Rapid dark aging of biomass burning as an overlooked source of oxidized organic aerosol

Oxidized organic aerosol (OOA) is a major component of ambient particulate matter, substantially impacting climate, human health, and ecosystems. OOA is readily produced in the presence of sunlight, and requires days of photooxidation to reach the levels observed in the atmosphere. High concentrations of OOA are thus expected in the summer; however, our current mechanistic understanding fails to explain elevated OOA during wintertime periods of low photochemical activity that coincide with periods of intense biomass burning. As a result, atmospheric models underpredict OOA concentrations by a factor of 3 to 5. Here we show that fresh emissions from biomass burning exposed to NO₂ and O₃ (precursors to the NO₃ radical) rapidly form OOA in the laboratory over a few hours and without any sunlight. The extent of oxidation is sensitive to relative humidity. The resulting OOA chemical composition is consistent with the observed OOA in field studies in major urban areas. Additionally, this dark chemical processing leads to significant enhancements in secondary nitrate aerosol, of which 50 to 60% is estimated to be organic. Simulations that include this understanding of dark chemical processing show that over 70% of organic aerosol from biomass burning is substantially influenced by dark oxidation. This rapid and extensive dark oxidation elevates the importance of nocturnal chemistry and biomass burning as a global source of OOA.

Highly oxidized organic aerosol (OOA) is a dominant component of particulate matter air pollution globally (1–3); however, sources of OOA remain uncertain, limiting the ability of models to accurately represent OOA and thus predict the associated climate, ecosystem, and health implications (4, 5). The current conceptual model of OOA formation suggests that anthropogenic OOA predominantly originates from the oxidation of volatile (VOCs), intermediate volatility (IVOCs), and semivolatile (SVOCs) organic compounds by the OH radical, resulting in lower-volatility products that condense to the particle phase (6). As the OH radical is formed through photolysis and has a very short atmospheric lifetime [less than a second (7)], this oxidation mechanism only occurs in the presence of sunlight. Further, the time scale for OOA formation through oxidation with OH in models is on the order of a few days (8). While this understanding is sufficient in explaining OOA concentrations in summer or periods with high solar radiation, atmospheric models fail to reproduce the observed concentration of OOA in the ambient atmosphere during winter and low-light conditions (9, 10). Fountoukis et al. (9) found simulated OOA concentrations significantly underestimated in wintertime Paris. Tsimpidi et al. (10) also reported an underprediction of simulated OOA globally in winter, suggesting missing sources of both primary OA (POA) and secondary formation pathways. This underproduction suggests a possible overlooked conversion pathway of organic vapors or particles to OOA that is not accounted for in current chemical transport and climate models.As stricter controls on fossil fuel combustion are implemented, residential biomass burning (BB) as a source of heating or cooking is becoming an increasingly important source of OA in urban environments (1, 11, 12). Further, increasing rates of wildfires from climate change are increasing the frequency of smoke-impacted days in urban areas (12–14). BB emissions include high concentrations of POA, SVOCs, IVOCs, and VOCs (15, 16), thus making BB a key source of OOA. Previous research has focused on quantifying the concentration of OOA formed through photochemical oxidation reactions (i.e., OH) with BB emissions (17, 18). However, oxidation of BB emissions in low or no sunlight is less well understood and is not included in chemical transport models. As opposed to OH, the NO₃ radical is formed through reactions with NO₂ and O₃ and is rapidly lost in the presence of sunlight (19). Thus, the NO₃ radical is only available in significant concentrations at night or other low-light conditions (20, 21). Previous research has established that biogenic VOCs may undergo oxidation at night when mixed with anthropogenic emissions containing NO₂ and O₃ (19, 22–27). There have been only a few studies that consider that nighttime oxidation of residential wood combustion may proceed through similar pathways (28–31); however, the magnitude and relevance to observed OOA in the ambient atmosphere has not yet been established. By combining laboratory experiments and ambient observations to inform a chemical transport model, we present strong evidence that nighttime oxidation of BB plumes (proceeding through reactions with O₃ and the NO₃ radical) is an important source of OOA.     

Investigational parathyroid hormone receptor analogs for the treatment of osteoporosis

Introduction: Intermittent parathyroid hormone (PTH) administration, acting through multiple signaling pathways, exerts an osteoanabolic effect on the skeleton that surpasses the effect of other antiosteoporotic agents. However, its efficacy is limited by the coupling effect and relatively common adverse events. Thus, the development of more sophisticated PTH receptor analogs seems imperative.

Areas covered: In this review, the authors summarize the role of PTH signaling pathway in bone remodeling. The authors also summarize investigational analogs targeting this pathway, which may be potential treatments for osteoporosis.

Expert opinion: β-arrestins are multifunctional cytoplasmic molecules that are decisive for regulating intracellular PTH signaling. Recently, in preclinical studies, arrestin analogs have achieved the anabolic bone effect of PTH without an accompanying increase in bone resorption. However, it is not yet known whether these analogs have adverse effects and there are no clinical data for their efficacy to date. On the other hand, several molecules derived either from PTH and PTH-related protein (PTHrP) molecules have been developed. Alternative routes of PTH 1 – 34 delivery (oral, transdermal), the PTH analog ostabolin and the N-terminal PTHrP analogs PTHrP 1 – 36 and abaloparatide, have recently been or are currently being tested in clinical trials and are more likely to become available for use in the near future.     

Electrophysiological markers predicting impeding AV‐block during ablation of atrioventricular nodal reentry tachycardia

1 Background

Radiofrequency (RF) ablation of the slow pathway (SP) in atrioventricular nodal reentry tachycardia (AVNRT) is occasionally complicated with atrioventricular block (AVB) often predicted by junctional beats (JB) with loss of ventriculo‐atrial (VA) conduction.

2 Methods

We analyzed retrospectively 153 patients undergoing ablation of SP for typical AVNRT. Patients were divided into two age groups: 127 ≤ 70 years and 26 > 70 years. We analyzed the interval between the atrial electrogram in the His‐bundle position and the distal ablation catheter [A(H)‐A(RFd)] and between the distal ablation catheter and the proximal coronary sinus catheter [A(RFd)‐A(CS)] before RF applications with and without JB. We evaluated if these intervals can be used as predictors of JB incidence and also of JB with loss of VA conduction. We also assessed if age influences the risk of loss of VA conduction.

3 Results

The A(H)‐A(RFd) and A(RFd)‐A(CS) intervals were significantly shorter in RF applications causing JB than those without JB (33 ± 11 ms vs 39 ± 9 ms, P < 0.001, 14 ± 9 ms vs 20 ± 7 ms, P < 0.001, respectively). The A(H)‐A(RFd) and A(RFd)‐A(CS) intervals were also significantly shorter in RFs causing JB with VA block than those with VA conduction (29 ± 11 ms vs 35 ± 11 ms, P < 0.001, 8 ± 8 ms vs 17 ± 8 ms, P < 0.001, respectively). Patients > 70 years had shorter intervals (36 ± 11 ms vs 29 ± 8 ms, P  =  0.012, 17 ± 8 ms vs 13 ± 7 ms, P  =  0.027, respectively), while VA block was more common in this age group.

4 Conclusions

The A(H)‐A(RFd) and A(RFd)‐A(CS) intervals can be used as markers for predicting JB occurrence as well as impending AVB. JB with loss of VA conduction occur more often in older patients possibly due to a higher position of SP.     

Pharmacosimulation of delays and interruptions during administration of tirofiban: a systematic comparison between EU and US dosage regimens

Journal of Thrombosis and Thrombolysis - Tirofiban is a glycoproteine (GP) IIb/IIIa receptor antagonist, which inhibits platelet-platelet aggregation and is a potential adjunctive antithrombotic...     

Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: early results of total therapy II

Cytogenetic abnormalities of chromosome 13 (CA 13) and those detected by fluorescence in situ hybridization (FISH 13) have both been associated with poor prognosis in multiple myeloma (MM) patients. The prognostic implications of CA, FISH 13 and other standard laboratory parameters were examined in the first 231 patients enrolled in Total Therapy II, an intensive cytotoxic chemotherapy programme with tandem autotransplants. Three-year projections of event-free survival (EFS) and overall survival (OS) were 71% and 77% respectively. CA 13 was detected in 14% and significantly correlated with FISH 13 (present in 51%), tumour burden, proliferative activity and lactic dehydrogenase (LDH). Both EFS and OS were significantly shorter in patients with CA 13, FISH 13, LDH >or= 190 U/l, beta2 microglobulin >or= 4 mg/l and C reactive protein >or= 4.0 mg/l; other CA was an additional risk factor for OS. Two-thirds of CA 13 patients were identified by FISH 13 and plasma-cell-labelling index (PCLI) >or= 0.4%; however, PCLI failed to identify additional risk groups in FISH subsets. Although present in considerably fewer patients, CA 13 imparted more rapid relapse (61% at 3 years) and death (43% at 3 years) than FISH 13 (38% and 35%; P = 0.02 and 0.1 respectively) and should be part of the initial work-up of patients with MM.     

Essential role of p21/waf1 in the mediation of the anti-proliferative effects of GHRH antagonist JMR-132

GHRH, besides its neuroendocrine action in controlling the release of GH from the pituitary, stimulates the growth of various cancers in vivo and in vitro by direct mechanism(s). However, the molecular mechanism that mediates these proliferative effects of GHRH in extrapituitary tissues remains poorly characterized. In the present study, we investigated whether the tumor suppressor p21/waf1 is involved in the mediation of the proliferative effects of GHRH in A549 human lung cancer epithelial cells. Exposure of A549 cells to the GHRH antagonist JMR-132 caused a significant inhibition in the rate of cell proliferation. In A549 cells, GHRH suppressed while JMR-132 increased the levels of p21 expression in a dose-dependent manner. This suggests that GHRH could regulate p21 levels. We then evaluated whether p21 is required in A549 cells for the regulation of cell proliferation by GHRH. To this end, we knocked-down p21 expression in A549 cells by siRNA and assessed the effects of antagonist JMR-132 on cell proliferation. We found that the loss of p21 expression abolished the anti-proliferative effects of JMR-132. Suppression of p21 expression by siRNA in human HT29 colon cancer cells and non-transformed mouse osteoblasts KS483 also blocked the anti-proliferative effects of JMR-132 suggesting that the regulation of cell proliferation by GHRH is p21 dependent. These results shed light on the molecular mechanism of action of GHRH antagonists in tumor tissues and suggest that the antineoplastic activity of GHRH antagonists could be considered for the treatment of cancers expressing p21.     

Isolation of drug-resistant variants of HIV-1 from patients on long-term zidovudine therapy. Canadian Zidovudine Multi-Centre Study Group

We determined whether drug-resistant variants of HIV-1 could be isolated from the peripheral blood mononuclear cells of 20 individuals with HIV infection (Centers for Disease Control groups II and III) on long-term zidovudine (AZT) therapy. Toward this end, zidovudine (10 microM) has been included in the tissue culture medium used to isolate HIV-1. Under these circumstances, virus with a zidovudine-resistant phenotype was successfully obtained in five out of 20 cases. This property of drug resistance appeared to be stable, and did not disappear upon extended replication of such virus in the absence of drug pressure. Drug-resistant virus could also be isolated from these subjects on subsequent occasions, but was not present in samples obtained prior to therapy. Replication of these zidovudine-resistant isolates in tissue culture was inhibited by each of four other nucleoside analogues. Thus, other drugs may be useful in controlling selective zidovudine-resistant variants of HIV-1.     

Management and treatment of hepatitis C virus in patients with HIV and hepatitis C virus coinfection: A practical guide for health care professionals

Concomitant HIV and hepatitis C virus (HCV) is a common yet complex coinfection. The present document is a practical guide for treating HCV infection in people coinfected with HIV. Effective antiretroviral therapies have prolonged survival rates for HIV-infected people over the past decade, which have made latent complications of HCV major causes of morbidity and mortality in these patients. Advances in the treatment of HCV (eg, combined pegylated interferon and ribavirin) offer the possibility of eradicating HCV infection in coinfected persons. The treatment of HCV must be considered in all cases. Intensive management of the adverse effects of HCV treatment is one of the factors for the success of these therapies. HCV eradication is predicted to decrease the mortality associated with coinfection and reduce the toxicity of HIV treatment.     

Peridevice Leak Following Amplatzer Left Atrial Appendage Occlusion: Cardiac Computed Tomography Classification and Clinical Outcomes

ObjectivesThis study aimed to investigate cardiac computed tomography (CT) and transesophageal echocardiography (TEE) peridevice leak (PDL) assessments, and the clinical relevance of PDL.BackgroundPDL assessment is integral during follow-up after left atrial appendage (LAA) occlusion. Comparative studies of TEE and cardiac CT are sparse, and the clinical relevance of PDL is uncertain.MethodsThis was a single-center observational study of consecutive patients undergoing LAA occlusion with Amplatzer devices (Amplatzer Cardiac Plug/Amulet) between 2010 and 2018 (N = 415). Patients with both 8-week CT and TEE were included for analysis (n = 346). Images were analyzed by blinded investigators (K.K. and A.S.). PDL on cardiac CT was classified from grade 1 to 3, based on PDL at the device disc, device lobe, and LAA contrast patency. Primary clinical outcome was a composite of ischemic stroke, transient ischemic attack, systemic embolism, or all-cause death.ResultsPDL was present in 110 patients (32%) by TEE, with 29 (8%) >3 mm. By cardiac CT, 210 patients (61%) had PDL at the disc, with contrast patency in 204 patients (59%). A grade 3 PDL (gap at disc, lobe, and LAA contrast patency) was present in 63 patients (18%). Bland-Altman analysis showed poor agreement between CT and TEE for leak sizing. CT and TEE detected PDL was not significantly associated with worse outcome, hazard ratio: 1.82 (95 % confidence interval: 0.95 to 3.50); p = 0.07 and hazard ratio: 1.43 (95% confidence interval: 0.74 to 2.76); p = 0.28, respectively.ConclusionsPDL occurrence is substantially higher with CT compared with TEE, with a large discrepancy between modalities in leak quantification. A novel CT-based classification is proposed, yet PDL was not associated with worse clinical outcome.     

Role of receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin and macrophage protein 1-alpha (MIP-1a) in monoclonal gammopathy of undetermined significance (MGUS)

The aim of this study was to evaluate the role of markers of bone remodelling, and osteoclast activation/function in patients with monoclonal gammopathy of undetermined significance (MGUS). We have measured serum levels of soluble RANKL (sRANKL), osteoprotegerin (OPG), macrophage inflammatory protein-1alpha (MIP-1alpha), markers of bone resorption [N-telopeptide of collagen type-I (NTX), and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)] and bone formation [bone-alkaline phosphatase (bALP)] in 40 MGUS patients. These parameters were compared with those of 42 newly diagnosed myeloma patients, and 45 healthy, gender- and age-matched controls. MGUS patients had elevated levels of NTX, sRANKL, and sRANKL/OPG ratio compared with controls (P < 0.0001). Furthermore, TRACP-5b, MIP-1alpha and NTX were decreased in patients with MGUS compared with myeloma patients (P < 0.001), while OPG and bALP were increased (P < 0.001). Serum levels of MIP-1alpha, as well as TRACP-5b, and sRANKL/OPG ratio were reduced, while bALP was increased in MGUS patients, even when compared with myeloma patients who had stage I/II disease. These results demonstrate that increased osteoclastogenesis leading to increased bone resorption is present in MGUS but seems to be compensated for by normal bone formation, which is absent in MM. Furthermore MIP-1alpha, bALP, and sRANKL/OPG may be useful tools for distinguishing between cases of MGUS and early myeloma.