7%, 35.4%]) Also, the overall TDI score in MS patients was lower than that in the control group (SMD=-1.00; 95% CI: [-1.44, -0.56]), and the level of Threshold (SMD= -0.47; 95% CI: [-0.75, -0.19]), Discrimination (SMD=-0.53; 95% CI: [-0.96, -0.10]), and Identification (SMD=-1.02; 95% CI: [-1.36, -0.68]) per se were lower in MS compared with control respectively. Conclusion: The results of this systematic review shows that the prevalence of olfactory dysfunction in MS patients is high and more attention needs to be drawn to this aspect of MS.
Proton Pump Inhibitors Directly Block hERG-potassium Channel and Independently Increase the Risk of QTc Prolongation in a Large Cohort of US Veterans
Background - Worldwide, there are millions of chronic proton pump inhibitors (PPIs) users, often without a compelling indication. Evidence indicates that PPI treatment can increase mortality, in part due to a higher risk of QTc-related malignant arrhythmias. Drug-induced hypomagnesemia is currently believed to be the underlying mechanism, and therefore serum magnesium monitoring is recommended to minimize arrhythmic risk. However, recent data suggest that PPIs might also directly interfere with cardiac electrophysiology. To test this hypothesis, a translational study was performed using a combination of electrophysiology, molecular dynamics simulations, and population data. Methods - First, the effect of different PPIs on the ether-a-go-go -related-gene potassium channel (hERG) current was evaluated in HEK293-cells expressing hERG. Then, free energy calculations were performed to investigate the binding of these drugs to hERG. Finally, the impact of PPIs on the risk of QTc prolongation was assessed in a retrospective observational cohort of 3867 US Veterans, including 1289 PPI-treated subjects. Results - Clinically-relevant concentrations of different PPIs induced a significant inhibition of the hERG-current in-vitro , pantoprazole and lansoprazole being the most potent compounds. Atomic simulations demonstrated that such a blocking class-effect is likely due to direct PPIs binding to hERG-channel pore cavity. Accordingly, in a US Veterans cohort, PPI treatment was independently associated with a ~20-40% increased risk of QTc prolongation, also regardless of hypomagnesemia. Moreover, a synergistic interaction between PPIs and most of the traditional QT-prolonging risk factors was demonstrated. Conclusions - Altogether, this study provides, for the first time, strong evidence that PPIs can per se promote QTc prolongation, by directly inhibiting hERG function. A careful evaluation of the benefit/risk ratio is recommended whenever PPIs are administered in subjects with other QT-prolonging risk factors, even in the absence of hypomagnesemia.
Arbuscular Mycorrhiza-Mediated Regulation of Polyamines and Aquaporins During Abiotic Stress: Deep Insights on the Recondite Players
Environmental stresses of (a)biotic origin induce the production of multitudinous compounds (metabolites and proteins) as protective defense mechanisms in plants. On account of the regulation of some of these compounds, arbuscular mycorrhizal fungi (AMF) reinforce the inherent tolerance of plants toward the stress of different origins and kind. This article reviews two specific fundamental mechanisms that are categorically associated with mycorrhiza in alleviating major abiotic stresses, salt, drought, and heavy metal (HM) toxicity. It puts emphasis on aquaporins (AQPs), the conduits of water and stress signals; and polyamines (PAs), the primordial stress molecules, which are regulated by AMF to assure water, nutrient, ion, and redox homeostasis. Under stressful conditions, AMF-mediated host AQP responses register distinct patterns: an upregulation to encourage water and nutrient uptake; a downregulation to restrict water loss and HM uptake; or no alterations. The patterns thereof are apparently an integrative outcome of the duration, intensity, and type of stress, AMF species, the interaction of fungal AQPs with that of plants, and the host type. However, the cellular and molecular bases of mycorrhizal influence on host AQPs are largely unexplored. The roles of PAs in augmenting the antioxidant defense system and improving the tolerance against oxidative stress are well-evident. However, the precise mechanism by which mycorrhiza accords stress tolerance by influencing the PA metabolism per se is abstruse and broadly variable under different stresses and plant species. This review comprehensively analyzes the current state-of-art of the involvement of AMF in “PA and AQP modulation” under abiotic stress and identifies the lesser-explored landscapes, gaps in understanding, and the accompanying challenges. Finally, this review outlines the prospects of AMF in realizing sustainable agriculture and provides insights into potential thrust areas of research on AMF and abiotic stress.
Remodeling of bronchial epithelium caused by asthmatic inflammation affects its response to rhinovirus infection
AbstractHuman rhinoviruses (HRV) are frequent cause of asthma exacerbations, however the influence of airway inflammation on the severity of viral infection is poorly understood. Here, we investigated how cytokine-induced remodeling of airway epithelium modulates antiviral response. We analyzed gene expression response in in vitro differentiated bronchial epithelium exposed to cytokines and next infected with HRV16. IL-13-induced mucous cell metaplasia (MCM) was associated with impaired ciliogenesis and induction of antiviral genes, resulting in lower susceptibility to HRV. Epithelial-mesenchymal transition caused by TGF-β was associated with increased virus replication and boosted innate response. Moreover, HRV infection per se caused transient upregulation of MCM markers and growth factors, followed by low-level virus replication and shedding. Our data suggest that the outcome of HRV infection depends on the type of lower airway inflammation and the extent of epithelial damage. Type-2 inflammation (eosinophilic asthma) may induce antiviral state of epithelium and decrease virus sensitivity, while growth factor exposure during epithelial repair may facilitate virus replication and inflammatory response. Additionally, responses to HRV were similar in cells obtained from asthma patients and control subjects, which implicates that antiviral mechanisms are not intrinsically impaired in asthma, but may develop in the presence of uncontrolled airway inflammation.
Aims: Bubble entropy (bEn) is an entropy metric with a limited dependence on parameters. bEn does not directly quantify the conditional entropy of the series, but it assesses the change in entropy of the ordering of portions of its samples of length m, when adding an extra element. The analytical formulation of bEn for autoregressive (AR) processes shows that, for this class of processes, the relation between the first autocorrelation coefficient and bEn changes for odd and even values of m. While this is not an issue, per se, it triggered ideas for further investigation. Methods: Using theoretical considerations on the expected values for AR processes, we examined a two-steps-ahead estimator of bEn, which considered the cost of ordering two additional samples. We first compared it with the original bEn estimator on a simulated series. Then, we tested it on real heart rate variability (HRV) data. Results: The experiments showed that both examined alternatives showed comparable discriminating power. However, for values of 10<m<20, where the statistical significance of the method was increased and improved as m increased, the two-steps-ahead estimator presented slightly higher statistical significance and more regular behavior, even if the dependence on parameter m was still minimal. We also investigated a new normalization factor for bEn, which ensures that bEn=1 when white Gaussian noise (WGN) is given as the input. Conclusions: The research improved our understanding of bubble entropy, in particular in the context of HRV analysis, and we investigated interesting details regarding the definition of the estimator.
Muscle sympathetic single-unit responses during rhythmic handgrip exercise and isocapnic hypoxia in males: the role of sympathoexcitation magnitude
A small proportion of postganglionic muscle sympathetic single units can be inhibited during sympathoexcitatory stressors in humans. However, whether these responses are dependent on the specific stressor or the level of sympathoexcitation remains unclear. We hypothesize that, when matched by sympathoexcitatory magnitude, different stressors can evoke similar proportions of inhibited single units. Multiunit and single-unit muscle sympathetic nerve activity (MSNA) were recorded in seven healthy, young males at baseline and during: 1) rhythmic handgrip exercise (40% of maximum voluntary contraction) and 2) acute isocapnic hypoxia (partial pressure of end-tidal O2: 47±3 mmHg). Single units were classified as activated, nonresponsive, or inhibited if the spike frequency was above, within, or below the baseline variability, respectively. By design, rhythmic handgrip and isocapnic hypoxia similarly increased multiunit total MSNA (D273±208 vs. D254±193 AU, P=0.84) and single-unit spike frequency (D8±10 vs. D12±13 spikes/min, P=0.12). Among 19 identified single units, the proportion of activated (47% vs. 68%) non-responsive (32% vs. 16%) and inhibited (21% vs. 16%) single units were not different between rhythmic handgrip and isocapnic hypoxia (P=0.42). However, only 9 (47%) single units behaved with concordant response patterns across both stressors (7 activated, 1 non-responsive, and 1 inhibited during both stressors). During the 1-min epoch with the highest increase in total MSNA during hypoxia (D595±282 AU, P<0.01) only 1 single unit was inhibited. These findings suggest that the proportion of muscle sympathetic single units inhibited during stress are associated with the level of sympathoexcitation and not the stressor per se in healthy young males.
Abstract Background: Zinc protoporphyrin (ZnPP) is a naturally occurring metalloprotoporphyrin (MPP) that is currently under development as a chemotherapeutic agent although its mechanism is unclear. Similar to natural and synthetic porphyrins, MPPs are thought to bind DNA and stabilize secondary structures such as guanine quadruplexes (G-4) and thus potentially impact telomerase activity and DNA synthesis which are important targets for chemotherapy. Interactions of MPPs with telomerase have not been previously reported. Methods: We wished to evaluate the effects of common MPPs, i.e., ZnPP, tin protoporphyrin (SnPP), and iron protoporphyrin (FePP), on cellular proliferation, apoptosis, and telomerase activity in hepatoma cells. The cytotoxicities of porphyrins were determined by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Native agarose gel electrophoresis was used to identify ZnPP binding of telomerase complexes. Inhibition of telomerase activity by ZnPP was assessed by conventional telomeric repeat amplification protocol (TRAP) and direct telomerase activity assays. Colocalization of ZnPP with telomerase was analyzed with immunofluorescence staining and confocal microscopic analysis. Results: ZnPP was the most effective MPP for decreasing DNA synthesis and cellular proliferation, while promoting apoptosis in cultured hepatocytes. Concurrently, ZnPP down-regulated telomerase expression and was the best overall inhibitor of telomerase activity in intact cells and in vitro assays, with IC50 and EC50 values of ca 2.5 and 6 µM respectively. The natural fluorescence properties of ZnPP enabled direct imaging in cellular fractions using non-denaturing agarose gel electrophoresis, western blots, and confocal fluorescence microscopy. ZnPP localized to large cellular complexes (> 600kD) that contained telomerase and dyskerin as confirmed with immunocomplex mobility shift, immunoprecipitation, and immunoblot analyses. Confocal fluorescence studies showed that ZnPP co-localized with telomerase reverse transcriptase (TERT) and telomeres in the nucleus of synchronized S-phase cells. ZnPP also co-localized with TERT in the perinuclear regions of log phase cells but did not co-localize with telomeres on the ends of metaphase chromosomes, a site known to be devoid of telomerase complexes. Taken together, these results suggest that ZnPP does not bind to telomeric sequences per se, but alternatively, interacts with other structural components of the telomerase complex to inhibit telomerase enzymatic activity. Conclusions. ZnPP can actively interfere with telomerase activity in neoplastic cells, thus eliciting pro-apoptotic and anti-proliferative properties. These data support further development of natural or synthetic protoporphyrins for use as chemotherapeutic agents to augment current treatment protocols for a number of neoplasms.
What Factors Reduce the Incidence of Early Dislocations in Aseptic Total Hip Revisions with Stem Retention?
AbstractIt is unclear which factors are the most important protectors for early postoperative dislocation in aseptic total hip arthroplasty (THA) revisions with stem retention. Therefore, we sought to determine what factors reduce the incidence of dislocations among these patients. Single institution retrospective review was made of 83 consecutive aseptic THA revisions of the head/liner and/or cup performed by five surgeons between 2017 and 2020. Periprosthetic infections and femoral component revisions were excluded. Demographics, preoperative diagnosis, revision type, surgical approach, use of dual mobility systems, length of stay, skin-to-skin time, transfusions, complications, and dislocations were assessed. Pearson correlation/logistic regression analyses were used to determine association/independent predictors of dislocation; α was set at 0.05. The overall dislocation rate was 12%. In Pearson correlation, only preoperative diagnosis (instability vs. other, −0.241, p = 0.028) and revision type (only liner vs. cup, −0.304, p = 0.005) were significantly associated with dislocations. In logistic regression, only preoperative diagnosis other than instability (odds ratio [OR] = 0.235, p = 0.038) and cup revision (OR = 0.130, p = 0.014) were found significant protectors against dislocation. Surgical approach and dual mobility systems were not independent predictors of dislocations (p = 0.184 and p = 0.083, respectively). Dislocation rates were significantly different between those cases that had the cup revised (4.0%) and those that did not (24.2%; p = 0.012). Preoperative diagnosis other than instability and cup revision seemed to be protective against early dislocation. Revision of the cup, in particular, seemed to be the most important factor to avoid dislocations while use of dual mobility liners per se did not significantly reduce that risk. The role of isolated liner exchanges in revision THA continues to evolve and should be reserved for appropriately selected patients.
Because patients with Chronic Obstructive Pulmonary Disease (COPD) are often physically inactive, it is still unclear whether the lower respiratory capacity in the locomotor muscles of these patients is due to cigarette smoking per se or is secondary to physical deconditioning. Accordingly, the purpose of this study was to examine mitochondrial alterations in the quadriceps muscle of 10 mice exposed to 8-months of cigarette smoke, a sedentary mouse model of emphysema, and 9 control mice, using immunoblotting, spectrophotometry, and high-resolution respirometry in permeabilized muscle fibers. Mice exposed to smoke displayed a two-fold increase in the oxidative stress marker, 4-HNE, (p < 0.05) compared with control mice. This was accompanied by significant decreases in protein expression of UCP3 (65%), ANT (58%), and mitochondrial complexes II-V (~60%-75%). In contrast, maximal ADP-stimulated respiration with complex I and II substrates (CON: 23.6 ± 6.6 and SMO: 19.2 ± 8.2 ρM·mg-1·s-1) or octanoylcarnitine (CON: 21.8 ± 9.0 and SMO: 16.5 ± 6.6 ρM·mg-1·s-1) measured in permeabilized muscle fibers, as well as citrate synthase activity, were not significantly different between groups. Collectively, our findings revealed that mice exposed to cigarette smoke for 8 months, which is typically associated with pulmonary inflammation and emphysema, exhibited a preserved mitochondrial respiratory capacity for various substrates, including free-fatty acid, in the skeletal muscle. However, the mitochondrial adaptations induced by cigarette smoke favored the development of chronic oxidative stress, which can indirectly contribute to augment the susceptibility to muscle fatigue and exercise intolerance.
Afforestation With Tropical N-Fixing Species in The Brazilian Atlantic Rainforest: Carbon and Nitrogen in The Soil Profile
Abstract Aims Atlantic Rainforest biome is one of the most threatened in the world by deforestation where afforestation programs are urgently needed. N-fixing species should be prioritized in re-establishing forest covers as they can enhance soil C and N and stimulate cycling of other nutrients. Yet, tropical ecosystems play a key role in global warming and remain underestimated in the global biogeochemical balances. We aimed to investigate the effects of tropical N-fixing species on soil C and N pools after pasture conversionMethods We selected: Plathymenia reticulata, Hymenaea courbaril, and Centrolobium tomentosum 27-year-old monospecific stands. We evaluated soil organic carbon (SOC), nitrogen (STN), and the natural abundance of 13C and 15N in the soil profile up to 100 cm depth. Results SOC was higher for P. reticulata, but an opposite pattern was observed when combining only soil layers up to 30 cm soil depth. Meanwhile, STN was similar across species and d15N values showed enrichment at intermediate soil layers indicating 14N gaseous loss. Most of the SOC originated from the planted trees rather than the former pasture, except beneath C. tomentosum where C4 derived C is decreasing at a slower rate. Conclusion This study presents novel insights in the understanding of tropical N-fixing species effects on soil C and N where specific-species traits appear to mediate SOC retention to the mineral soil rather than the N-fixing ability per se.