Use of short-acting beta2-agonists during pregnancy and the risk of pregnancy-induced hypertension

BACKGROUND: The effect of inhaled short-acting beta(2)-agonists (SABAs) on pregnancy outcome, especially hypertensive complications, is not well documented. After the finding of a possible protective association of inhaled SABAs with pregnancy-induced hypertension (PIH) in a previous study, we decided to further investigate their effect on this condition. OBJECTIVE: We sought to determine the effect of inhaled SABA use during pregnancy on the risk of PIH (gestational hypertension, preeclampsia, or eclampsia) in asthmatic women. METHODS: Three of Quebec's administrative databases were linked to constitute a cohort of asthmatic women who had at least 1 delivery between 1990 and 2000. A nested case-control study was performed using up to 10 control subjects matched to each case patient for the year of conception and gestational age. Statistical analyses considered 22 confounders. RESULTS: The cohort was composed of 3505 asthmatic women who had a total of 4593 pregnancies. Three hundred two patients with PIH and 3013 control subjects were identified. Compared with nonuse, inhaled SABA use during pregnancy was significantly associated with a reduced risk of PIH (adjusted rate ratios: >0-3 doses/week, 0.62 (95% CI, 0.44-0.87); > 3-10 doses/week, 0.51 (95% CI, 0.34-0.79); and >10 doses/week, 0.48 (95% CI, 0.30-0.75)). CONCLUSIONS: To our knowledge, this is the first study reporting that inhaled SABA use during pregnancy is associated with a reduced risk of PIH. Potential explanations include pharmacologic and physiological effects or residual confounding. CLINICAL IMPLICATIONS: These results increase the evidence about the safety of inhaled SABAs in this population, although they should not undervalue the importance of maintaining good control of asthma symptoms.     

Motor cortical measures of use-dependent plasticity are graded from distal to proximal in the human upper limb

In humans, it is well established that practicing simple, repetitive movements with the distal upper limb induces short-term plasticity in the neural pathways that control training. It is unknown how the neural response to similar training at more proximal joints differs. The purpose of this study was to quantify how ballistic training at proximal and distal upper limb joints influences measures of corticomotor plasticity. To accomplish this goal, we had subjects repetitively practice simple movements for 30 min using the index finger, wrist, or elbow. Before and after training, transcranial magnetic stimulation (TMS) was used to activate the corticomotor pathways innervating the trained joint. We assessed the effect of training by quantifying changes in TMS-elicited joint movements and motor-evoked potentials in the training agonists and antagonists. These measures of training-induced neural plasticity were graded from distal to proximal in the upper limb. Training had the greatest immediate effect on the pathways controlling the index finger and this effect decreased for more proximal joints. Our results suggest that the relative sizes and properties of the cortical areas controlling the proximal and distal upper limb influence the effect of training on the corticomotor pathways. These results have implications for how training influences the neural pathways controlling movement in the proximal and distal portions of the human upper limb and the degree to which these effects can be quantified using TMS.     

Toxicity of pamam‐coated gold nanoparticles in different unicellular models

Polyamidoamine (PAMAM) dendrimers are used for many pharmaceutical and biomedical applications. However, the toxicological risks of several PAMAM‐based compounds are still not fully evaluated, despite evidences of PAMAM deleterious effects on biological membranes, leading to toxicity. In this report, we investigated the toxicity of generation 0 PAMAM‐coated gold nanoparticles (AuG0 NPs) in four different models to determine how different cellular systems are affected by PAMAM‐coated NPs. Toxicity was evaluated in two mammalian cell lines, Neuro 2A and Vero, in the green alga Chlamydomonas reinhardtii and the bacteria Vibrio fischeri. AuG0 NP treatments reduced cell metabolic activity in algal and bacterial cells, measured by esterase enzymatic activity (C. reinhardtii) and luminescence emission (V. fischeri). EC50 value after 30 min of treatment was similar in both organisms, with 0.114 and 0.167 mg mL^?1 for C. reinhardtii and V. fischeri, respectively. On the other hand, AuG0 NPs induced no change of mitochondrial activity in mammalian cells after 24 h of treatment to up to 0.4 mg mL^?1 AuG0 NPs. Change in the absorption spectra of AuG0 NP in the mammalian cell culture media may indicate an alteration of NP properties that contributed to the low toxicity of AuG0 NPs in mammalian cells. For a safe development of PAMAM‐based nanomaterials, the difference of sensitivity between mammalian and microbial cells, as well as the modulation of NPs toxicity by medium properties, should be taken into account when designing PAMAM NPs for applications that may lead to their introduction in the environment. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 328–336, 2014.     

P-glycoprotein targeting: a unique strategy to selectively eliminate immunoreactive T cells

T lymphocytes have been found to harbor P-glycoprotein (Pgp) and to demonstrate modulation of its ion channel transporter function according to the state of activation of T lymphocytes. We hypothesized that cytotoxic chemicals that are extruded by Pgp could be used to specifically eliminate immunoreactive T-cell populations. In this study, we evaluated the capacity of 4,5-dibromorhodamine methyl ester (TH9402), a photosensitizer structurally similar to rhodamine, a dye transported by Pgp, and which becomes highly cytotoxic on activation with visible light to selectively deplete alloreactive T lymphocytes. Stimulation of T cells with mitogens or allogeneic major histocompatibility complex-mismatched cells resulted in the preferential retention of the TH9402 rhodamine-derivative in activated T cells, both CD4+ and CD8+. Photodynamic cell therapy of TH9402-exposed T cells led to the selective elimination of immunoreactive T-cell populations. In addition, this treatment preserved resting T cells and their capacity to respond to third-party cells. Inhibition of Pgp enhanced cellular trapping of the dye in nonactivated T cells and resulted in their depletion after exposure to light. Targeting of Pgp-deficient cells may therefore represent an appealing strategy for the prevention and treatment of graft-versus-host disease and other alloimmune or autoimmune disorders.     

Treatment of therapy-induced preleukemic syndrome

Summary Two young adult patients with therapy-induced preleukemic syndrome and Hodgkin's disease as primary malignancy were treated with aggressive antileukemic regimens before the establishment of leukemic conversion. Pretreatment clinical staging procedures did not reveal recurrence of Hodgkin's disease. One of the regimens consisted of an HLA-identical allogeneic bone marrow transplant and the other of high dose cytosine arabinoside. Both therapeutic approaches have proved successful in restoring normal hematopoiesis with reversal to normal karyotypes and unmaintained remiisions 556 and 192 days post-treatment. The rationale for such a therapeutic approach in the preleukemic stage of therapy-induced leukemogenesis is discussed.     

Association between proton pump inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites

BACKGROUND:

There are data suggesting a link between proton pump inhibitor (PPI) use and the development of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites; however, these data are controversial.

OBJECTIVE:

To assess whether the use of PPIs in cirrhotic patients with ascites is associated with an increased risk for SBP.

METHODS:

A retrospective case-control study (June 2004 to June 2010) was conducted at the Centre Hospitalier de l’Université de Montréal in Montreal, Quebec. Fifty-one cirrhotic patients admitted with paracentesis-proven SBP (≥250 neutrophils/mm³), occurring within seven days of hospital admission, met the inclusion criteria. These patients were matched 1:2 (for age, Child-Pugh class and year of admission) with 102 comparable cirrhotic patients with ascites who were admitted for conditions other than SBP.

RESULTS:

Patients with SBP had a significantly higher rate of pre-hospital PPI use (60.8%) compared with cirrhotic patients without SBP (42.2%; P=0.03). On multivariate analysis, PPI use was the only factor independently associated with SBP (OR 2.09 [95% CI 1.04 to 4.23]; P=0.04). Thirty-five (35%) patients in both groups had no documented indication for PPI use in their charts. Forty-five percent of the remaining cirrhotic patients with SBP had an inappropriate indication, as defined in the protocol, for PPI use compared with 25% of controls.

CONCLUSIONS:

Cirrhotic patients with SBP were twice as likely to have taken PPIs than patients without SBP. These findings reinforce the association between PPI use and SBP observed in other studies. A high percentage of cirrhotic patients were taking a PPI without any documented indication.     

Volcano-induced regime shifts in millennial tree-ring chronologies from northeastern North America

Dated records of ice-cap growth from Arctic Canada recently suggested that a succession of strong volcanic eruptions forced an abrupt onset of the Little Ice Age between A.D. 1275 and 1300 [Miller GH, et al. (2012) Geophys Res Lett 39(2):L02708, 10.1029/2011GL050168]. Although this idea is supported by simulation experiments with general circulation models, additional support from field data are limited. In particular, the Northern Hemisphere network of temperature-sensitive millennial tree-ring chronologies, which principally comprises Eurasian sites, suggests that the strongest eruptions only caused cooling episodes lasting less than about 10 y. Here we present a new network of millennial tree-ring chronologies from the taiga of northeastern North America, which fills a wide gap in the network of the Northern Hemisphere''s chronologies suitable for temperature reconstructions and supports the hypothesis that volcanoes triggered both the onset and the coldest episode of the Little Ice Age. Following the well-expressed Medieval Climate Anomaly (approximately A.D. 910–1257), which comprised the warmest decades of the last millennium, our tree-ring-based temperature reconstruction displays an abrupt regime shift toward lower average summer temperatures precisely coinciding with a series of 13th century eruptions centered around the 1257 Samalas event and closely preceding ice-cap expansion in Arctic Canada. Furthermore, the successive 1809 (unknown volcano) and 1815 (Tambora) eruptions triggered a subsequent shift to the coldest 40-y period of the last 1100 y. These results confirm that series of large eruptions may cause region-specific regime shifts in the climate system and that the climate of northeastern North America is especially sensitive to volcanic forcing.Tree-ring chronologies are the type of proxy record most used to develop climate reconstructions covering the last millennium (1). These chronologies have been integrated into large-scale networks, often with additional proxies, to document the amplitude, duration, and forcing mechanisms of the Medieval Climate Anomaly, the Little Ice Age, and the recent warming trend. However, the spatial coverage of long tree-ring records must be improved to allow a better understanding of regional variations in past climate (1, 2). For example, in eastern North America, millennial climate reconstructions have been constructed from tree species and sites sensitive to drought and precipitation (3), whereas temperatures were inferred solely from low-resolution proxies, such as pollen data (4, 5). Furthermore, only tree-ring-based climate reconstructions shorter than a millennium or using chronologies poorly replicated before A.D. 1500 have been published for the entire North American boreal forest (6, 7), whereas several millennial, highly replicated, temperature-sensitive tree-ring records have been developed across the Eurasian boreal zone. This lack of data is an important issue that causes the poor representation of North America in long-term, large-scale temperature reconstructions (1, 4).The feasibility of reconstructing volcanic forcing from tree-ring data has been debated, especially in regards to large and successive eruptions. Two of the largest eruptions of the last millennium, the A.D. 1257 Samalas and A.D. 1815 Tambora events, were both closely followed and preceded by additional large eruptions in 1227, 1275, 1284, 1809, and 1835 (8−11). Whereas general circulation model experiments suggest that the impacts of large and successive eruptions might have influenced climate systems for periods ranging from 20 y to several decades, or even centuries (12–16), Northern Hemisphere tree-ring-based temperature reconstructions only display negative temperature anomalies lasting between 2 and 10 y (17–20). Region-specific responses of the climate system to volcanic forcing may in part explain this discrepancy (17). For example, large and successive eruptions may have had stronger impacts on summer temperatures in northeastern North America (hereafter NENA) than elsewhere. An extensive Northern Hemisphere network of tree-ring density chronologies supports this idea, showing that the coldest 1816 temperature anomalies occurred over the Quebec-Labrador Peninsula (21), where they may have persisted for several decades (7). The idea is also supported by the abrupt acceleration of ice-cap growth in the Eastern Canadian Arctic during A.D. 1275–1300, at the onset of the Little Ice Age, as a consequence of a series of eruptions (22). However, the lack of millennial, well-replicated, and temperature-sensitive tree-ring chronologies in the NENA sector precludes the examination of the volcano−temperature relationship in a long-term context with an annual resolution.In this study, we have built a network of six highly replicated millennial tree-ring chronologies from large stocks of black spruce [Picea mariana (Mill.) B.S.P.] subfossil trees preserved in lakes of the NENA taiga from which we developed a millennial reconstruction (A.D. 910–2011) of regional July−August temperatures. For this purpose, we selected homogeneous sites with infrequent and well-documented ecological disturbances (23), and sampled homogeneous subfossil and living samples to maximize the robustness of our reconstruction. We then used a Bayesian mixture of probability distributions with dependence (also referred to as hidden Markov models or Markov switching models; see refs. 24 and 25) to detect possible regime shifts in summer temperatures triggered by series of large eruptions and to provide new insights concerning the climate history of NENA during the last 1,100 y.     

Withdrawal reflexes in the upper limb adapt to arm posture and stimulus location

Introduction: Withdrawal reflexes in the leg adapt in a context‐appropriate manner to remove the limb from noxious stimuli, but the extent to which withdrawal reflexes adapt in the arm remains unknown. Methods: We examined the adaptability of withdrawal reflexes in response to nociceptive stimuli applied in different arm postures and to different digits. Reflexes were elicited at rest, and kinetic and electromyographic responses were recorded under isometric conditions, thereby allowing motorneuron pool excitability to be controlled. Results: Endpoint force changed from a posterior–lateral direction in a flexed posture to predominantly a posterior direction in a more extended posture [change in force angle (mean ± standard deviation) 35.6 ± 5.0°], and the force direction changed similarly with digit I stimulation compared with digit V (change = 22.9 ± 2.9°). Conclusions: The withdrawal reflex in the human upper limb adapts in a functionally relevant manner when elicited at rest. Muscle Nerve 49 : 716–723, 2014     

A GABAergic depolarizing potential in the hippocampus disclosed by the convulsant 4-aminopyridine

Intracellular recordings from hippocampal pyramidal cells in the CA1 subfield of the 'in vitro' slice in the presence of 4-aminopyridine (4-AP, 5-50 microM) revealed a long-lasting (up to 1.5 s) depolarizing potential which occurred either spontaneously or following orthodromic stimulation. This potential was: capable of blocking both direct and synaptic activation of the cell; sensitive to bath application of low concentrations of bicuculline methiodide; and associated to an extracellular current sink in the dendrites as suggested by the extracellular field potentials recorded at different levels along an axis perpendicular to the stratum pyramidale. It is concluded that the long-lasting depolarizing potential evoked by 4-AP is caused by the activation of GABA receptors localized in the dendritic region of the CA1 subfield.