Dynamical evidence for causality between galactic cosmic rays and interannual variation in global temperature

As early as 1959, it was hypothesized that an indirect link between solar activity and climate could be mediated by mechanisms controlling the flux of galactic cosmic rays (CR) [Ney ER (1959) Nature 183:451–452]. Although the connection between CR and climate remains controversial, a significant body of laboratory evidence has emerged at the European Organization for Nuclear Research [Duplissy J, et al. (2010) Atmos Chem Phys 10:1635–1647; Kirkby J, et al. (2011) Nature 476(7361):429–433] and elsewhere [Svensmark H, Pedersen JOP, Marsh ND, Enghoff MB, Uggerhøj UI (2007) Proc R Soc A 463:385–396; Enghoff MB, Pedersen JOP, Uggerhoj UI, Paling SM, Svensmark H (2011) Geophys Res Lett 38:{"type":"entrez-nucleotide","attrs":{"text":"L09805","term_id":"177519"}}L09805], demonstrating the theoretical mechanism of this link. In this article, we present an analysis based on convergent cross mapping, which uses observational time series data to directly examine the causal link between CR and year-to-year changes in global temperature. Despite a gross correlation, we find no measurable evidence of a causal effect linking CR to the overall 20th-century warming trend. However, on short interannual timescales, we find a significant, although modest, causal effect between CR and short-term, year-to-year variability in global temperature that is consistent with the presence of nonlinearities internal to the system. Thus, although CR do not contribute measurably to the 20th-century global warming trend, they do appear as a nontraditional forcing in the climate system on short interannual timescales.The basic principles behind a possible connection between galactic cosmic rays (CR) and global temperature (GT) are as follows: It has been known since the invention of the cloud chamber in 1911 by Charles Thomson Rees Wilson that ionizing radiation leads to atmospheric cloud nucleation. Although the prime source of ionizing radiation in the global troposphere is CR, the flux of CR reaching the troposphere depends on the solar wind. The solar wind is a stream of ionized gases that blows outward from the Sun, and its intensity varies strongly with the level of surface activity on the Sun. The Earth''s magnetic field shields the planet from much of the solar wind, deflecting that wind like water around the bow of a ship. When solar activity is great, the solar wind is strong, swiping away CR arriving at the top of the atmosphere. These CR are hypothesized to affect cloud formation and cloudiness, and therefore GT. The net radiative effect of cloudiness depends on the difference between incoming solar radiation and outgoing long-wave radiation. Increased cloudiness in the upper troposphere reduces outgoing long-wave radiation, thereby resulting in warming of the planet. Increased cloudiness in the lower troposphere causes less incoming radiation, and therefore cooling of the planet. Data suggest (6) that the amount of CR is positively correlated with the amount of low-level clouds but has no effect on middle- or high-level clouds. Although this is still an open question (7, 8), the reduction in flux in CR in times of high solar activity is hypothesized to result in less cloud nucleation and fewer cloud condensation nuclei, and consequently, reduced low-level cloud amounts. This, in turn, leads to a higher solar radiation flux at the Earth’s surface, and warmer temperatures. Conversely, a weaker solar wind results in cooler temperatures. The actual chemical processes and reactions involved in this problem are complex, but a growing body of experimental and theoretical work has uncovered a chemical pathway by which CR ionization may increase nucleation rates to levels appropriate for cloud condensation nuclei (2–5, 9–11 and references therein). This suggests a superficially simple network linking the Sun, CR, and global climate, with the interaction between the Sun and CR having a potential influence on the climate system. However reasonable this may be, as described in a 2006 review (12), “The suggested mechanisms are, however, too complex to evaluate meaningfully at present.”     

TRPC6 channel translocation into phagosomal membrane augments phagosomal function

Defects in the innate immune system in the lung with attendant bacterial infections contribute to lung tissue damage, respiratory insufficiency, and ultimately death in the pathogenesis of cystic fibrosis (CF). Professional phagocytes, including alveolar macrophages (AMs), have specialized pathways that ensure efficient killing of pathogens in phagosomes. Phagosomal acidification facilitates the optimal functioning of degradative enzymes, ultimately contributing to bacterial killing. Generation of low organellar pH is primarily driven by the V-ATPases, proton pumps that use cytoplasmic ATP to load H⁺ into the organelle. Critical to phagosomal acidification are various channels derived from the plasma membrane, including the anion channel cystic fibrosis transmembrane conductance regulator, which shunt the transmembrane potential generated by movement of protons. Here we show that the transient receptor potential canonical-6 (TRPC6) calcium-permeable channel in the AM also functions to shunt the transmembrane potential generated by proton pumping and is capable of restoring microbicidal function to compromised AMs in CF and enhancement of function in non-CF cells. TRPC6 channel activity is enhanced via translocation to the cell surface (and then ultimately to the phagosome during phagocytosis) in response to G-protein signaling activated by the small molecule (R)-roscovitine and its derivatives. These data show that enhancing vesicular insertion of the TRPC6 channel to the plasma membrane may represent a general mechanism for restoring phagosome activity in conditions, where it is lost or impaired.Chronic infection and inflammation in the airways in cystic fibrosis (CF), as well as chronic obstructive pulmonary disease (COPD), tuberculosis, and asthma are now among the most common chronic diseases. Pulmonary infection associated with these diseases has historically been treated with antibiotics that kill bacteria but also select for development of resistance in the pathogen in the chronically infected lung (1, 2). One solution to antimicrobial drug resistance is to target the host rather than the pathogen. This strategy necessitates finding alternative targets or signaling strategies amplifying or restoring bactericidal capacity in the cells charged with the task of resolving chronic infection.Mononuclear phagocytes orchestrate the innate immune response in the lung through the combinatorial interplay between the phagocytic uptake and killing of bacterial invaders, clearance of apoptotic cells, antigen presentation, and secretion of vesicle-bound signaling molecules to recruit help in the resolution of infection. Ionic fluxes across the phagosomal membrane that encloses the pathogen produce a hostile acidic environment developed through the action of a V-ATPase proton translocation. However, a positive intraphagosomal membrane potential generated by proton translocation minimizes the proton content of the phagosome. An influx of Cl⁻ via Cl⁻ channels reduces the membrane potential generated by the proton pump, thereby, allowing maximal acidification of the phagolysosomal compartment, which in turn maximizes the activation of lysosomal degradative enzymes, generation of hypochlorous acid, and consequent bacterial killing (3, 4). We have previously demonstrated that murine alveolar macrophages (AMs) use the anion channel cystic fibrosis transmembrane conductance regulator (CFTR) as a Cl⁻ permeation pathway in the phagosomal membrane. In CF, loss of functional CFTR in the AM alkalinizes the phagosomal lumen and allows antimicrobial-resistant bacterial pathogens to survive macrophage surveillance.Not all tissue macrophages use CFTR as a charge compensation pathway in phagolysosomal acidification (4). In fact, recent data suggest that multiple V-ATPase charge-shunt pathways can exist in diverse macrophage lineages (5) via lysosomal recruitment and membrane insertion upon particle uptake. This observation led us to search for possible alternative charge-shunt pathways in pulmonary macrophages and how they might be activated or targeted to the maturing phagosome. Could a pharmacological tool circumvent the defect in CF AMs and activate alternative pathways to rescue both organellar acidification and bactericidal activity in cells expressing mutations in CFTR? Such a tool might activate parallel charge-shunt pathways used in peritoneal macrophages for maximum acidification, thereby allowing them to clear bacteria independently of CFTR expression as well as amplify the microbicidal response in the presence of functional CFTR. The transport proteins and channels active in peritoneal macrophage bacterial clearance have not been described but may involve a K⁺/H⁺ exchanger important in promoting excitatory synaptic vesicle filling (6) or a cation channel moving positive charge out of the phagolysosomal compartment, as has been suggested for macrophage cell lines (7).We began our investigations pursuing a novel pharmacological strategy to identify compounds that would resolve bacterial infection in the CF lung without the use of antimicrobials. We picked a cellular defect in CF because of the availability of animal models and extended our observations to non-CF human pulmonary cells. We designed screening assays of phagosome function, which could be used in a clinical setting as both diagnostic and investigational tools. We interrogated host function by studying surface receptor-mediated mechanisms that might provide parallel signaling pathways in subcellular organellar function in the resolution of disease.We report that a series of small molecules first identified in chemotherapeutics, (R)-roscovitine [2-(R)-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine] and its derivatives, restore microbicidal function to compromised AMs in CF and enhance function in non-CF cells. The compounds use a G protein-mediated signaling pathway, which results in the mobilization of transient receptor potential canonical-6 (TRPC6) calcium-permeable, nonselective cation channels to the plasma membrane and subsequently to the phagosomal membrane. Members of the TRP channel family have been implicated in a number of critical phagocytic functions, including particle uptake, migration, and reactive oxygen species (ROS) production (5, 8–11). Numerous studies (12–15) have suggested TRP channels as potential targets for the development of therapies in pulmonary inflammation because of their abundant and diverse cellular expression throughout the respiratory tree. Although TRPC6 channels have been previously identified in lung macrophages and shown to be up-regulated in COPD, their precise role in the pathophysiology of the disease is yet to be determined (16). Perhaps more relevant to our study, a TRPC6-mediated Ca²⁺ influx is increased in human CF airway epithelial cells, possibly because of a functional association between CFTR and TRPC6 that is lost in CF (17), with unknown consequences. To our knowledge, this study is the first to associate TRPC6 channels a specific drug-targeting strategy for the resolution chronic pulmonary infection.     

Relationships between tumor grade and neurocognitive functioning in patients with glioma of the left temporal lobe prior to surgical resection

Background

Various tumor characteristics have been associated with neurocognitive functioning (NCF), though the role of tumor grade has not been adequately examined.

Methods

Seventy-two patients with histologically confirmed grade IV glioma (n = 37), grade III glioma (n = 20), and grade II glioma (n = 15) in the left temporal lobe completed preoperative neuropsychological assessment. Rates of impairment and mean test performances were compared by tumor grade with follow-up analysis of the influence of other tumor- and patient-related characteristics on NCF.

Results

NCF impairment was more frequent in patients with grade IV tumor compared with patients with lower-grade tumors in verbal learning, executive functioning, as well as language abilities. Mean performances significantly differed by tumor grade on measures of verbal learning, processing speed, executive functioning, and language, with the grade IV group exhibiting worse performances than patients with lower-grade tumors. Group differences in mean performances remained significant when controlling for T1-weighted and fluid attenuated inversion recovery MRI-based lesion volume. Performances did not differ by seizure status or antiepileptic and steroid use.

Conclusions

Compared with patients with grade II or III left temporal lobe glioma, patients with grade IV tumors exhibit greater difficulty with verbal learning, processing speed, executive functioning, and language. Differences in NCF associated with glioma grade were independent of lesion volume, seizure status, and antiepileptic or steroid use, lending support to the concept of “lesion momentum” as a primary contributor to deficits in NCF of newly diagnosed patients prior to surgery.     

Clinical characteristics,pathophysiology, and management of noncentral nervous system cancer‐related cognitive impairment in adults

Answer questions and earn CME/CNE Over the past few decades, a body of research has emerged confirming what many adult patients with noncentral nervous system cancer have long reported—that cancer and its treatment are frequently associated with cancer‐related cognitive impairment (CRCI). The severity of CRCI varies, and symptoms can emerge early or late in the disease course. Nonetheless, CRCI is typically mild to moderate in nature and primarily involves the domains of memory, attention, executive functioning, and processing speed. Animal models and novel neuroimaging techniques have begun to unravel the pathophysiologic mechanisms underlying CRCI, including the role of inflammatory cascades, direct neurotoxic effects, damage to progenitor cells, white matter abnormalities, and reduced functional connectivity, among others. Given the paucity of research on CRCI with other cancer populations, this review synthesizes the current literature with a deliberate focus on CRCI within the context of breast cancer. A hypothetical case‐study approach is used to illustrate how CRCI often presents clinically and how current science can inform practice. While the literature regarding intervention for CRCI is nascent, behavioral and pharmacologic approaches are discussed. CA Cancer J Clin 2015;65: 123–138. © 2014 American Cancer Society.     

Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death

Importance of interphase fluorescent in situ hybridization (FISH) with cytoplasmic staining of immunoglobulin FISH (cIg-FISH) on bone marrow is not well understood in light chain amyloidosis (AL). This is in contrast with multiple myeloma where prognostic and treatment related decisions are dependent on cytogenetic testing. This retrospective study reviewed 401 AL patients with cIg-FISH testing performed at our institution between 2004 and 2012. Eighty-one percent of patients had an abnormal cIg-FISH. Common abnormalities involved translocations of chromosome 14q32 (52%), specifically: t(11;14) (43%), t(14;16) (3%) and t(4;14) (2%). Other common abnormalities include monosomy 13/deletion 13q (30%), trisomies 9 (20%), 15 (14%), 11 (10%) and 3 (10%). Median overall survival for this cohort of patients is 3.5 years. When plasma cell burden was greater than 10% trisomies predicted for worse survival (44 vs 19 months), and when it was ⩽10% t(11;14) predicted for worse survival (53 months vs not reached). Abnormal cIg-FISH was significantly associated with advanced cardiac involvement, and remained a prognostic factor on multivariate analysis. This large AL cohort demonstrates that abnormal FISH at diagnosis is prognostic for survival and advanced cardiac disease. Particularly, trisomies and t(11;14) affect survival when degree of plasma cell burden is considered.     

Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk

Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82×10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48×10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83×10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.     

Expression of Interleukin-1 and temporomandibular disorder: Contemporary review of the literature

Objective: Temporomandibular disorders (TMD) are a group of conditions affecting the temporomandibular joint (TMJ), leading to jaw dysfunction, joint and muscle pain, and a decrease in quality of life. A communication network of pro- and anti-inflammatory mediators called cytokines maintains the homeostasis of the TMJ. This review will focus on the Interleukin (IL) family of cytokines, which have been quantified in TMJ synovial fluids in a variety of studies. IL-1α and IL-1β have pro-inflammatory effects, while the endogenous receptor antagonist (IL-1RA) inhibits the pro-inflammatory effects of IL-1.

Methods: A literature search (2006–2016) to identify eligible studies was completed using the PubMed database. Studies identified used saline irrigation to quantify cytokine profiles in synovial fluid of healthy and/or dysfunctional joints.

Results: The initial search yielded 111 articles, 5 of which met the inclusion criteria after inter-reviewer discussion.

Conclusions: Articles that compared IL-1 concentrations in TMD vs. control groups found significant differences.