Τετάρτη, 30 Μαρτίου 2016

Quantitative Trait Locus Analysis of Mating Behavior and Male Sex Pheromones in Nasonia Wasps

A major focus in speciation genetics is to identify the chromosomal regions and genes that reduce hybridization and gene flow. We investigated the genetic architecture of mating behavior in the parasitoid wasp species pair Nasonia giraulti and Nasonia oneida that exhibit strong prezygotic isolation. Behavioral analysis showed that N. oneida females had consistently higher latency times and broke off the mating sequence more often in the mounting stage when confronted with N. giraulti males compared with males of their own species. N. oneida males produce a lower quantity of the long-range male sex pheromone, (4R,5S)-5-hydroxy-4-decanolide (RS-HDL). Crosses between the two species yielded hybrid males with various pheromone quantities and these males were used in mating trials with females of either species to measure female mate discrimination rates. A quantitative trait locus (QTL) analysis involving 475 recombinant hybrid males (F2), 2148 reciprocally backcrossed females (F3), and a linkage map of 52 equally spaced neutral single nucleotide polymorphism (SNP) markers plus SNPs in 40 candidate mating behavior genes revealed four QTL for male pheromone amount depending on partner species. Our results demonstrate that the RS-HDL pheromone plays a role in the mating system of N. giraulti and N. oneida, but also that additional communication cues are involved in mate choice. No QTL were found for female mate discrimination which points at a polygenic architecture of female choice with strong environmental influences

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DREADD-induced Activation of Subfornical Organ Neurons Stimulates Thirst and Salt Appetite

The subfornical organ (SFO) plays a pivotal role in body fluid homeostasis through its ability to integrate neurohumoral signals and subsequently alter behavior, neuroendocrine function and autonomic outflow. The purpose of the present study was to evaluate whether selective activation of SFO neurons using virally-mediated expression of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) stimulated thirst and salt appetite. Male C57Bl/6 mice (12-15 weeks) received an injection of rAAV2-CaMKII-HA-hM3D(Gq)-IRES-mCitrine targeted at the SFO. At 2 wks later, acute injection of clozapine N-oxide (CNO) produced dose-dependent increases in water intake of mice with DREADD expression in the SFO. CNO also stimulated the ingestion of 0.3M NaCl. Acute injection of CNO significantly increased the number of Fos-positive nuclei in the SFO of mice with robust DREADD expression. Furthermore, in vivo single-unit recordings demonstrate that CNO significantly increases the discharge frequency of both AngII- and NaCl-responsive neurons. In vitro current-clamp recordings confirm bath application of CNO produces a significant membrane depolarization and increase in action potential frequency. In a final set of experiments, chronic administration of CNO approximately doubled 24-h water intake without an effect on salt appetite. These findings demonstrate DREADD-induced activation of SFO neurons stimulates thirst, and DREADDs are a useful tool to acutely or chronically manipulate neuronal circuits influencing body fluid homeostasis.

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Patterns of Genome-Wide Variation in Glossina fuscipes fuscipes Tsetse Flies from Uganda

The tsetse fly Glossina fuscipes fuscipes (Gff) is the insect vector of the two forms of Human African Trypanosomiasis (HAT) that exist in Uganda. Understanding Gff population dynamics and the underlying genetics of epidemiologically relevant phenotypes is key to reducing disease transmission. Using ddRAD sequence technology, complemented with whole-genome sequencing, we developed a panel of ~73,000 single-nucleotide polymorphisms distributed across the Gff genome that can be used for population genomics and to perform Genome-Wide-Association studies. We used these markers to estimate genomic patterns of linkage disequilibrium (LD) in Gff and used the information, in combination with outlier-locus detection tests, to identify candidate regions of the genome under selection. LD in individual populations decays to half of its maximum value (r2max/2) between 1,359 and 2,429 bp. The overall LD estimated for the species reaches r2max/2 at 708 bp, an order of magnitude slower than in Drosophila. Using 53 infected (Trypanosoma spp.) and uninfected flies from four genetically distinct Ugandan populations adapted to different environmental conditions, we were able to identify SNPs associated with the infection status of the fly and local environmental adaptation. The extent of LD in Gff likely facilitated the detection of loci under selection, despite the small sample size. Furthermore, it is probable that LD in the regions identified is much higher than the average genomic LD due to strong selection. Our results show that even modest sample sizes can reveal significant genetic associations in this species, which has implications for future studies given the difficulties of collecting field specimens with contrasting phenotypes for the association analysis.

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Receptive field size, chemical and thermal responses and fiber conduction velocity of rat chorda tympani geniculate ganglion neurons

Afferent chorda tympani (CT) fibers innervating taste and somatosensory receptors in fungiform papillae have neuron cell bodies in the geniculate ganglion (GG). The GG/CT fibers branch in the tongue to innervate taste buds in several fungiform papillae. To investigate receptive field characteristics of GG/CT neurons we recorded extracellular responses from GG cells to application of chemical and thermal stimuli. Receptive field size was mapped by electrical stimulation of individual fungiform papillae. Response latency to electrical stimulation was used to determine fiber conduction velocity. Responses of GG neurons to lingual application of stimuli representing five taste qualities, and water at 4°C, were used to classify neuron response properties. Neurons classified as SALT, responding only to NaCl and NH4Cl, had a mean receptive field size of 6 papillae. Neurons classified as OTHER responded to salts and other chemical stimuli and had smaller mean receptive fields of 4 papillae. Neurons that responded to salts and cold stimuli, classified as SALT/THERMAL, and neurons responding to salts, other chemical stimuli and cold, classified as OTHER/THERMAL, had mean receptive field sizes of 6 papillae. Neurons responding only to cold stimuli, categorized as THERMAL, had receptive fields of 1-2 papillae located at the tongue tip. Based on conduction velocity most of the neurons were classified as C fibers. Neurons with large receptive fields had higher conduction velocities than neurons with small receptive fields. These results demonstrate that GG neurons can be distinguished by receptive field size, response properties and afferent fiber conduction velocity derived from convergent input of multiple taste organs.

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Network Feedback Regulates Motor Output across a Range of Modulatory Neuron Activity

Modulatory projection neurons alter network neuron synaptic and intrinsic properties to elicit multiple different outputs. Sensory and other inputs elicit a range of modulatory neuron activity which is further shaped by network feedback. Yet little is known regarding how the impact of network feedback on modulatory neurons regulates network output across a physiological range of modulatory neuron activity. Identified network neurons, a fully described connectome, and a well-characterized, identified modulatory projection neuron enabled us to address this issue in the crab (Cancer borealis) stomatogastric nervous system. The modulatory neuron MCN1 activates and modulates two networks which generate rhythms via different cellular mechanisms and at distinct frequencies. MCN1 is activated at rates of 5 - 35 Hz in vivo and in vitro. Additionally, network feedback elicits MCN1 activity time-locked to motor activity. We asked how network activation, rhythm speed and neuron activity levels are regulated by the presence or absence of network feedback across a physiological range of MCN1 activity rates. There were both similarities and differences in responses of the two networks to MCN1 activity. Many parameters in both networks were sensitive to network feedback effects on MCN1 activity. However for most parameters, MCN1 activity rate did not determine the extent to which network output was altered by the addition of network feedback. These data demonstrate that the influence of network feedback on modulatory neuron activity is an important determinant of network output, and feedback can be effective in shaping network output regardless of the extent of network modulation.

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Effects of mild hypohydration on cooling during cold-water immersion following exertional hyperthermia



We investigated the effects of mild hypohydration compared to euhydration on the cooling efficacy of cold-water immersion (CWI).


Fourteen participants (eight male, six female; age 26 ± 5 years; ht 1.77 ± 0.08 m; wt 72.2 ± 8.8 kg; 20.6 ± 7.4 % body fat) completed one euhydrated (EU) trial followed by one hypohydrated trial (HY; via 24 h fluid restriction) in an environmental chamber (33.6 ± 0.9 °C, 55.8 ± 1.7 % RH). Volitional exercise was performed in a manner that matched end-exercise rectal temperature (T re) through repeating exercise mode and intensity. Participants were then immersed in ice water (2.0 ± 0.8 °C) until T re reached 38.1 °C or for a maximum of 15 min. T re, heart rate (HR), skin blood flux (SBF) and mean skin temperature (T sk) were monitored continuously during cooling.


Pre-cooling body mass was decreased in the HY trial (−2.66 ± 1.23 % body mass) and maintained in the EU trial (−0.66 ± 0.44 %) compared to baseline mass (P < 0.001). Cooling rates were faster when EU (0.14 ± 0.05 °C/min) compared to HY (0.11 ± 0.05 °C/min, P = 0.046). HR, SBF, and T sk were not different between EU and HY trials (P > 0.05), however, all variables significantly decreased with immersion independent of hydration status (P < 0.001).


The primary finding was that hypohydration modestly attenuates the rate of cooling in exertionally hyperthermic individuals. Regardless of hydration status, the cooling efficacy of CWI was preserved and should continue to be utilized in the treatment of exertional hyperthermia.

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The mind–muscle connection in resistance training: friend or foe?


The results of Calatayud et al. (Eur J Appl Physiol, 2015. doi:10.1007/s00421-015-3305-7) indicate that focusing on the pectoralis major and triceps brachii muscles during bench press exercise selectively enhanced their activation, and thus suggest a training strategy. However, the authors did not discuss the well-established negative effects that focusing on specific muscle groups has on exercise performance. For proper perspective of the results and their practical utility, it is helpful to note the interplay between negative and positive effects of different focus conditions.

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Submaximal exercise intensity modulates acute post-exercise heart rate variability



This study investigated whether short-term heart rate variability (HRV) can be used to differentiate between the immediate recovery periods following three different intensities of preceding exercise.


12 males cycled for 8 min at three intensities: LOW (40–45 %), MOD (75–80 %) and HIGH (90–95 %) of heart rate (HR) reserve. HRV was assessed during exercise and throughout 10-min seated recovery.


1-min HR recovery was reduced following greater exercise intensities when expressed as R–R interval (RRI, ms) (p < 0.001), but not b min−1 (p = 0.217). During exercise, the natural logarithm of root mean square of successive differences (Ln-RMSSD) was higher during LOW (1.66 ± 0.47 ms) relative to MOD (1.14 ± 0.32 ms) and HIGH (1.30 ± 0.25 ms) (p ≤ 0.037). Similar results were observed for high-frequency spectra (Ln-HF—LOW: 2.9 ± 1.0; MOD: 1.6 ± 0.6; HIGH: 1.6 ± 0.3 ms2, p < 0.001). By 1-min recovery, higher preceding exercise intensities resulted in lower HRV amongst all three intensities for Ln-RMSSD (LOW: 3.45 ± 0.58; MOD: 2.34 ± 0.81; HIGH: 1.66 ± 0.78 ms, p < 0.001) and Ln-HF (LOW: 6.0 ± 1.0; MOD: 4.3 ± 1.4; HIGH: 2.8 ± 1.4 ms2, p < 0.001). Similarly, by 1-min recovery 'HR-corrected' HRV (Ln-RMSSD: RRI × 103) was different amongst all three intensities (LOW: 3.64 ± 0.49; MOD: 2.90 ± 0.65; HIGH: 2.40 ± 0.67, p < 0.001). These differences were maintained throughout 10-min recovery (p ≤ 0.027).


Preceding exercise intensity has a graded effect on recovery HRV measures reflecting cardiac vagal activity, even after correcting for the underlying HR. The immediate recovery following exercise is a potentially useful period to investigate autonomic activity, as multiple levels of autonomic activity can be clearly differentiated between using HRV. When investigating post-exercise HRV it is critical to account for the relative exercise intensity.

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Muscle focal vibration in healthy subjects: evaluation of the effects on upper limb motor performance measured using a robotic device



Muscle vibration is a technique that applies a low-amplitude/high-frequency vibratory stimulus to a specific muscle using a mechanical device. The aim of this study was to evaluate, using robot-based outcomes, the effects of focal muscle vibration, at different frequencies, on the motor performance of the upper limb in healthy subjects.


Forty-eight volunteer healthy subjects (age: 31 ± 8 years) were enrolled. Subjects were assigned to three different groups: the first group, in which subjects underwent muscle vibration treatment with a frequency of 100 Hz; the second group of subjects underwent the same treatment protocol, but using a frequency of vibration of 200 Hz; finally, the control group did not undergo any treatment. The robot-based evaluation session consisted of visually guided reaching task, performed in the sagittal plane.


Our results showed that the vibration treatment improved upper limb motor performance of healthy subjects from the baseline (T0) to 10 days after the end of the treatment (T2), but only the group treated with a frequency of 200 Hz reached statistical significance. Specifically, in this group we found an increase of the number of repetitions (T0: 51.4 ± 22.7; T2: 66.3 ± 11.8), and the smoothness of the movement, as showed by a decrease of the Normalized Jerk (T0: 10.5 ± 2.8; T2: 7.7 ± 0.5).


The results of our study support the use of focal muscle vibration protocols in healthy subjects, to improve motor performance.

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Adipocytokine and ghrelin levels in relation to bone mineral density in prepubertal rhythmic gymnasts entering puberty: a 3-year follow-up study



To investigate changes in bone mineral density (BMD) in rhythmic gymnasts (RG) entering puberty and their age-matched untrained controls (UC) over the 36-month period, and associations with leptin, adiponectin and ghrelin over this period.


Whole body (WB), lumbar spine (LS) and femoral neck (FN) BMD, WB bone mineral content (BMC), and leptin, adiponectin and ghrelin were measured in 35 RG and 33 UC girls at baseline and at 12-month intervals over the next 3 years. The change over the 36 months was calculated (∆ score).


The pubertal development over the next 36 months was slower in RG compard to UC, while there was no difference in bone age development between the groups. BMD at all sites was higher in RG in comparison with UC at every measurement point. ∆LS BMD and ∆FN BMD, but not ∆WB BMD and ∆WB BMC, were higher in RG compared with UC. None of the measured hormones at baseline or their ∆ scores correlated with ∆BMD and ∆BMC in RG. Baseline fat free mass correlated with ∆WB BMD and ∆WB BMC in RG, while baseline leptin was related to ∆WB BMC, ∆WB BMD and ∆LS BMD in UC.


Measured baseline hormones and their ∆ scores did not correlate with increases in bone mineral values in RG entering puberty. Although the pubertal development in RG was slower than in UC, high-intensity training appeared to increase BMD growth and counterbalance negative effects of slow pubertal develpment, lower fat mass and leptin in RG.

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Suppression of activation of muscle sympathetic nerve during non-noxious local cooling after the end of local cooling in normal adults



While non-noxious local cooling is widely used in physical medicine, its effect on muscle sympathetic nerve activity (MSNA) and cardiovascular regulation are not clear. The purpose of the present study was to assess the responses of MSNA, blood pressure (BP), heart rate (HR) and local blood flow during non-noxious local cooling.


The study included two protocols. Both protocols consisted of 10-min rest in supine position, followed by 15-min local cooling (15 °C) of the shin and anterior foot, and 20-min recovery. MSNA of the right common peroneal nerve, BP, HR, and shin skin temperature (TSK) were recorded in eight men in the first protocol, while leg blood flow (LBF) was measured in the same subjects by strain-gauge plethysmography in the second protocol.


TSK gradually decreased from 31.5 ± 0.02 to 16.0 ± 1.01 °C (mean ± SEM) during local cooling, and gradually increased after the end of local cooling. No subject complained of pain, and BP and HR remained constant. The MSNA burst rate increased significantly (p < 0.05) to 141.1 ± 12.5 % during local cooling, but decreased significantly (p < 0.05) to 73.6 ± 5.9 % during the recovery period. Total MSNA also increased to 148.0 ± 14.2 % (p < 0.05) during local cooling, and decreased to 74.0 ± 13.9 % (p < 0.05) at recovery. LBF remained constant through the experiment.


The results suggest that MSNA is activated by non-noxious local cooling, and attenuated after the end of local cooling without any changes in HR and BP.

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Mind–muscle connection revisited: do 100 studies about beanbag tossing, stick balancing, and dart throwing have any relevance for strength training?

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Measurement of gastrocnemius muscle elasticity by shear wave elastography: association with passive ankle joint stiffness and sex differences



Passive joint stiffness is an important quantitative measure of flexibility, but is affected by muscle volume and all of the anatomical structures located within and over the joint. Shear wave elastography can assess muscle elasticity independent of the influences of muscle volume and the other nearby anatomical structures. We determined how muscle elasticity, as measured using shear wave elastography, is associated with passive joint stiffness and patient sex.


Twenty-six healthy men (24.4 ± 5.9 years) and 26 healthy women (25.2 ± 4.8 years) participated in this study. The passive ankle joint stiffness and tissue elasticity of the medial gastrocnemius (MG) were quantified with the ankle in 30° plantar flexion (PF), a neutral anatomical position (NE), and 20° dorsiflexion (DF).


No significant difference in passive joint stiffness by sex was observed with the ankle in PF, but significantly greater passive ankle joint stiffness in men than in women was observed in NE and DF. The MG elasticity was not significantly associated with joint stiffness in PF or NE, but it was significantly associated with joint stiffness in DF. There were no significant differences in MG elasticity by sex at any ankle position.


Muscle elasticity, measured independent of the confounding effects of muscle volume and the other nearby anatomical structures, is associated with passive joint stiffness in the joint position where the muscle is sufficiently lengthened, but does not vary by sex in any joint position tested.

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Effect of acute hypoxia on inspiratory muscle oxygenation during incremental inspiratory loading in healthy adults



To non-invasively examine the effect of acute hypoxia and inspiratory threshold loading (ITL) on inspiratory muscles [sternocleidomastoid (SCM), scalene (SA) and parasternal (PS)] oxygenation in healthy adults using near-infrared spectroscopy (NIRS).


Twenty healthy adults (12 M/8 F) were randomly assigned to perform two ITL tests while breathing a normoxic or hypoxic (FIO2 = 15 %) gas mixture. NIRS devices were placed over the SCM, PS, SA, and a control muscle, tibialis anterior (TA), to monitor oxygenated (O2Hb), deoxygenated (HHb), total hemoglobin (tHb) and tissue saturation index (TSI). With the nose occluded, subjects breathed normally for 4 min through a mouthpiece that was connected to a weighted threshold loading device. ITL began by adding a 100-g weight to the ITL device. Then, every 2 min 50-g was added until task failure. Vital signs, ECG and ventilatory measures were monitored throughout the protocol.


Participants were 31 ± 12 year and had normal spirometry. At task failure, the maximum load and ventilatory parameters did not differ between the hypoxic and normoxic ITL. At hypoxic ITL task failure, SpO2 was significantly lower, and ∆HHb increased more so in SA, SCM and PS than normoxic values. SCM ∆TSI decreased more so during hypoxic compared to normoxic ITL. ∆tHb in the inspiratory muscles (SCM, PS and SA) increased significantly compared to the decrease in TA during both hypoxic and normoxic ITL.


The SCM, an accessory inspiratory muscle was the most vulnerable to deoxygenation during incremental loading and this response was accentuated by acute hypoxia.

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Swim performance and thermoregulatory effects of wearing clothing in a simulated cold-water survival situation



Accidental cold-water immersion (CWI) impairs swim performance, increases drowning risk and often occurs whilst clothed. The impact of clothing on thermoregulation and swim performance during CWI was explored with the view of making recommendations on whether swimming is viable for self-rescue; contrary to the traditional recommendations.


Ten unhabituated males (age 24 (4) years; height 1.80 (0.08) m; mass 78.50 (10.93) kg; body composition 14.8 (3.4) fat %) completed four separate CWIs in 12 °C water. They either rested clothed or naked (i.e. wearing a bathing costume) or swum self-paced clothed or naked for up to 1 h. Swim speed, distance covered, oxygen consumption and thermal responses (rectal temperature (T re), mean skin temperature (T msk) and mean body temperature T b) were measured.


When clothed, participants swum at a slower pace and for a significantly shorter distance (815 (482) m, 39 (19) min) compared to when naked (1264 (564) m, 52 (18) min), but had a similar oxygen consumption indicating clothing made them less efficient. Swimming accelerated the rate of T msk and T b cooling and wearing clothing partially attenuated this drop. The impairment to swimming performance caused by clothing was greater than the thermal benefit it provided; participants withdrew due to exhaustion before hypothermia developed.


Swimming is a viable self-rescue method in 12 °C water, however, clothing impairs swimming capability. Self-rescue swimming could be considered before clinical hypothermia sets in for the majority of individuals. These suggestions must be tested for the wider population.

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Discriminating between two autonomic profiles related to posture in Olympic athletes



Autonomic assessment might be useful in training management. We planned to assess whether oscillatory metrics of RR variability (such as LFnu) would be more efficient than static indices from low order statistics (RR variance) at discriminating laying rest from stand posture, as an analog of a shift to sympathetic dominance.


We studied a large population of elite Olympic athletes: a total of 406 athletes (162 females and 244 males, of similar age 21.7 and 24.4 years) participating to the selection for the upcoming 2016 Olympic games. We employed various methods to extract autonomic indices from RR variability and employed a stepwise statistical approach combining factor and discriminant analysis.


We observed that that relative power of oscillatory components from spectral analysis of RR variability (such as LF or HF in nu) and indices from symbolic analysis (particularly 0V) clearly outperform RR variance in discriminating between two physiological conditions (laying rest and stand) related to posture and autonomic activation.


In world class Olympic athletes we have shown that a small subset of RR variability indices, related to sympathovagal balance, may be more appropriate than RR variance to assess excitatory sympathetic autonomic responsiveness of the SA node. These findings may have practical implications for the use of RR variability in guiding training and predicting success in competitions.

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Low-intensity resistance training with blood flow restriction improves vascular endothelial function and peripheral blood circulation in healthy elderly people



The present study aimed to investigate the effects of low-intensity resistance training with blood flow restriction (BFR resistance training) on vascular endothelial function and peripheral blood circulation.


Forty healthy elderly volunteers aged 71 ± 4 years were divided into two training groups. Twenty subjects performed BFR resistance training (BFR group), and the remaining 20 performed ordinary resistance training without BFR. Resistance training was performed at 20 % of each estimated one-repetition maximum for 4 weeks. We measured lactate (Lac), norepinephrine (NE), vascular endothelial growth factor (VEGF) and growth hormone (GH) before and after the initial resistance training. The reactive hyperemia index (RHI), von Willebrand factor (vWF) and transcutaneous oxygen pressure in the foot (Foot-tcPO2) were assessed before and after the 4-week resistance training period.


Lac, NE, VEGF and GH increased significantly from 8.2 ± 3.6 mg/dL, 619.5 ± 243.7 pg/mL, 43.3 ± 15.9 pg/mL and 0.9 ± 0.7 ng/mL to 49.2 ± 16.1 mg/dL, 960.2 ± 373.7 pg/mL, 61.6 ± 19.5 pg/mL and 3.1 ± 1.3 ng/mL, respectively, in the BFR group (each P < 0.01). RHI and Foot-tcPO2 increased significantly from 1.8 ± 0.2 and 62.4 ± 5.3 mmHg to 2.1 ± 0.3 and 68.9 ± 5.8 mmHg, respectively, in the BFR group (each P < 0.01). VWF decreased significantly from 175.7 ± 20.3 to 156.3 ± 38.1 % in the BFR group (P < 0.05).


BFR resistance training improved vascular endothelial function and peripheral blood circulation in healthy elderly people.

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Increased endothelial microparticles and oxidative stress at extreme altitude



Hypoxia and oxidative stress affect endothelial function. Endothelial microparticles (MP) are established measures of endothelial dysfunction and influence vascular reactivity. To evaluate the effects of hypoxia and antioxidant supplementation on endothelial MP profiles, a double-blind, placebo-controlled trial, during a high altitude expedition was performed.


29 participants were randomly assigned to a treatment group (n = 14), receiving vitamin E, C, A, and N-acetylcysteine daily, and a control group (n = 15), receiving placebo. Blood samples were obtained at 490 m (baseline), 3530, 4590, and 6210 m. A sensitive tandem mass spectrometry method was used to measure 8-iso-prostaglandin F and hydroxyoctadecadienoic acids as markers of oxidative stress. Assessment of MP profiles including endothelial activation markers (CD62+MP and CD144+MP) and cell apoptosis markers (phosphatidylserine+MP and CD31+MP) was performed using a standardized flow cytometry-based protocol.


15 subjects reached all altitudes and were included in the final analysis. Oxidative stress increased significantly at altitude. No statistically significant changes were observed comparing baseline to altitude measurements of phosphatidylserine expressing MP (p = 0.1718) and CD31+MP (p = 0.1305). Compared to baseline measurements, a significant increase in CD62+MP (p = 0.0079) and of CD144+MP was detected (p = 0.0315) at high altitudes. No significant difference in any MP level or oxidative stress markers were found between the treatment and the control group.


Hypobaric hypoxia is associated with increased oxidative stress and induces a significant increase in CD62+ and CD144+MP, whereas phosphatidylserine+MP and CD31+MP remain unchanged. This indicates that endothelial activation rather than an apoptosis is the primary factor of hypoxia induced endothelial dysfunction.

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Nachrichten aus der internationalen Fachliteratur

Anästhesiol Intensivmed Notfallmed Schmerzther 2016; 51: 148-150
DOI: 10.1055/s-0041-109682

In dieser Rubrik werden Nachrichten aus der Wissenschaft kurz und prägnant für Sie zusammengefasst. In dieser Ausgabe mit folgenden Themen:

© Georg Thieme Verlag Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Parenchymal Pulmonary Disease in Systemic Idiopathic Juvenile Arthritis: A Case Report

Source: Annals of Paediatric Rheumatology
Mariana Domingues, Paula Estanqueiro, Maria Helena Estêvão, Manuel Salgado.
Parenchymal pulmonary disease is a rare and poorly described manifestation of systemic juvenile idiopathic arthritis (sJIA). We report the case of a girl, 6.5 years-old, admitted due to an alleged infectious pneumonia in the context of 14 days of fever, pulmonary consolidation and pleural effusion unresponsive to antibiotics. The latter association of hip and cervical arthritis, hepatosplenomegaly and persistent elevated acute phase reactants evoked the diagnosis of sJIA, which promptly improved with oral prednisolone and oral methotrexate. This case illustrates parenchymal pulmonary involvement as the main manifestation of sJIA.

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The Hallmarks of Rheumatic Fever in Developing Countries (Pakistan and Afghanistan)

Source: Annals of Paediatric Rheumatology
Muhammad Ishaq, Sameera Ishaq, Imran Khan, Sabeen Khan Al-Juniad.
Rheumatic fever is a multisystem disorder resulting from post streptococcal infection. It reflects a generalized vasculitic process with the following features: (1) rheumatic arthritis (significantly affecting the large joints), (2) carditis, (3) rheumatic chorea, (4) erythema marginatum, and (5) subcutaneous nodules. In this study, we observed these features singly or in variable combinations. Initially, acute rheumatic fever with carditis, in some untreated cases, progressed to chronic rheumatic heart disease, with devastating outcome.

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Do Biological Agents be Useful in the Treatment of Amyloidosis Related FMF?

Source: Annals of Paediatric Rheumatology
Ipek Akil, Havva Evrengul.
Familial Mediterranean Fever (FMF), is an autosomal recessive disease associated with mutations in the MEFV gene. A 13-year-old female patient was admitted to hospital with vomiting and increasing abdominal pain. Her physical examination showed generalized edema. Laboratory examination revealed proteinuria, hypoalbuminemia, hypercholesterolemia. Renal biopsy showed AA-type amyloidosis and homozygous M694V mutation was detected. Colchicine was started. However, heavy proteinuria persisted despite colchicine treatment and infliximab treatment was administered. Since patient developed edema, proteinuria, hypoalbuminemia, after tenth dose of infliximab therapy, resistance was considered and treatment was discontinued. Anakinra therapy was initiated. Anakinra treatment was stopped after six months due to the patient was rejected any more using that treatment and end stage renal failure was developed. Although biological agents may be useful in the treatment of amyloidosis caused by FMF, the progression of illness despite treatment with these agents has been reported in many patients

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A Child with Sicca like Symptoms

Source: Annals of Paediatric Rheumatology
Muna Al Mutairi, Atef Helmi, Nashaat ElSayed Farara, Fawaz Al Rafaei, Mohsen Al Ajmi, Kamelia Velikova.
Childhood sarcoidosis is a rare multisystem granulomatous disorder of unknown cause. We describe a 12 years old Kuwaiti girl presented with bilateral parotid gland swelling of four weeks duration followed by dry eyes and difficulty in swallowing with a negative autoimmune work up. We intended to elaborate the clinical presentation of childhood sarcoidosis.

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How to make community paramedicine work for your agency, Part I

The following is paid content sponsored by EMS Management & Consultants.

By EMS1 BrandFocus staff

Community paramedicine, also known as mobile integrated health, is catching on nationwide as a way to improve patient care while reducing costs. These programs are designed to better serve the community by redirecting the people using a disproportionate amount of emergency services to more appropriate, cost-effective providers.

Many of these so-called "frequent fliers" lack insurance and suffer from poor health literacy, chronic health problems, mental illness or addiction, and too often, these patients put a strain on EMS agencies even as they fall through the cracks. To determine whether a community paramedicine program is right for your agency and community, you must identify critical areas for improvement and gather data to support your argument.

Begin with a needs assessment

First, define the problem areas. What is the need? Are your agency's resources stretched thin by a few frequent fliers? Is your local hospital looking to reduce readmissions? Are you getting a lot of calls for chronic, non-emergency issues?

A single frequent flier can put a lot of distress on a health care system. Anytime an ambulance is out of service, the capability of the system to treat the next patient is lower, plus the Medicare reimbursement rates for ambulance transport don't cover the actual cost of an ambulance ride.

A patient who calls once a day or every other day becomes a significant stress on the system – but you can't refuse a call, because you never know when that incident may be critical. However, when a person continues to call for non-emergency issues, you can monitor the pattern and determine how to redirect that patient to appropriate care.

"A lot of patients call EMS because they're lonely, or they're calling because they're out of their meds, and if they get transported to the hospital they get their meds," said Regina Godette-Crawford, advocacy liaison with EMS Management & Consultants. "We need to assess what the patient's real issues are and stop the ambulance calls. Are they also tapped into social services? Are there behavioral issues? You'll find out that there's a common denominator in most."

It's important to identify these gaps in care and how EMS can help close them, working together with a variety of health care providers to find what's best for your patients. This may require cooperation with local social services agencies to better understand the referral system, or with a hospital to define a set of frequently encountered conditions with repeated calls, high readmission rates and less-than-optimal outcomes. Look for opportunities to improve how you collaboratively care for those patients.

Generally, your target patients are both the most expensive and least likely to pay. In most cases, improved care also means reduced overall costs.

Gather data to demonstrate the need

You will need numbers to show that a problem exists so that you can make your case to policymakers. A good place to start is your patient care reports and billing data. Look for patterns. Are the majority of your calls non-emergency concerns? Is there a clearly identifiable set of high-frequency patients that every medic in your system knows by name?

Look beyond your response times and survival rates for local patterns and gaps in care. Tracking how frequently your agency makes referrals to social service agencies is another useful metric. Measuring these referrals will enable you to report these patterns to policymakers and show the need for interventions that can make a lasting difference in patients' lives and ease the strain on the system by directing them to more appropriate providers.

"There really is more bang for your buck in doing what's best for the patient," said Godette-Crawford, "but you've got to be able to sell that, and the only way that you can sell that is to show data."

Making the case for a community paramedicine program

In order to gain support for a community paramedicine program, you'll need to communicate three things to policymakers: how the current system is not meeting the community's health care needs, the adverse effects these problems have on your agency and the overall system, and how your proposed solution will help close the gap.

Be prepared to share and explain the data you've collected. You'll also need these numbers to measure cost savings and improved patient outcomes to gauge the success of your program once it's launched.

Once you've gathered your data to demonstrate the need for a new solution, it can be helpful to use an evaluation tool like the one from the federal Health Resources and Services Administration (HRSA) to help you assess your community's needs and your agency's strengths. Many states require agencies to complete the HRSA assessment before launching a program, and whether required or not, using a widely respected set of criteria will help you make your case.

Identify community partners and begin conversations

Community paramedicine is, by definition, a collaborative effort. Your needs assessment will tell you who should be involved in the planning discussions. Meet with representatives from the health care organizations that are most likely to play a part. Generally, this will include public health and social services agencies, but you may also want to bring private hospitals, home health agencies and other practitioners to the table, depending on who else is involved in treating your target population.

Some agencies may compete. For example, home health nurses may balk at the idea of paramedics making home visits that provide similar services. Others, like hospitals looking to reduce readmissions for a particular condition, may provide limited funding for a pilot program to establish cost savings. It's important to bring these stakeholders to the table to establish the scope of your program, set goals and build consensus.

"Building a coalition and marketing it to build community engagement is critical," said Godette-Crawford, an advocate for community paramedicine programs and other EMS issues in North Carolina. "You're going to have a very fragmented system if you don't partner together, and the whole point is coming together to have a unified approach to this that would benefit everybody."

Is community paramedicine the right strategy for your agency?

There is no blueprint for success, but a comprehensive community paramedicine program must be built on a careful assessment of the health needs of your community and strategic partnerships with a spectrum of health care providers. Read Part II of this article, coming in May, to learn more about key steps to launching a community paramedicine program.

For more information about community paramedicine and other EMS issues, contact EMS Management & Consultants.

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Classification of Vasculitis in Childhood

Source: Annals of Paediatric Rheumatology
Ezgi Deniz Batu, Yelda Bilginer.
Vasculitides are heterogeneous diseases characterized by inflammation in the vessel wall. The primary systemic vasculitides in childhood are quite uncommon except for Ig A vasculitis/Henoch-Schönlein purpura and Kawasaki disease. Besides the relative frequency of vasculitis subtypes, clinical characteristics and prognosis also tend to differ between children and adults. Because of the heterogeneous nature of vasculitis, it is difficult to identify proper subgroups. The nomenclature systems (names and definitions), classification, and diagnostic criteria are used to categorize vasculitides and these have evolved and have been revised with the substantial improvement in our understanding of vasculitis pathogenesis through advanced diagnostic tests and genetic studies. In the process of revision, the eponyms were replaced by more descriptive terms, new vasculitis categories were defined, the radiologic technologies and biomarkers (such as acute phase reactants and anti-neutrophil cytoplasmic antibodies) were incorporated, and the categorization depended on vessel size, type, and etiopathogenesis. The Chapel Hill Consensus Conferences 2012, the American College of Rheumatology criteria and the Ankara 2008 criteria constitute the major attempts for categorization and classification of vasculitides. The Diagnostic and Classification Criteria for Vasculitides study is currently underway to develop and validate diagnostic criteria and to improve classification criteria. Further multicenter prospective studies will help to incorporate the classification systems more into the clinical practice. Here, we review the current nomenclature, classification system, and classification criteria of vasculitides especially in childhood.

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When overdoses go wild: Protecting the EMS provider

EMS providers face a variety of hazards while on the job. About 10 percent of all EMS provider injuries are a result of some form of violence [1]. An unknown percentage of these violent acts involve patients who have abused some form of drug or medication, and present in an altered state. This article explores violent patient behavior associated with substance abuse, as well as how to anticipate and manage these situations as to minimize their danger.

Epidemiology of patient violence
While there is are no definitive statistics specific to the incidence of substance abuse-related violence against EMS providers, a 2002 study that looked at the nature of prehospital violent behavior concluded that the perceived presence of alcohol and drug use was predictive of violent behavior, along with police presence, the presence of gang members and perceived psychiatric disorder [2].

Chemistry of emotion and behavior
How humans create, experience and regulate emotion is not well understood. Chemical neurotransmitters such as dopamine, serotonin, and GABA are known to be involved in feelings such as being happy or being sad.

How we react to certain situations is rooted within the body's autonomic nervous system. Two branches, the sympathetic and parasympathetic systems work in conjunction in each other, regulating most bodily functions on a minute-to-minute basis.

The sympathetic system is the source of the well-described "flight or fight" reflex, where the body is programmed to react to sudden stress by increasing heart rate, contractility, and respiratory rate. Blood is shunted away from the skin and GI tract and toward the heart, lung, kidneys and the broad muscle beds. The brain experiences fear, stress and anxiety. Altogether, this response to a stressor serves the body well in protecting it from harm. But this same response may be triggered by the effects of substance abuse and overdose, creating a potentially dangerous situation for patients and EMS providers alike.

Specific drugs related to violence
There are a wide variety of drugs that can be used recreationally and sometimes, illicitly to solicit a sense of pleasure and euphoria. A subset of drugs have been associated with aggressive or violent behavior. Additionally, prescription medications designed specifically to manage various psychiatric conditions have known to trigger acts of verbal and/or physical aggression, sometimes unexpectedly. Here are the drugs EMS providers commonly encounter.

Ethyl alcohol, or ethanol is the intoxicating ingredient in beer, wine and spirits. Ethanol is a central nervous system depressant, raising levels of GABA neurotransmitters that first cause a euphoric effect, followed by a general slowing of bodily functions. Excessive amounts will cause both cognitive and physical dysfunction.

Alcohol is considered to be the most common drug associated with violence. People can become angry and aggressive while under the influence of ethanol. Being verbally or physically abused by another person is twice as likely to occur if ethanol is involved [3].

What makes ethanol-driven violence more unpredictable is that there is no dose-effect relationship. It is unclear why ethanol can make one person feel happy and sleepy, but cause another person to be hostile and violent.

Ethanol is also commonly used in conjunction with other drugs. It can have an additive effect, especially with other GABA related drugs such as benzodiazepines (diazepam and midazolam, for example.)

As the name indicates, this general classification of drugs stimulates the central nervous system, specifically the sympathetic portion. A common subclass of stimulants is amphetamines. Drugs such Adderall (dextroamphetamine), used to treat attention deficit disorder, belong to this category, as well as illicit drugs like methamphetamine.

An emerging stimulant, alpha-PVP is a strong stimulant with highly addictive properties. It belongs in the same classification as "bath salts." People who have used alpha-PVP, also known as Flakka, have been known to be very physically violent, paranoid and difficult to control. The behavior is reminiscent of the older drug phenycycline, or PCP.

There is a wide regiment of prescription medications that are used to treat a variety of psychiatric conditions. Several have been linked to high incidences of aggressive or violent behavior [4]. The five most common medications in this category are listed in the following table.

Drug name

Trade Name

Used to treat



Depression, obsessive-compulsive disorder



Depression, obsessive-compulsive disorder, anxiety



Obsessive-compulsive disorder



Anxiety disorders



Anxiety disorders

Anti-smoking medication
Varenicline (Chantix) is an anti-smoking medication that works to reduce nicotine cravings by affecting the nicotinic acetylcholine receptor sites in the brain. It is 18 times more likely to be linked with violent behavior when compared to other medications [4].

Anti-malaria medication
Mefoquine (Lariam) is used to treat malaria, and has been long associated with increased violent behavior.

Anabolic steroids
Anabolic–androgenic steroids are synthetic forms of testosterone, the male sex hormone. Anabolic steroids are used by some athletes to improve physical performance. High doses of anabolic steroids have been linked to greater irritability and aggression, although the relationship is highly variable.

Cannabis withdrawal
Several studies have found a possible relationship between marijuana use and interpersonal violence [5], especially in teenagers [6]. However, there is no clear link established. People who are withdrawing from marijuana use have reported greater irritability which can lead to aggressive behavior in people with a previously known history of aggression [7].

General safety practice guidelines
EMS providers are responsible for the safety of their patients, as well as the care they receive in the field setting. The potential for violence when a patient is under the influence of a drug or medication increases the chances of danger to the caregiver. Under extreme circumstances where the rescuer's life is in danger, the patient ceases to be a patient and should be considered an assailant. Retreating from the scene in these circumstances and waiting for law enforcement assistance is appropriate.

However in most circumstances EMS and other public safety providers must quickly develop a plan to safely manage a potentially violent patient. Maintaining a heightened sense of situational awareness by all rescuers can keep the scene in control and anticipate sudden changes in the patient's behavior. The EMS provider rendering direct patient care should be covered by another member of team who can quickly assist if the patient's behavior changes during the assessment and management phase.

Consider the possibility of sudden violence if the patient is exhibiting one or more of these behaviors:

  • Sudden erratic movements
  • Tightening of facial muscles, arms, hands into fists
  • Darting eye movement
  • Fixed stare
  • Shifting balance into an aggressive posture
  • Raised voice, rapid speech
  • Rapid breathing

The initial management approach is to stay calm and listen. Allow the patient to vent while sizing up the situation for potential weapons and escape routes. Actively engage with the patient's conversation; acknowledge what the patient is saying or feeling while not injecting your own opinion into the discussion. Affirm the patient's statements ("I hear you saying…."); this may help the patient calm down some and establish a working relationship or rapport with you.

Avoid trapping patients into situations where they feel they have no options. Give options whenever possible. An example might be the choice of walking to the unit or being wheeled on the gurney. The choices should be realistic; someone with altered mental status would not have the option of refusing care.

If verbal defusing techniques are not effective, a plan must be rapidly developed to restrain the patient physically, chemically or both. No fewer than five rescuers are needed to safely restrain a patient. The team must quickly decide who will gain the patient's attention while the other embers surround the patient. Control is taken in one simultaneous motion and soft restraints applied.

Patients must be restrained in a supine position. Chemical restraint with benzodiazepines or haloperidol have been demonstrated to be safe and effective. If you suspect excited delirium consider ketamine for patient sedation.

Most importantly, EMS providers must remain in control of their own emotions in these highly stressful situations. Remaining calm reduces the chances of escalating an already bad situation into a disastrous one.


1. Centers for Disease Control and Prevention. Emergency Medical Services Workers: Injury and Illness Data. http://ift.tt/1q3uzqj. Retrieved 10 January 2016.

2. Grange J and Corbett SW. Violence against emergency medical services personnel. Pre Emerg Care 6(2): 186-90. 2002.

3. Morgan A, McAtamney A. Key issues in alcohol-related violence. Australian Institute of Criminology, December 2009.

4. Moore TJ, Glenmullen J, Furberg CD. Prescription Drugs Associated with Reports of Violence Towards Others. PLoS ONE 5(12): e15337. December 2010. http://ift.tt/1OMzP80"id=10.1371/journal.pone.0015337 retrieved 12 January 2016.

5. Moore TM, Stuart GL. A review of the literature on marijuana and interpersonal violence. Aggression and Violent Behavior 2005;10:171-192.

6. Copeland J, Rooke S, Swift W. Changes in cannabis use among young people: impact on mental health. Current Opinion in Psychiatry 2013;26(4):325-329.

7. Smith PH, Homish GG, Leonard KE, Collins RL. Marijuana withdrawal and aggression among a representative sample of U.S. marijuana users. Drug Alcohol Depend. 2013 Sep 1;132(1-2):63-8.

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When overdoses go wild: Protecting the EMS provider

Learn how to anticipate, recognize, and manage violent patient encounters to minimize danger to yourself and the patient

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SAE Standards for ambulance safety

Recommendations from SAE describe specific testing standards to minimize the risk of injury to providers and patients during an ambulance collision

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SAE Standards for ambulance safety

In 2014, the Society of Automotive Engineers released a set of four updated recommendations regarding safety standards for ambulances. The SAE is a professional organization that primarily develops "best practices" for the automotive, aerospace, and commercial vehicle industries. The four new recommendations join two existing sets of standards, and cover patient compartment restraint, litter integrity, equipment mounting systems, and both front- and side-impact safety systems.

The guidelines for ambulance safety were developed in conjunction with NIOSH and the Ambulance Manufacturers Division of the National Truck Equipment Association. Although a U.S. based group, the SAE recommendations are meant to be used globally in the development and production of ambulances and equipment.

Who determines ambulance design specifications"
The process of regulating ambulance safety varies significantly state by state. In the United States, the federal government outlines a set of specifications in a General Service Administration document called the KKK-A1822 (often referred to as "the Triple-K"). This set of specifications, developed in 1976, has gone through several updates, most of which were influenced by the evolving SAE recommendations [1].

In addition to the Triple-K, the National Fire Protection Association has also published its own ambulance design standards, called NFPA 1917. Like the Triple-K, NFPA 1917 incorporates many of the SAE recommendations for crash safety.

Finally, the Commission on Accreditation of Ambulance Services (CAAS) has a separate set of standards called GVS v1.0 that, like the Triple-K and the NFPA, is based on the SAE safety recommendations.

Although these three documents vary slightly in scope, they all set forth a number of best practices regarding ambulance design that agree with many of the current SAE recommendations. However, the adoption of any standard at all is not federally mandated.

Currently, 30 states use all or part of the Triple-K in their ambulance safety standards. Six states have no legislated ambulance design regulations at all, and the remaining states have regulations that may or may not include Triple-K or SAE specifications [2].

Although the Triple-K standards appear to be the most widely used, they are set to expire in October 2016, leaving the NFPA and CAAS standards in relative competition for adoption as the industry standard in EMS [3]. EMS leaders should research what standards, if any, are mandated in the state in which they operate.

Although state regulations play a major role in the adoption and implementation of any ambulance safety standards, other factors come into play. For example, any agency that receives equipment funding through the Assistance to Firefighters Grant is required, through the terms of the grant, to comply with published SAE standards regardless of any state regulations [4].

Individual equipment manufacturers, in an effort to be competitive and at the top of the market, design and sell products that meet many, if not all, of the SAE standards. Because of this, states without any regulation at all may still meet some or all of the suggested safety standards simply by nature of the equipment used in the ambulances operating within the state.

The actual SAE recommendations
The bulk of the SAE recommendations describe specific testing standards to be used by equipment manufacturers to ensure the safety of patients and providers during ambulance operations. These tests strongly resemble those used by civilian auto manufacturers. In fact, a main point of the 2014 SAE recommendations is to provide patient compartment occupants with the same level of crash protection as passenger vehicles.

These standards include impact testing utilizing crash-test manikins positioned in front, side and rear facing ambulance seats, as well as secured to a gurney using the recommended combination of lap and shoulder belts. The SAE outlines both static and dynamic testing procedures with the goal of providing manufacturers with clear standards for evaluating the safety of their products. The recommended testing also includes equipment restraint systems, and systems used to secure the gurney in the patient compartment.

Traditionally, patient cots were secured in the patient compartment with a standard antler and rail system that stabilizes the head of the cot with floor-mounted metal antlers, and locks the foot of the cot into a side mounted rail. Patients are typically secured to the cot using a combination of lap and shoulder belts designed, in theory, to prevent forward movement of the patient during a collision.

A NIOSH study conducted during the development of the SAE standards showed that during a front-impact collision at a speed of 30 mph, the antler and rail system allowed for approximately 30 inches of forward movement of the patient cot and patient. The force of a front impact at 30 mph was significant enough to cause the gurney to break free of the antlers, sending a restrained patient forward into the space often occupied by the captain's chair or jump seat in the patient compartment [5].

The 2014 SAE standard J3027 requires that the patient cot be configured in such a fashion that forward movement of the cot and patient during a front-end collision is limited to 14 inches, rather than the previous 30 inches [6]. In July of 2015, the GSA adopted Change Notice 8, which added this requirement for cot and patient security (SAE J3027) into the KKK standard. This means that traditional antler and rail systems will no longer be compliant, should states adopt this aspect of the KKK standard.

The additional SAE standards also cover equipment-mounting systems and provide requirements for interior surface delethalization, making impact surfaces less likely to injure the patient or health care provider in the event of a collision. Equipment mounting systems in SAE compliant ambulances would need to show stability of standard equipment like oxygen cylinders and cardiac monitors during front, side, and rollover collision conditions.

Surface delethalization also involves replacing current hard impact surfaces with padded materials, or materials that collapse upon significant impact, in order to reduce injuries to providers during collisions.

Research and development continues in the area of provider restraint in the patient compartment. Identifying and implementing an effective provider restraint system is a challenging task, as the restraint must simultaneously allow movement during patient care while providing security in the event of a collision.

A variety of provider restraint systems exist, from bench seats that slide and swivel to retractable harness restraints that allow full movement around the patient compartment. While the SAE does not currently specify a specific restraint system, it does provide recommendations for the maximum allowable movement of a restrained provider in the patient compartment during an ambulance collision.

Another interesting inclusion in the SAE standards is an evaluation of provider body size and shape. The NIOSH EMS Anthropometry Study evaluated 680 human subjects in an attempt to identify common body sizes and shapes so that ergonomically efficient standards could be developed for ambulance construction and restraint systems [7].

This project is set to end in 2016, and will likely affect ongoing updates to the SAE standards. It is worth noting that the Triple-K, NFPA, and CAAS standards are all based on a provider weight of between 171 and 175 pounds, which may not accurately reflect the average provider size [3].

Improve safety habits
It is widely recognized that ambulance crashes are a significant problem. Between 1992 and 2011, an estimated 4,500 vehicle crashes involving an ambulance occurred each year. Of those, 34 percent involved injuries, and an average of 29 fatal crashes occurred each year [8].

The 2014 SAE standards, if adopted, will take years to fully implement as existing apparatus and equipment are replaced with new, compliant products. Until such time as ambulances become compliant with the new standards, providers should continue to practice safe habits when driving or working in an ambulance.

During patient care and transport, providers should be restrained by lap-shoulder belts when in front and rear facing seats, and lap belts when in side facing seats. Any additional restraint systems installed in an individual ambulance, such as five point harnesses, should be utilized whenever possible.

Patients should be secured to the patient cot with all available straps. Providers should be familiar with the manufacturer recommendations regarding proper fit of patient cot straps or seatbelts to ensure the patient is as protected as well as possible in the event of a collision.

Given the propensity of antler-rail mounted gurneys to move significantly forward during a collision, providers should avoid sitting directly behind the head of the patient cot whenever possible.

Heavy bags and equipment should be routinely secured during ambulance operations. Oxygen cylinders, cardiac monitors, and larger suction units should all be firmly stabilized to prevent movement during a collision or rollover. Loose equipment unsecured in the patient compartment, even small items, should be avoided. Cabinets and bins should either be securely closed or the items inside them otherwise confined to the inside of the cabinet space.

Finally, there is no substitute for careful, aware, defensive driving when it comes to maximizing the safety of patients and providers, as well as the drivers and occupants of other vehicles. An Emergency Vehicle Operation Course provides necessary training in safe ambulance driving.

It is critical to avoid distractions while driving such as eating, drinking, radio usage, GPS navigation and smartphone communication. Communication between the driver and the provider in the patient compartment regarding bumps, sharp turns, and other road conditions is of high importance.

It remains the individual responsibility of each provider to always use seatbelts and restraints in the manner in which they were intended, to minimize the potential for injury in the event of a collision. As with any other aspect of EMS work, personal safety for the provider must be the first priority during ambulance operations.


1. Vogt F (1976). "Equipment: Federal Specification, Ambulance KKK-A-1822". Emerg Med Serv 5 (3): 58, 60–4. PMID 1028572.

2. "Executive Summary, Understanding the SAE Conversation." Executive Summary. Ferno. Web. 13 Mar. 2016.

3. "AEV Briefing on Current Status of Ambulance Standards Projects." NAEMT.org. Web. 13 Mar. 2016.

4. "Assistance Firefighter Grant." Fema.gov. Web. 13 Mar. 2016.

5. Castillo, Dawn, Thomas Bobick, and Stephanie Pratt. "New Research and Findings from the NIOSH Division of Safety Research." ASSE Professional Development Conference and Exposition. American Society of Safety Engineers, 2013.

6. "Ambulance Patient Compartment Seating Integrity and Occupant Restraint." J3026. Web. 13 Mar. 2016.

7. "EMERGENCY MEDICAL SERVICES WORKERS." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 2014. Web. 13 Mar. 2016.

8. "NHTSA Traffic Safety Facts 2011." National Highway Traffic Safety Administration. NHTSA.gov. Web. 13 Mar. 2016

9. "About SAE International." SAE Mission and Vision Statements. Web. 15 Mar. 2016.

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Editorial board members

Publication date: January–March 2016
Source:Mutation Research/Reviews in Mutation Research, Volume 767

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NH Firefighter Killed By Falling Tree

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NH Firefighter Killed By Falling Tree

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EMT - Safety Technician - On-Site Health & Safety

Have you enjoyed working as an EMT...but wish your role involved more skills, better wages, and a viable opportunity for career growth" We're On-Site Health & Safety...an established, twenty-year, multi-state Health & Safety Company, looking for qualified candidates to join our growing team across the country in challenging, non-traditional injury management settings. OSHS Health & Safety ...

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Fort Smith EMS Medic - Fort Smith EMS

Paramedic working 12 hour shifts, 3 days week 1, 4 days week 2, 84 hour schedule. Providing emergent care for the citizens of Fort Smith.

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Myocardial triggers involved in remote ischemic preconditioning activation

New Findings

What is the central question of this study?

Ischemia/reperfusion of peripheral tissues protects the heart from subsequent myocardial ischemia/reperfusion injury, a phenomenon referred to as remote ischemic preconditioning (rIPC). This study evaluated the possible myocardial triggers of rIPC.

What is the main finding and its importance?

rIPC reduces infarct size through a vagal pathway and a mechanism involving Akt and eNOS phosphorylation, opening of mitochondrial K+ATP channels and increasing of mitochondrial H2O2 production. All these phenomena occur prior to the myocardial ischemia, therefore they could act as "triggers" of rIPC.

Aims: It has been proposed that remote ischemic preconditioning (rIPC) activates a parasympathetic neural pathway. However, the myocardial rIPC intracellular mechanism remains unclear. Here we characterized some of the intracellular signals participating as rIPC triggers. Methods and Results: Isolated rat hearts were subjected to 30 minutes of global ischemia and 120 minutes of reperfusion (Non-rIPC). In a second group, before the isolation of the heart, a rIPC protocol (3 cycles of hindlimb ischemia/reperfusion) was performed. The infarct size was measured with tetrazolium staining. Akt and eNOS expression/phosphorylation, and mitochondrial H2O2 production were evaluated at the end of rIPC protocol, before myocardial ischemia/reperfusion. rIPC significantly decreased the infarct size and induced Akt and eNOS phosphorylation. The protective effect on infarct size was abolished by cervical vagal section (CVS), L-NAME (NO synthesis inhibitor) and 5-HD (mK+ATP channels blocker). Mitochondrial production of H2O2 was increased by rIPC while it was abolished by CVS, L-NAME and 5-HD. Conclusions: rIPC activates a parasympathetic vagal pathway and a mechanism involving the Akt and eNOS phosphorylation, the opening of mK+ATP, and the release of H2O2 by the mitochondria. These entire phenomena occur prior to the myocardial ischemia, which could act as triggers of rIPC.

This article is protected by copyright. All rights reserved

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The insulinotropic effect of exogenous GLP-1 is not affected by acute vagotomy in anaesthetized pigs

New Findings

What is the central question of this study?

We investigated whether intestinal vagal afferents are necessary for the insulinotropic effect of GLP-1 infused GLP-1 into a mesenteric artery or a peripheral vein before and after acute truncal vagotomy.

What is the main finding and its importance?

We found no effect of truncal vagotomy on the insulinotropic effect of exogenous GLP-1 and speculate that high circulating levels of GLP-1 after intravenous infusion may have overshadowed any neural signalling component. We propose that further investigations in to the possible vagal afferent signalling of GLP-1 would best be pursued using enteral stimuli to provide high subepithelial levels of endogenous GLP-1.

Glucagon-like peptide 1(GLP-1) is secreted from the gut in response to luminal stimuli and stimulates insulin secretion glucose dependently. Due to rapid enzymatic degradation of GLP-1 by dipeptidyl peptidase-4 (DPP-4), a signalling pathway involving activation of intestinal vagal afferents has been proposed. We conducted two series of experiments in α-chloralose-anaesthetized pigs. Protocol I: pigs (n = 14) were allocated for either intravenous(iv) or intra-arterial(mesenteric) GLP-1 infusions (1 and 2 pmol kg−1 min−1, 30 min) while maintaining permissive glucose levels at 6 mmol l−1 by iv glucose infusion. GLP-1 infusions were repeated after acute truncal vagotomy. Protocol II: pigs (n = 27) were allocated into 6 groups. GLP-1 was infused intravenously or intra-arterially(mesenteric) for 1 h at 3 pmol kg−1 min−1or 30 pmol kg−1 min−1. During steady state (21 min into the GLP-1 infusion), glucose (0.2 g/kg, iv) was administered over 9 min to stimulate beta cell secretion. 30 min after the glucose infusion GLP-1 infusions were discontinued. Following a washout period the vagal trunks were severed in 4/6 groups (vagal trunks were left intact in 2/6 groups), whereupon all infusions were repeated. We found no effect of vagotomy on insulin or glucagon secretion during administration of exogenous GLP-1 in any experiment. We speculate that the effect of exogenous GLP-1 overshadowed any effect occurring via the vagus. Within dosage groups, total GLP-1 levels were similar but intact GLP-1 levels were much lower when infused via the mesenteric artery due to extensive degradation of GLP-1 in the splanchnic bed. This demonstrates the effectiveness with which intestinal capillary DPP-4 protects the systemic circulation from intact GLP-1, consistent with a local role for GLP-1 involving activation of vagal pathways.

This article is protected by copyright. All rights reserved

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A proportional assist ventilator to experimentally unload respiratory muscles during exercise in humans

New Findings

What is the central question of this study?

Can a modern proportional assist ventilator (PAV) function to sufficiently unload the respiratory muscles during exercise?

What is the main finding and its importance?

A PAV can be constructed with contemporary hardware and software and be used during all exercise intensities to unload the respiratory muscles by up to 70%. Previously, PAVs have allowed researchers to address many fundamental physiological problems in clinical and healthy populations, but those versions are no longer functional or available. We describe the creation of a PAV that permits researchers to use it as an experimental tool.

Manipulating the normally occurring work of breathing (WOB) during exercise can provide insights into whole-body regulatory mechanisms in clinical and healthy subjects. One method to reduce the WOB utilizes a proportional assist ventilator (PAV). Suitable commercially available units are not capable for used during heavy exercise. This investigation was undertaken in order to create a PAV and assess the degree to which the WOB could be reduced during exercise. A PAV works by creating a positive mouth pressure (Pm) during inspiration which consequently reduces the WOB. Spontaneous breathing patterns can be maintained and the amplitude of Pm is calculated using the equation of motion and predetermined proportionality constants. We generated positive Pm using a breathing apparatus consisting of rigid tubing, solenoid valves to control airflow direction and a proportional valve connected to compressed gas. Healthy male and female subjects were able to successfully use the PAV while performing cycle exercise over a range of intensities (50–100% maximum workload) for different durations (30 s to 20 min) and different protocols (constant vs. progressive workload). Inspiratory WOB was reduced up to 90%, while total WOB was be reduced 70%. The greatest reduction in WOB (50–75%) occurred during submaximal exercise, but at maximal ventilations (>180 l min−1) a 50% reduction was still possible. The calculated change in WOB and subsequent reduction in respiratory muscle oxygen consumption resulted in equivalent reductions in whole-body oxygen consumption. With adequate familiarization and practice, our PAV can consistently reduce the WOB across a range of exercise intensities.

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Thinking of VACTERL-H? Rule out fanconi anemia according to PHENOS

VACTERL-H association includes three of eight features: vertebral anomalies, anal atresia, congenital heart disease, tracheo-esophageal fistula, esophageal atresia, renal, limb anomalies, and hydrocephalus. The VACTERL-H phenotype among cases with FA is considered to be about 5%; the frequency of FA among patients with VACTERL-H is unknown. We examined 54 patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome Cohort for features of VACTERL-H, including imaging studies (radiology and ultrasound). Eighteen of the fifty-four patients had three or more VACTERL-H features. The presence of VACTERL-H association in 33% of those with FA is much higher than the previous estimate of 5% (P < 0.0001). We created the acronym PHENOS (Pigmentation, small Head, small Eyes, central Nervous system (not hydrocephalus), Otology, and Short stature) which includes all major phenotypic features of FA that are not in VACTERL-H; these findings were more frequent in the patients with FA who had VACTERL-H. Identification of any components of the VACTERL-H association should lead to imaging studies, and to consideration of the diagnosis of FA, particularly if the patient has radial ray and renal anomalies, as well as many features of PHENOS. There was no association of the presence or absence of VACTERL-H with development of cancer, stem cell transplant, or survival. Early diagnosis will lead to genetic counseling and early surveillance and management of complications of FA. © 2016 Wiley Periodicals, Inc.

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Physiological adaptations to chronic stress in healthy humans – why might the sexes have evolved different energy utilisation strategies?

Key Points

  • The human stress response activates the autonomic nervous system and endocrine systems to increase performance during environmental challenges.
  • This response is usually beneficial, improving the chance of overcoming environmental challenges, but costs resources such as energy.
  • Humans and other animals are known to adapt their responses to acute stress when they are stimulated chronically, presumably to optimise resource utilisation. Characterisation of these adaptations has been limited.
  • Using advanced imaging techniques, we show that cardiovascular and endocrine physiology, reflective of energy utilisation during acute stress, and energy storage (fat) differ between the sexes when they are exposed to chronic stress.
  • We examine possible evolutionary explanations for these differences, related to energy use, and point out how these physiological differences could underpin known disparities between the sexes in their risk of important cardiometabolic disorders such as obesity and cardiovascular disease.


Obesity and associated diseases, such as cardiovascular disease, are the dominant human health problems in the modern era. Humans develop these conditions partly because they consume excess energy and exercise too little. Stress might be one of the factors contributing to these disease-promoting behaviours. We postulate that sex-specific primordial energy optimisation strategies exist, which developed to help cope with chronic stress but have become maladaptive in modern societies, worsening health. To demonstrate the existence of these energy optimisation strategies, we recruited 88 healthy adults with varying adiposity and chronic stress exposure. Cardiovascular physiology at rest and during acute stress (Montreal Imaging Stress Task), and body fat distribution were measured using advanced magnetic resonance imaging methods, together with endocrine function, cardiovascular energy use and cognitive performance. Potential confounders such as lifestyle, social class and employment were accounted for. We found that women exposed to chronic stress had lower adiposity, greater acute stress cardiovascular responses and better cognitive performance. Conversely, chronic stress-exposed men had greater adiposity and lower cardiovascular responses to acute stress. These results provide initial support for our hypothesis that differing sex-specific energy conservation strategies exist. We propose that these strategies have initially evolved to benefit humans but are now maladaptive and increase the risk of disorders such as obesity, especially in men exposed to chronic stress.

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De novo exonic deletion of KDM6A in a Chinese girl with Kabuki syndrome: A case report and brief literature review

Kabuki syndrome (KS) is a rare condition with multiple congenital anomalies and mental retardation. Exonic deletions, disrupting the lysine (K)-specific demethylase 6A (KDM6A) gene have been demonstrated as rare cause of KS. Here, we report a de novo 227-kb deletion in chromosome Xp11.3 of a 7-year-old Chinese girl with KS. Besides the symptoms of KS, the patient also presented with skin allergic manifestations, which were considered to be a new, rare feature of the phenotypic spectrum. The deletion includes the upstream region and exons 1–2 of KDM6A and potentially causes haploinsuffiency of the gene. We also discuss the mutation spectrum of KDM6A and clinical variability of patients with KDM6A deletion through a literature review. © 2016 Wiley Periodicals, Inc.

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Insulin resistance: A new consequence of altered carotid body chemoreflex?


Metabolic diseases affect millions of individuals across the world and represent a group of chronic diseases of very high prevalence and relatively low therapeutic success, making them suitable candidates for pathophysiological studies. The sympathetic nervous system (SNS) contributes to the regulation of energy balance and energy expenditure both in physiological and pathological states. For instance, drugs that stimulate sympathetic activity decrease food intake, increase resting metabolic rate and increase the thermogenic response to food, while pharmacological blockade of the SNS has opposite effects. Likewise, dysmetabolic features like, insulin resistance, dyslipidemia and obesity are characterized by a basal overactivation of the SNS. Recently, a new line of research linking the SNS to metabolic diseases has emerged with the report that the carotid bodies (CBs) are involved in the development of insulin resistance. The CBs are arterial chemoreceptors that classically sense changes in arterial blood O2, CO2, and pH levels and whose activity is known to be increased in rodent models of insulin resistance. We have shown that selective bilateral resection of the nerve of the CB, the carotid sinus nerve (CSN), totally prevents diet-induced insulin resistance, hyperglycemia, dyslipidemia, hypertension as well as sympathoadrenal overactivity. These results imply that the beneficial effects of CSN resection on insulin action and glucoregulation, are modulated by target-related efferent sympathetic nerves through a reflex that is initiated in the CBs. It also highlights modulation of CB activity as a putative future therapeutic intervention for metabolic diseases.

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Identification of a novel insertion mutation in FGFR3 that causes thanatophoric dysplasia type 1

Thanatophoric dysplasia is a type of short-limbed neonatal dwarfism that is usually lethal in the perinatal period. It is characterized by short limbs, a narrow, bell-shaped thorax, macrocephaly with a prominent forehead, and flattened vertebral bodies. These malformations result from autosomal dominant mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. In this report, we describe a novel FGFR3 insertion mutation in a fetus with shortened limbs, curved femurs, and a narrow thorax. The diagnosis of thanatophoric dysplasia type 1 was suspected clinically, and FGFR3 sequencing showed a c.742_743insTGT variant, which predicts p.R248delinsLC. In vivo studies in zebrafish demonstrated that this mutation resulted in the overexpression of zebrafish Fgfr3, leading to the over-activation of downstream signaling and dorsalized embryos. To date, no insertions or deletions in FGFR3 have been reported to cause thanatophoric dysplasia types 1 or 2; therefore, this represents the first report to describe such a mutation. © 2016 Wiley Periodicals, Inc.

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Cellular plasticity in the adult liver and stomach


Adult tissues maintain function and architecture through robust homeostatic mechanisms mediated by self-renewing cells capable of generating all resident cell types. However, severe injury can challenge the regeneration potential of such a stem/progenitor compartment. Indeed, upon injury adult tissues can exhibit massive cellular plasticity in order to achieve proper tissue regeneration, circumventing an impaired stem/progenitor compartment. Several examples of such plasticity have been reported in both rapidly and slowly self-renewing organs and follow conserved mechanisms. Upon loss of the cellular compartment responsible for maintaining homeostasis, quiescent or slowly-proliferating stem/progenitor cells can acquire high proliferation potential and turn into active stem cells, or, alternatively, mature cells can de-differentiate into stem-like cells or re-enter the cell cycle to compensate for the tissue loss. This extensive cellular plasticity acts as a key mechanism to respond to multiple stimuli in a context-dependent manner, enabling tissue regeneration in a robust fashion. In this review cellular plasticity in the adult liver and stomach will be examined, highlighting the diverse cell populations capable of repairing the damaged tissue.

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TP63 mutation in a patient with acro-dermo-ungual-lacrimal-tooth syndrome: Additional evidence of molecular overlap of the ADULT and EEC syndromes

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Timely exercise for controlling glucose and oxidative stress. Reply to Chacko E. [letter]

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On the mechanism of biological activation by tritium


Publication date: June 2016
Source:Journal of Environmental Radioactivity, Volume 157
Author(s): T.V. Rozhko, G.A. Badun, I.A. Razzhivina, O.A. Guseynov, V.E. Guseynova, N.S. Kudryasheva
The mechanism of biological activation by beta-emitting radionuclide tritium was studied. Luminous marine bacteria were used as a bioassay to monitor the biological effect of tritium with luminescence intensity as the physiological parameter tested. Two different types of tritium sources were used: HTO molecules distributed regularly in the surrounding aqueous medium, and a solid source with tritium atoms fixed on its surface (tritium-labeled films, 0.11, 0.28, 0.91, and 2.36 MBq/cm2). When using the tritium-labeled films, tritium penetration into the cells was prevented. The both types of tritium sources revealed similar changes in the bacterial luminescence kinetics: a delay period followed by bioluminescence activation. No monotonic dependences of bioluminescence activation efficiency on specific radioactivities of the films were found. A 15-day exposure to tritiated water (100 MBq/L) did not reveal mutations in bacterial DNA. The results obtained give preference to a "non-genomic" mechanism of bioluminescence activation by tritium. An activation of the intracellular bioluminescence process develops without penetration of tritium atoms into the cells and can be caused by intensification of trans-membrane cellular processes stimulated by ionization and radiolysis of aqueous media.

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Quality Improvement Analyst, 911 - Allina Health

*Responsibilities Identify patient care opportunities for improvement. Develop tracking tools and measures for improvement and report to AHEMS Leadership on regular basis. Assist in determining the parameters needed to be measured for AHEMS care goals Audit and abstract patient care records to identify trends and to measure progress and improvement opportunities Work with physicians and managers to ...

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After four decades, a Texas EMT is still eager to answer calls

In 1990, EMT Richard Ponikiewski already had 13 years in EMS, and was about to answer the most difficult call of his career.

"It was around 2 a.m.," the 57-year-old Irving, Texas native recalls. "We were sent to an apartment complex for an unresponsive four-year-old. The mother had just gotten home and called 9-1-1 when she wasn't able to wake up her son.

"When we got to the scene, a firefighter came running through the house with the child in his arms. That little boy was in bad, bad shape.

"The mother's boyfriend had been watching the kid and his two-year-old brother. They'd been taking a bath and had splashed some water on the floor. When the boyfriend saw that, he beat the older boy unconscious for not knowing better.

"I wish I could tell you what we did en route, or what happened when we got to the hospital, but I don't remember any of it. All I can say is the boy died."

But there's more to the story. The boundary between our jobs and personal lives isn't always as well-defined as we think.

"After the call, I was sitting on the bumper of the truck at the hospital waiting for my partner to finish up. He came out of the ER and asked me if was okay. I said, 'Yeah, why?' Then he said, 'Do you know why we're here?' I couldn't remember. I still can't recall anything that happened from the time we left the scene until we walked out of the ER."

Ponikiewski's patient had been the same age as his son, Dustin, with almost identical blonde hair and blue eyes. To Richard, the two boys had been one.

"I came to understand that I'd blocked out most of the memories of that call because it was just so horrible to see someone like my son lying there, all beat up.

"Whenever I do peds now, I look at them and think how helpless they are; how much they depend on their parents. Then I see mom and dad and wonder what they've been doing to care for their kids. I mean, why shouldn't a child with a fever get Tylenol? Almost 99 percent of the time, they don't."

Ponikiewski knows it isn't his place to lecture parents about childcare. "The customer is always right – isn't that the way it's supposed to be? Besides, my folks always taught me not to say anything I'd regret later."

EMS is where you find it
Discretion wasn't the only EMS-applicable advice Ponikiewski got as a youngster. In high school, after injuries interfered with his efforts to play both football and baseball, one of the athletic trainers introduced him to emergent care.

"He showed me not only how to treat injuries, but how to help prevent them, by taping ankles and things like that," Ponikiewski says. "I started to think, 'Hey, this isn't a bad gig.'

"The trainer tried to get me into a local college where I could learn to do his job. I didn't get accepted, but I figured I could still find a way to do something medical."

Right after graduation in 1977, Ponikiewski got certified as an Emergency Care Attendant and went to work for Dallas-based American Ambulance.

"They were a mom-and-pop service with three or four trucks that did mostly transfers and stand-bys," the 39-year EMS veteran says. "I was their jack-of-all trades. Sometimes I'd be in the field and sometimes I'd dispatch. If they needed a spot filled, I'd do it."

Shortly after he became an EMT in 1978, Ponikiewski had two memorable calls.

"The first one was a routine transport from a nursing home to the hospital," he says. "The patient was the proverbial little old lady in her '90s, all contracted.

"I was assessing her on the way when she stopped breathing. There was no pulse, so I started CPR.

"At the hospital, everyone was working on her, trying to get IVs and get her intubated, when this doctor comes over and says, 'Why are you doing CPR on a dead lady? She's stiff, leave her alone.' He didn't believe she'd been breathing just a few minutes earlier. That really made me feel bad.

"The other call was an elderly female we were transporting by airplane to her home in Tennessee, where she could die with dignity.

"About halfway there, the pilot asked, 'Do you smell that?' I thought he was joking until I got a whiff of gasoline.

'That's our fuel,' he said. 'We have a leak. We need to find an airport.'

"We landed pretty quickly in Hope, Arkansas, which happens to be the birthplace of Bill Clinton. It was a Sunday, so it took a little while to find a mechanic. We carried the patient into the local FBO (fixed-base operator) and waited about three hours while they fixed the fuel line. We eventually got to Winchester, Tennessee without any other trouble."

Moving on from mom-and-pop
When another agency took over American Ambulance's district in 1986, Richard went to work for MedStar Mobile Healthcare, serving a population of 800,000 in Fort Worth and 13 neighboring cities. He's been there ever since.

From 1993 until 2013, Ponikiewski partnered with Ronnie Ferguson, a paramedic who became a good friend and mentor.

"We got to do something you hardly ever hear about in EMS," says Ponikiewski. "We delivered the daughter and granddaughter of one of our patients.

"Ronnie was always trying to get me to better myself; to become a medic like him. He'd quiz me on calls: What should we do next? Why?

"Unfortunately, Ronnie died of colon cancer in 2013. I try to pass along to students some of what he used to say to me: Don't be so gung-ho about doing everything at once. Start with the basics. Understand what's going on before you start pushing drugs."

Sounds like Ronnie would be proud.

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Evaluation of the risk factors associated with rectal neuroendocrine tumors: a big data analytic study from a health screening center



Rectal neuroendocrine tumor (NET) is the most common NET in Asia. The risk factors associated with rectal NETs are unclear because of the overall low incidence rate of these tumors and the associated difficulty in conducting large epidemiological studies on rare cases. The aim of this study was to exploit the benefits of big data analytics to assess the risk factors associated with rectal NET.


A retrospective case–control study was conducted, including 102 patients with histologically confirmed rectal NETs and 52,583 healthy controls who underwent screening colonoscopy at the Center for Health Promotion of the Samsung Medical Center in Korea between January 2002 and December 2012. Information on different risk factors was collected and logistic regression analysis applied to identify predictive factors.


Four factors were significantly associated with rectal NET: higher levels of cholesterol [odds ratio (OR) = 1.007, 95 % confidence interval (CI), 1.001–1.013, p = 0.016] and ferritin (OR = 1.502, 95 % CI, 1.167–1.935, p = 0.002), presence of metabolic syndrome (OR = 1.768, 95 % CI, 1.071–2.918, p = 0.026), and family history of cancer among first-degree relatives (OR = 1.664, 95 % CI, 1.019–2.718, p = 0.042).


The findings of our study demonstrate the benefits of using big data analytics for research and clinical risk factor studies. Specifically, in this study, this analytical method was applied to identify higher levels of serum cholesterol and ferritin, metabolic syndrome, and family history of cancer as factors that may explain the increasing incidence and prevalence of rectal NET.

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Ipragliflozin, a sodium–glucose cotransporter 2 inhibitor, ameliorates the development of liver fibrosis in diabetic Otsuka Long–Evans Tokushima fatty rats



It is widely understood that insulin resistance (IR) critically correlates with the development of liver fibrosis in several types of chronic liver injuries. Several experiments have proved that anti-IR treatment can alleviate liver fibrosis. Sodium–glucose cotransporter 2 (SGLT2) inhibitors comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules, improving IR. The aim of this study was to elucidate the effect of an SGLT2 inhibitor on the development of liver fibrosis using obese diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and their littermate nondiabetic Long–Evans Tokushima Otsuka (LETO) rats.


Male OLETF and LETO rats were intraperitoneally injected with porcine serum twice a week for 12 weeks to augment liver fibrogenesis. Different concentrations of ipragliflozin (3 and 6 mg/kg) were orally administered during the experimental period. Serological and histological data were examined at the end of the experimental period. The direct effect of ipragliflozin on the proliferation of a human hepatic stellate cell (HSC) line, LX-2, was also evaluated in vitro.


OLETF rats, but not LETO rats, received 12 weeks of porcine serum injection to induce severe fibrosis. Treatment with ipragliflozin markedly attenuated the development of liver fibrosis and expression of hepatic fibrosis markers, such as alpha smooth muscle actin, collagen 1A1, and transforming growth factor beta (TGF-β), and improved IR in a dose-dependent manner in OLETF rats. In contrast, the proliferation of LX-2 in vitro was not affected, suggesting that ipragliflozin had no significant direct effect on the proliferation of HSCs.


In conclusion, our dataset suggests that an SGLT2 inhibitor could alleviate the development of liver fibrosis by improving IR in naturally diabetic rats. This may provide the basis for creating new therapeutic strategies for chronic liver injuries with IR.

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