bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Aging on Influenza Virus Infection Dynamics
Authors: Hernandez-Vargas Esteban A. , Wilk Esther , Canini Laetitia , Toapanta Franklin R. , Binder Sebastian C. , Uvarovskii Alexey , Ross Ted M. , Guzmán Carlos A. , Perelson Alan S. , Meyer-Hermann Michael
Published: January 2014

The consequences of influenza virus infection are generally more severe in individuals over 65 years of age (the elderly). Immunosenescence enhances the susceptibility to viral infections and renders vaccination less effective. Understanding age-related changes in the immune system is crucial in order to design prophylactic and immunomodulatory strategies to reduce morbidity and mortality in the elderly. Here, we propose different mathematical models to provide a quantitative understanding of the immune strategies in the course of influenza virus infection using experimental data from young and aged mice. Simulation results suggested a central role of CD8
+
T cells for adequate viral clearance kinetics in young and aged mice. Adding the removal of infected cells by natural killer cells did not improve the model fit in either young or aged animals. We separately examined the infection-resistant state of cells promoted by the cytokines alpha/beta interferon (IFN-α/β), IFN-γ, and tumor necrosis factor alpha (TNF-α). The combination of activated CD8
+
T cells with any of the cytokines provided the best fits in young and aged animals. During the first 3 days after infection, the basic reproductive number for aged mice was 1.5-fold lower than that for young mice (
P
< 0.05).

IMPORTANCE
The fits of our models to the experimental data suggest that the increased levels of IFN-α/β, IFN-γ, and TNF-α (the “inflammaging” state) promote slower viral growth in aged mice, which consequently limits the stimulation of immune cells and contributes to the reported impaired responses in the elderly. A quantitative understanding of influenza virus pathogenesis and its shift in the elderly is the key contribution of this work.
Lichen scrofulosorum
Authors: Joshi Harshal S , Zacharia Asha , Warrier Anup
Published: January 2014

Tuberculosis is a common disease. The cutaneous form of tuberculosis known as tuberculid is an uncommon disease and is easily misdiagnosed. Lichen scrofulosorum is a rare form of tuberculid seen in children and young adults with or without other manifestations of tuberculosis. We report a case of a young adult with lichen scrofulosorum along with tuberculous lymphadenitis. The skin lesions responded promptly to antitubercular therapy with complete clearance of the lesions. Identification of the skin manifestation was especially important in this case because the lymph node biopsy was inconclusive, with tissue culture proving the diagnosis only after 4 weeks.
Prolonged spontaneous normocalcaemia in pseudohypoparathyroidism from resorption of soft tissue calcium deposits: a cautionary tale
Authors: Carter Erin E , Kline Gregory
Published: January 2014

A 42-year-old man diagnosed with pseudohypoparathyroidism and Albright's hereditary osteodystrophy as an infant was lost to follow-up and remained, unmonitored, on calcitriol and calcium for over 20 years. He presented after having an ST-elevation myocardial infarction. In addition to coronary artery calcifications, he was found to have diffuse subcutaneous and joint calcifications. His calcium, phosphate and parathyroid hormone (PTH) levels were normal, and given the lack of prior documentation in the diagnosis he was instructed to discontinue calcitriol and calcium until further investigations were completed. Despite stopping the medication, his serum calcium remained normal for over 1 year. It was not until 18 months later, when his soft tissue calcium stores were depleted, that he finally developed symptomatic hypocalcaemia and an elevated PTH. This case not only emphasises the importance of long-term follow-up for patients with pseudohypoparathyroidism, but also highlights the potential complications of long-term, unmonitored, calcitriol use.
The effect of community-acquired bacteraemia on return to workforce, risk of sick leave, permanent disability pension and death: a Danish population-based cohort study
Authors: Dalager-Pedersen Michael , Koch Kristoffer , Wernich Thomsen Reimar , Schønheyder Henrik Carl , Nielsen Henrik
Published: January 2014

Objectives

Little is known about the prognosis of community-acquired bacteraemia (CAB) in workforce adults. We assessed return to workforce, risk for sick leave, disability pension and mortality within 1 year after CAB in workforce adults compared with blood culture-negative controls and population controls.

Design

Population-based cohort study.

Setting

North Denmark, 1996–2011.

Participants

We used population-based healthcare registries to identify all patients aged 20–58 years who had first-time blood cultures obtained within 48 h of medical hospital admission, and who were part of the workforce (450 bacteraemia exposed patients and 6936 culture-negative control patients). For each bacteraemia patient, we included up to 10 matched population controls.

Primary and secondary outcome measures

Return to workforce, risk of sick leave, permanent disability pension and mortality within 1 year after bacteraemia. Regression analyses were used to compute adjusted relative risks (RRs) with 95% CIs.

Results

One year after admission, 78% of patients with CAB, 85.7% of culture-negative controls and 96.8% of population controls were alive and in the workforce, and free from sick leave or disability pension. Compared with culture-negative controls, bacteraemia was associated with an increased risk for long-term sick leave (4-week duration, 40.2% vs 23.9%, adjusted RR, 1.51; CI 1.34 to 1.70) and an increased risk for mortality (30-day mortality, 4% vs 1.4%, adjusted RR, 2.34, CI 1.22 to 4.50; 1-year mortality, 8% vs 3.9%, adjusted RR, 1.73; CI 1.18 to 2.55). Bacteraemia patients had a risk for disability pension similar to culture-negative controls (2.7% vs 2.6%, adjusted RR, 0.99, CI 0.48 to 2.02) but greater than population controls (adjusted RR, 5.20; 95% CI 2.16 to 12.50).

Conclusions

CAB is associated with long duration of sick leave and considerable mortality in working-age adults when compared with blood culture-negative controls, and an increased 1-year risk for disability pension when compared with population controls.
For debate: the Operational Patient Care Pathway
Authors: Bricknell Martin
Published: January 2014

This paper introduces the Operational Patient Care Pathway which is a unified approach for clinical care to all operational patients arising from the Defence population at risk (PAR) exposed to the ‘all-hazards environment’ while deployed on military operations. It comprises three organisational models: the Healthcare Cycle, the Chain of Care and the Operational Patient Care Pathway. It is supported by a number key definitions including: the ‘All-Hazards Environment’, the Defence PAR, and the seven Capabilities of Operational Healthcare. Key new clinical concepts include: Tactical Field Care, Care under Fire, Enhanced Field Care, Prolonged Field Care, Progressive Resuscitation and Enhanced Diagnostics. The Operational Patient Care Pathway has been introduced to embed the medical lessons from the last decade of military operations into concepts and doctrine for the Defence Medical Services of the future. Readers of this journal are encouraged to debate the Operational Patient Care Pathway paper in order to enable a final version to be published in the next revision of Joint Medical Doctrine.
Analysis of early angiographic outcome using unique large diameter coils in comparison with standard coils in the embolization of cerebral aneurysms: a retrospective review
Authors: Mascitelli Justin R , Patel Aman B , Polykarpou Maritsa F , Patel Aanand A , Moyle Henry
Published: January 2014

Background

The initial experience with the large diameter Penumbra Coil 400 (PC400) system has been positive regarding safety, efficacy, improved packing density and cost effectiveness, but follow-up data are limited.

Methods

This is a single-center retrospective review of 76 aneurysms treated with PC400 coils compared with 301 aneurysms treated with a variety of different bare platinum and bioactively coated coils. Atypical and giant aneurysms were excluded as well as those that had undergone previous treatment. Occlusion classification was determined immediately after the procedure and at short-term follow-up.

Results

Compared with controls, in the PC400 group fewer coils were used (3.53 vs 5.44, p<0.05), procedure time was decreased (48 vs 64 min, p<0.05) and packing density was increased (31.7% vs 24.8%, p<0.05). There were more grade III aneurysms (71.1% vs 38.2%, p<0.05) and fewer grade I aneurysms (13.2% vs 30.2%, p<0.05) in the PC400 group than in the control group immediately after the procedure. At first follow-up, however, more aneurysms in the PC400 group improved (51.3% vs 28.7%, p<0.05) in angiographic grade leading to similar rates of acceptable outcome (grades I or II) at first follow-up (PC400 79.5% vs control 77.2%). The adverse event rate was similar in the two groups.

Conclusions

Large diameter PC400 coils can be used to safely treat cerebral aneurysms with fewer coils, decreased procedure time and increased packing density compared with standard coils. The early angiographic outcome is similar to that achieved with standard coils.
Soil characteristics mediate the distribution and response of boreal trees to climatic variability
Authors: Gewehr Sylvie , Drobyshev Igor , Berninger Frank , Bergeron Yves
Published: January 2014

We studied the effects of the soil organic layer (SOL) accumulation on growth and distribution of black spruce (Picea mariana (Mill.) BSP) and trembling aspen (Populus tremuloides Michx.) within the Quebec Clay Belt. At the landscape scale, spruce was present over a much larger gradient in SOL thickness (∼1 to 100 cm) than aspen (∼1 to 30 cm). For trees between 60 and 100 years old, SOL thickness had no effect on the basal area increment (BAI) of spruce but showed a strong and negative correlation with BAI in aspen. Radial growth of black spruce was favored by higher precipitation in June of the previous growing season, higher temperatures in early winter and in spring, and by low temperatures in summer. SOL thickness had statistically significant but moderate effects on the climate–growth relationships in spruce, apparently affecting root insulation during the dormant period and water availability during the growing period. In aspen, current-year June temperature was the most important factor positively correlated with growth. The SOL thickness affected the relationship between the aspen growth and (i) January temperature and (ii) June–August monthly drought code. We predict that the response of black spruce to climate change should be rather uniform across the study region, while the response of aspen is likely to be strongly mediated by SOL thickness.
Immune response in nasopharynx, lung, and blood elicited by experimental nasal pneumococcal vaccines containing live or heat-killed lactobacilli as mucosal adjuvants
Authors: Vintiñi Elisa O. , Medina Marcela
Published: January 2014

This work analyzes the humoral and cellular immune responses induced by live (LcV) and heat-killed (LcM) Lactobacillus casei associated with the pneumococcal antigen (P-Ag) at the nasopharynx level, considering nasal-associated lymphoid tissue (NALT) as the primary inductive site of the mucosal immune system, and lung and blood as effector sites. Levels of P-Ag IgA and IgG antibodies, main types of B and T cells, and cytokines in mucosal and systemic compartments were evaluated. The results showed that both LcM+P-Ag and LcV+P-Ag vaccines effectively induced IgA and IgG anti-P-Ag Abs in the upper and lower respiratory tract and plasma. These results correlated with increased IgA+ cells in NALT and lung that was induced by the experimental vaccines. Moreover, numbers of IgG+ cells increased in the blood. Profiles of inflammatory and regulatory cytokines were evaluated and their possible implications for the defense against pneumococci was assessed. Considering the overall results, the potential mechanisms of immune stimulation induced by LcM and LcV used as adjuvants are discussed. LcV and LcM showed similar effects on the immune system. Strain viability is not crucial for the stimulation of the antigen-specific immune response, and LcM is a convenient and effective mucosal adjuvant.
Per Theodor Cleve: a short résumé and his radiolarian results from the Swedish Expedition to Spitsbergen in 1898
Authors: Bjørklund Kjell R. , Itaki Takuya , Dolven Jane K.
Published: January 2014

Abstract. Cleve’s material from the Swedish Expedition to Spitsbergen in 1898 has been re-examined and lectotypes and some paralectotypes have been established for three spumellarian species, eight nassellarian species, and three phaeodarian species. In addition, important species in the Cleve collection, including three spumellarian species, 10 nassellarian species and three phaeodarian species have been illustrated and commented on. Some of Cleve’s identifications were erroneous, and we have carefully discussed these in our re-evaluation of Cleve’s species concepts.
Physiological contractility of cardiomyocytes in the wall of mouse and rat azygos vein
Authors: Liu Rong , Feng Han-Zhong , Jin J.-P.
Published: January 2014

We recently demonstrated the abundant presence of cardiomyocytes in the wall of thoracic veins of adult mouse and rat. The highly differentiated morphology and myofilament protein contents of the venous cardiomyocytes suggested contractile functions. Here we further investigated the contractility of mouse and rat azygos venous rings compared with that of atrial strips and ventricular papillary muscle. 5-Bromo-4-chloro-indolyl-galactopyranoside (X-gal) staining of transgenic mouse vessels expressing lacZ under a cloned cardiac troponin T promoter demonstrated that the venous cardiomyocytes are discontinuous from atrial myocardium and aligned in the wall of thoracic veins perpendicular to the vessel axis. Histological sections displayed sarcomeric striations in the venous cardiomyocytes, which indicate an encirclement orientation of myofibrils in the vessel wall. Mechanical studies found that the rings of mouse and rat azygos vein produce strong cardiac type twitch contractions when stimulated with electrical pacing in contrast to the weak and slow smooth muscle contractions induced using 90 mM KCl. The twitch contraction and relaxation of mouse azygos veins further exhibited a cardiac type of β-adrenergic responses. Quantitative comparison showed that the contractions of venous cardiomyocytes are slightly slower than those of atrium muscle but significantly faster than those of ventricular papillary muscle. These novel findings indicate that the cardiomyocytes abundant in the wall of rodent thoracic veins possess fully differentiated cardiac muscle phenotype despite their anatomical and functional segregations from the heart.
A novel β-adrenergic response element regulates both basal and agonist-induced expression of cyclin-dependent kinase 1 gene in cardiac fibroblasts
Authors: Gaspard Gerard J. , MacLean Jessica , Rioux Danielle , Pasumarthi Kishore B. S.
Published: January 2014

Cardiac fibrosis, a known risk factor for heart disease, is typically caused by uncontrolled proliferation of fibroblasts and excessive deposition of extracellular matrix proteins in the myocardium. Cyclin-dependent kinase 1 (CDK1) is involved in the control of G2/M transit phase of the cell cycle. Here, we showed that isoproterenol (ISO)-induced cardiac fibrosis is associated with increased levels of CDK1 exclusively in fibroblasts in the adult mouse heart. Treatment of primary embryonic ventricular cell cultures with ISO (a nonselective β-adrenergic receptor agonist) increased CDK1 protein expression in fibroblasts and promoted their cell cycle activity. Quantitative PCR analysis confirmed that ISO increases CDK1 transcription in a transient manner. Further, the ISO-responsive element was mapped to the proximal −100-bp sequence of the CDK1 promoter region using various 5′-flanking sequence deletion constructs. Sequence analysis of the −100-bp CDK1 minimal promoter region revealed two putative nuclear factor-Y (NF-Y) binding elements. Overexpression of the NF-YA subunit in primary ventricular cultures significantly increased the basal activation of the −100-bp CDK1 promoter construct but not the ISO-induced transcription of the minimal promoter construct. In contrast, dominant negative NF-YA expression decreased the basal activity of the minimal promoter construct and ISO treatment fully rescued the dominant negative effects. Furthermore, site-directed mutagenesis of the distal NF-Y binding site in the −100-bp CDK1 promoter region completely abolished both basal and ISO-induced promoter activation of the CDK1 gene. Collectively, our results raise an exciting possibility that targeting CDK1 or NF-Y in the diseased heart may inhibit fibrosis and subsequently confer cardioprotection.
The inhibitory effect of simvastatin and aspirin on histamine responsiveness in human vascular endothelial cells
Authors: Absi Mais , Bruce Jason I. , Ward Donald T.
Published: January 2014

Statins and aspirin deliver well-established cardiovascular benefits resulting in their increased use as combined polypills to decrease risk of stroke and heart disease. However, the direct endothelial effect of combined statin/aspirin cotreatment remains unclear. Histamine is an inflammatory mediator that increases vascular permeability, and so we examined the effect of treating human umbilical vein endothelial cells (HUVECs) for 24 h with 1 μM simvastatin and 100 μM aspirin on histamine responsiveness. Subsequent histamine (1 μM) challenge increased intracellular calcium (Ca2+i) concentration, an effect that was significantly inhibited by combined simvastatin/aspirin pretreatment but not when then the compounds were given separately, even at 10-fold higher concentrations. In contrast, the Ca2+i mobilization response to ATP challenge (10 μM) was not inhibited by combined simvastatin/aspirin pretreatment. The H1 receptor antagonist pyrilamine significantly inhibited both histamine-induced Ca2+i mobilization and extracellular signal-regulated kinase (ERK) activation, whereas ranitidine (H2 receptor antagonist) was without effect. However, combined simvastatin/aspirin pretreatment failed to decrease H1 receptor protein expression ruling out receptor downregulation as the mechanism of action. Histamine-induced ERK activation was also inhibited by atorvastatin pretreatment, while simvastatin further inhibited histamine-induced vascular endothelial cadherin phosphorylation as well as altered HUVEC morphology and inhibited actin polymerization. Therefore, in addition to the known therapeutic benefits of statins and aspirin, here we provide initial cellular evidence that combined statin/aspirin treatment inhibits histamine responsiveness in HUVECs.
Intermittent hypoxia-induced endothelial barrier dysfunction requires ROS-dependent MAP kinase activation
Authors: Makarenko Vladislav V. , Usatyuk Peter V. , Yuan Guoxiang , Lee May M. , Nanduri Jayasri , Natarajan Viswanathan , Kumar Ganesh K. , Prabhakar Nanduri R.
Published: January 2014

The objective of the present study was to determine the impact of simulated apnea with intermittent hypoxia (IH) on endothelial barrier function and assess the underlying mechanism(s). Experiments were performed on human lung microvascular endothelial cells exposed to IH-consisting alternating cycles of 1.5% O2 for 30s followed by 20% O2 for 5 min. IH decreased transendothelial electrical resistance (TEER) suggesting attenuated endothelial barrier function. The effect of IH on TEER was stimulus dependent and reversible after reoxygenation. IH-exposed cells exhibited stress fiber formation and redistribution of cortactin, vascular endothelial-cadherins, and zona occludens-1 junction proteins along with increased intercellular gaps at cell-cell boundaries. Extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) were phosphorylated in IH-exposed cells. Inhibiting either ERK or JNK prevented the IH-induced decrease in TEER and the reorganization of the cytoskeleton and junction proteins. IH increased reactive oxygen species (ROS) levels, and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride, a membrane-permeable antioxidant, prevented ERK and JNK phosphorylation as well as IH-induced changes in endothelial barrier function. These results demonstrate that IH via ROS-dependent activation of MAP kinases leads to reorganization of cytoskeleton and junction proteins resulting in endothelial barrier dysfunction.
Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine
Authors: Zheng Haifeng , Park Kyung Sik , Koh Sang Don , Sanders Kenton M.
Published: January 2014

Interstitial cells of Cajal (ICC) generate slow waves in gastrointestinal (GI) muscles. Previous studies have suggested that slow wave generation and propagation depends on a voltage-dependent Ca2+ entry mechanism with the signature of a T-type Ca2+ conductance. We studied voltage-dependent inward currents in isolated ICC. ICC displayed two phases of inward current upon depolarization: a low voltage-activated inward current and a high voltage-activated current. The latter was of smaller current density and blocked by nicardipine. Ni2+ (30 μM) or mibefradil (1 μM) blocked the low voltage-activated current. Replacement of extracellular Ca2+ with Ba2+ did not affect the current, suggesting that either charge carrier was equally permeable. Half-activation and half-inactivation occurred at −36 and −59 mV, respectively. Temperature sensitivity of the Ca2+ current was also characterized. Increasing temperature (20–30°C) augmented peak current from −7 to −19 pA and decreased the activation time from 20.6 to 7.5 ms [temperature coefficient (Q10) = 3.0]. Molecular studies showed expression of Cacna1g (Cav3.1) and Cacna1h (Cav3.2) in ICC. The temperature dependence of slow waves in intact jejunal muscles of wild-type and Cacna1h −/− mice was tested. Reducing temperature decreased the upstroke velocity significantly. Upstroke velocity was also reduced in muscles of Cacna1h −/− mice, and Ni2+ or reduced temperature had little effect on these muscles. Our data show that a T-type conductance is expressed and functional in ICC. With previous studies our data suggest that T-type current is required for entrainment of pacemaker activity within ICC and for active propagation of slow waves in ICC networks.
Water-perfused esophageal high-resolution manometry: normal values and validation
Authors: Kessing Boudewijn F. , Weijenborg Pim W. , Smout André J. P. M. , Hillenius Sem , Bredenoord Albert J.
Published: January 2014

Water-perfused high-resolution manometry (HRM) catheters with 36 unidirectional pressure channels have recently been developed, but normal values are not yet available. Furthermore, the technique has not been validated and compared with solid-state HRM. We therefore aimed to develop normal values for water-perfused HRM and to assess the level of agreement between water-perfused HRM and solid-state HRM. We included 50 healthy volunteers (mean age 35 yr, range 21–64 yr; 15 women, 35 men). Water-perfused HRM and solid-state HRM were performed in a randomized order. Normal values were calculated as 5th and 95th percentile ranges, and agreement between the two systems was assessed with intraclass correlation coefficient (ICC) statistics. The 5th–95th percentile range was 3.0–6.6 cm/s for contractile front velocity (CFV), 141.6–3,674 mmHg·s·cm for distal contractile integral (DCI), 6.2–8.7 s for distal contraction latency (DL), and 1.0–18.8 mmHg for integrated relaxation pressure (IRP 4s). Mean (SD) and ICC for water-perfused HRM and solid-state HRM were 4.4 (1.1) vs. 3.9 (0.9) cm/s, ICC: 0.49 for CFV; 1,189 (1,023) vs. 1,092 (1,019) mmHg·s·cm, ICC: 0.90 for DCI; 7.4 (0.8) vs. 6.9 (0.9) s, ICC: 0.50 for DL; and 8.1 (4.8) vs. 7.9 (5.1), ICC: 0.39 for IRP 4s. The normal values for this water-perfused HRM system are only slightly different from previously published values with solid-state HRM, and moderate to good agreement was observed between the two systems, with only small differences in outcome measures.
Computational modeling of anoctamin 1 calcium-activated chloride channels as pacemaker channels in interstitial cells of Cajal
Authors: Lees-Green Rachel , Gibbons Simon J. , Farrugia Gianrico , Sneyd James , Cheng Leo K.
Published: January 2014

Interstitial cells of Cajal (ICC) act as pacemaker cells in the gastrointestinal tract by generating electrical slow waves to regulate rhythmic smooth muscle contractions. Intrinsic Ca2+ oscillations in ICC appear to produce the slow waves by activating pacemaker currents, currently thought to be carried by the Ca2+-activated Cl− channel anoctamin 1 (Ano1). In this article we present a novel model of small intestinal ICC pacemaker activity that incorporates store-operated Ca2+ entry and a new model of Ano1 current. A series of simulations were carried out with the ICC model to investigate current controversies about the reversal potential of the Ano1 Cl− current in ICC and to predict the characteristics of the other ion channels that are necessary to generate slow waves. The model results show that Ano1 is a plausible pacemaker channel when coupled to a store-operated Ca2+ channel but suggest that small cyclical depolarizations may still occur in ICC in Ano1 knockout mice. The results predict that voltage-dependent Ca2+ current is likely to be negligible during the slow wave plateau phase. The model shows that the Cl− equilibrium potential is an important modulator of slow wave morphology, highlighting the need for a better understanding of Cl− dynamics in ICC.
Angiotensin-converting enzyme 2 mediates hyperfiltration associated with diabetes
Authors: Tikellis Chris , Brown Russel , Head Geoffrey A. , Cooper Mark E. , Thomas Merlin C.
Published: January 2014

The degradation of ANG II by angiotensin-converting enzyme 2 (ACE2), leading to the formation of ANG(1–7), is an important step in the regulation of the renin-angiotensin-aldosterone system (RAAS), and one that is significantly altered in the diabetic kidney. This study examined the role of ACE2 in the hyperfiltration associated with diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and ACE2 knockout (KO) mice. C57BL6 mice were further randomized to receive the selective ACE2 inhibitor MLN-4760. After 2 wk of study, animals were subjected to micropuncture experiments. The renal reserve was further assessed in C57BL6 mice and ACE2 KO mice after exposure to a high-protein diet. The induction of diabetes in wild-type mice was associated with increased renal ACE2 activity, hyperfiltration, and renal hypertrophy. On micropuncture, diabetes was associated with increased tubular free flow and stop-flow pressure, enhanced tubuloglomerular feedback reactivity, and an increased maximal response indicative of increased glomerular hydrostatic capillary pressure. Each of these increases were prevented in diabetic ACE2 KO mice and diabetic mice treated with a selective ACE2 inhibitor for 2 wk. However, unlike chronically treated animals, ACE2 inhibition with MLN-4760 had no acute effect on stop-flow pressure or tubuloglomerular feedback reactivity. ACE2 KO mice also failed to increase their creatinine clearance in response to a high-protein diet. The results of our study suggest that ACE2 plays a key role in the recruitment of the renal reserve and hyperfiltration associated with diabetes.
Theta phase shift in spike timing and modulation of gamma oscillation: a dynamic code for spatial alternation during fixation in rat hippocampal area CA1
Authors: Takahashi Muneyoshi , Nishida Hiroshi , David Redish A. , Lauwereyns Johan
Published: January 2014

Although hippocampus is thought to perform various memory-related functions, little is known about the underlying dynamics of neural activity during a preparatory stage before a spatial choice. Here we focus on neural activity that reflects a memory-based code for spatial alternation, independent of current sensory and motor parameters. We recorded multiple single units and local field potentials in the stratum pyramidale of dorsal hippocampal area CA1 while rats performed a delayed spatial-alternation task. This task includes a 1-s fixation in a nose-poke port between selecting alternating reward sites and so provides time-locked enter-and-leave events. At the single-unit level, we concentrated on neurons that were specifically active during the 1-s fixation period, when the rat was ready and waiting for a cue to pursue the task. These neurons showed selective activity as a function of the alternation sequence. We observed a marked shift in the phase timing of the neuronal spikes relative to the theta oscillation, from the theta peak at the beginning of fixation to the theta trough at the end of fixation. The gamma-band local field potential also changed during the fixation period: the high-gamma power (60–90 Hz) decreased and the low-gamma power (30–45 Hz) increased toward the end. These two gamma components were observed at different phases of the ongoing theta oscillation. Taken together, our data suggest a switch in the type of information processing through the fixation period, from externally cued to internally generated.
Spatiotemporal stimulus properties modulate responses to trajectory changes in a locust looming-sensitive pathway
Authors: Dick Paul C. , Gray John R.
Published: January 2014

The lobula giant movement detector (LGMD) and descending contralateral movement detector (DCMD) constitute one motion-sensitive pathway in the locust visual system that is implicated in collision-avoidance behaviors. While this pathway is thought to respond preferentially to objects approaching on a direct collision course, emerging studies suggest the firing rate is able to monitor more complicated movements that would occur under natural conditions. While previous studies have compared the response of the DCMD to objects on collision courses that travel at different speeds, velocity has not been manipulated for other simple or compound trajectories. Here we test the possibility that the LGMD/DCMD pathway is capable of responding uniquely to complex aspects of object motion, including translation and trajectory changes at different velocities. We found that the response of the DCMD to translational motion initiated in the caudal visual field was a low-amplitude peak in firing rate that occurred before the object crossed 90° azimuth that was invariant to different object velocities. Direct looms at different velocities resulted in peak firing rates that occurred later in time and with greater amplitude for higher velocities. In response to transitions from translational motion to a collision course, the firing rate change depended on both the location within the visual field and the velocity. These results suggest that this pathway is capable of conveying information about multiple properties of a moving object's trajectory.
Impact of subthreshold membrane potential on synaptic responses at dendritic spines of layer 5 pyramidal neurons in the prefrontal cortex
Authors: Seong Hannah J. , Behnia Rudy , Carter Adam G.
Published: January 2014

Glutamatergic inputs onto cortical pyramidal neurons are received and initially processed at dendritic spines. AMPA and NMDA receptors generate both synaptic potentials and calcium (Ca) signals in the spine head. These responses can in turn activate a variety of Ca, sodium (Na), and potassium (K) channels at spines. In principle, the roles of these receptors and channels can be strongly regulated by the subthreshold membrane potential. However, the impact of different receptors and channels has usually been studied at the level of dendrites. Much less is known about their influence at spines, where synaptic transmission and plasticity primarily occur. Here we examine single-spine responses in the basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. Using two-photon microscopy and two-photon uncaging, we first show that synaptic potentials and Ca signals differ at resting and near-threshold potentials. We then determine how subthreshold depolarizations alter the contributions of AMPA and NMDA receptors to synaptic responses. We show that voltage-sensitive Ca channels enhance synaptic Ca signals but fail to engage small-conductance Ca-activated K (SK) channels, which require greater numbers of inputs. Finally, we establish how the subthreshold membrane potential controls the ability of voltage-sensitive Na channels and K channels to influence synaptic responses. Our findings reveal how subthreshold depolarizations promote electrical and biochemical signaling at dendritic spines by regulating the contributions of multiple glutamate receptors and ion channels.
Characterization of pruriceptive trigeminothalamic tract neurons in rats
Authors: Moser Hannah R. , Giesler Glenn J.
Published: January 2014

Rodent models of facial itch and pain provide a valuable tool for distinguishing between behaviors related to each sensation. In rats, pruritogens applied to the face elicit scratching using the hindlimb while algogens elicit wiping using the forelimb. We wished to determine the role of trigeminothalamic tract (VTT) neurons in carrying information regarding facial itch and pain to the forebrain. We have characterized responses to facially applied pruritogens (serotonin, BAM8–22, chloroquine, histamine, capsaicin, and cowhage) and noxious stimuli in 104 VTT neurons recorded from anesthetized rats. Each VTT neuron had a mechanically sensitive cutaneous receptive field on the ipsilateral face. All pruriceptive VTT neurons also responded to noxious mechanical and/or thermal stimulation. Over half of VTT neurons responsive to noxious stimuli also responded to at least one pruritogen. Each tested pruritogen, with the exception of cowhage, produced an increase in discharge rate in a subset of VTT neurons. The response to each pruritogen was characterized, including maximum discharge rate, response duration, and spike timing dynamics. Pruriceptive VTT neurons were recorded from throughout superficial and deep layers of the spinal trigeminal nucleus and were shown to project via antidromic mapping to the ventroposterior medial nucleus or posterior thalamic nuclei. These results indicate that pruriceptive VTT neurons are a subset of polymodal nociceptive VTT neurons and characterize a system conducive to future experiments regarding the similarities and differences between facial itch and pain.
Large-scale identification of proteins involved in the development of a sexually dimorphic behavior
Authors: Zupanc Günther K. H. , Ilieş Iulian , Sîrbulescu Ruxandra F. , Zupanc Marianne M.
Published: January 2014

Sexually dimorphic behaviors develop under the influence of sex steroids, which induce reversible changes in the underlying neural network of the brain. However, little is known about the proteins that mediate these activational effects of sex steroids. Here, we used a proteomics approach for large-scale identification of proteins involved in the development of a sexually dimorphic behavior, the electric organ discharge of brown ghost knifefish, Apteronotus leptorhynchus. In this weakly electric fish, the discharge frequency is controlled by the medullary pacemaker nucleus and is higher in males than in females. After lowering the discharge frequency by chronic administration of β-estradiol, 2-dimensional difference gel electrophoresis revealed 62 proteins spots in tissue samples from the pacemaker nucleus that exhibited significant changes in abundance of >1.5-fold. The 20 identified protein spots indicated, among others, a potential involvement of astrocytes in the establishment of the behavioral dimorphism. Indeed, immunohistochemical analysis demonstrated higher expression of the astrocytic marker protein GFAP and increased gap-junction coupling between astrocytes in females compared with males. We hypothesize that changes in the size of the glial syncytium, glial coupling, and/or number of glia-specific potassium channels lead to alterations in the firing frequency of the pacemaker nucleus via a mechanism mediating the uptake of extracellular potassium ions from the extracellular space.
Methodological Framework for Estimating the Correlation Dimension in HRV Signals
Authors: Bolea Juan , Laguna Pablo , Remartínez José María , Rovira Eva , Navarro Augusto , Bailón Raquel
Published: January 2014

This paper presents a methodological framework for robust estimation of the correlation dimension in HRV signals. It includes (i) a fast algorithm for on-line computation of correlation sums; (ii) log-log curves fitting to a sigmoidal function for robust maximum slope estimation discarding the estimation according to fitting requirements; (iii) three different approaches for linear region slope estimation based on latter point; and (iv) exponential fitting for robust estimation of saturation level of slope series with increasing embedded dimension to finally obtain the correlation dimension estimate. Each approach for slope estimation leads to a correlation dimension estimate, calledD^2,D^2⊥, andD^2max.D^2andD^2maxestimate the theoretical value of correlation dimension for the Lorenz attractor with relative error of 4%, andD^2⊥with 1%. The three approaches are applied to HRV signals of pregnant women before spinal anesthesia for cesarean delivery in order to identify patients at risk for hypotension.D^2keeps the 81% of accuracy previously described in the literature whileD^2⊥andD^2maxapproaches reach 91% of accuracy in the same database.
2-Year BMI Changes of Children Referred for Multidisciplinary Weight Management
Authors: Cheng Jennifer K. , Wen Xiaozhong , Coletti Kristen D. , Cox Joanne E. , Taveras Elsie M.
Published: January 2014

Objective.To examine body mass index (BMI) changes among pediatric multidisciplinary weight management participants and nonparticipants.Design.In this retrospective database analysis, we used multivariable mixed effect models to compare 2-year BMIz-score trajectories among 583 eligible overweight or obese children referred to the One Step Ahead program at the Boston Children’s Primary Care Center between 2003 and 2009.Results.Of the referred children, 338 (58%) attended the program; 245 (42%) did not participate and were instead followed by their primary care providers within the group practice. The mean BMIz-score of program participants decreased modestly over a 2-year period and was lower than that of nonparticipants. The group-level difference in the rate of change in BMIz-score between participants and nonparticipants was statistically significant for 0–6 months (P=0.001) and 19–24 months (P=0.008); it was marginally significant for 13–18 months (P=0.051) after referral. Younger participants (<5 years) had better outcomes across all time periods examined.Conclusion.Children attending a multidisciplinary program experienced greater BMIz-score reductions compared with usual primary care in a real world practice; younger participants had significantly better outcomes. Future research should consider early intervention and cost-effectiveness analyses.
Hyperparathyroidism Two Years after Radioactive Iodine Therapy in an Adolescent Male
Authors: Gomez Danielle L. , Shulman Dorothy I.
Published: January 2014

Primary hyperparathyroidism is a very rare complication following radioactive iodine therapy. There is typically a latency period of more than a decade following radiation exposure and, therefore, it is observed almost exclusively in adults. Consequently, pediatricians are not aware of the association. We present a case of primary hyperparathyroidism due to a solitary parathyroid adenoma occurring in an adolescent male two years following radioactive iodine treatment for papillary thyroid carcinoma. Periodic screening of serum calcium following ablative doses of radioactive iodine for thyroid cancer may be justified even in adolescents.
Application of Acoustic Emission on the Characterization of Fracture in Textile Reinforced Cement Laminates
Authors: Blom J. , Wastiels J. , Aggelis D. G.
Published: January 2014

This work studies the acoustic emission (AE) behavior of textile reinforced cementitious (TRC) composites under flexural loading. The main objective is to link specific AE parameters to the fracture mechanisms that are successively dominating the failure of this laminated material. At relatively low load, fracture is initiated by matrix cracking while, at the moment of peak load and thereafter, the fiber pull-out stage is reached. Stress modeling of the material under bending reveals that initiation of shear phenomena can also be activated depending on the shape (curvature) of the plate specimens. Preliminary results show that AE waveform parameters like frequency and energy are changing during loading, following the shift of fracturing mechanisms. Additionally, the AE behavior of specimens with different curvature is very indicative of the stress mode confirming the results of modeling. Moreover, AE source location shows the extent of the fracture process zone and its development in relation to the load. It is seen that AE monitoring yields valuable real time information on the fracture of the material and at the same time supplies valuable feedback to the stress modeling.
Emergent Median Sternotomy for Mediastinal Hematoma: A Rare Complication following Internal Jugular Vein Catheterization for Chemoport Insertion—A Case Report and Review of Relevant Literature
Authors: Biswas Saptarshi , Sidani Marwa , Abrol Sunil
Published: January 2014

Mediastinal hematoma is a rare complication following insertion of a central venous catheter with only few cases reported in the English literature. We report a case of a 71-year-old female who was admitted for elective chemoport placement. USG guided right internal jugular access was attempted using the Seldinger technique. Resistance was met while threading the guidewire. USG showed a chronic clot burden in the RIJ. A microvascular access was established under fluoroscopic guidance. Rest of the procedure was completed without any further issues. Following extubation, the patient complained of right-sided chest pain radiating to the back. Chest X-ray revealed a contained white out in the right upper lung field. She became hemodynamically unstable. Repeated X-ray showed progression of the hematoma. Median Sternotomy showed posterior mediastinal hematoma tracking into right pleural cavity. Active bleeding from the puncture site at RIJ-SCL junction was repaired. Patient had an uneventful recovery. Injury to the central venous system is the result of either penetrating trauma or iatrogenic causes as in our case. A possible explanation of our complication may be attributed to the forced manipulation of the dilator or guidewire against resistance. Clavicle and sternum offer bony protection to the underlying vital venous structures and injuries often need sternotomy with or without neck extension. Division of the clavicle and disarticulation of the sternoclavicular joint may be required for optimum exposure. Meticulous surgical technique, knowledge of the possible complications, and close monitoring in the postprocedural period are of utmost importance. Chest X-ray showed to be routinely done to detect any complication early.
Potent Anti-Inflammatory and Antiproliferative Effects of Gambogic Acid in a Rat Model of Antigen-Induced Arthritis
Authors: Cascão Rita , Vidal Bruno , Raquel Helena , Neves-Costa Ana , Figueiredo Nuno , Gupta Vineet , Fonseca João Eurico , Ferreira Moita Luis
Published: January 2014

Background. We have previously reported a continuous activation of caspase-1 and increased interleukin (IL)-1βlevels in early rheumatoid arthritis (RA). These observations raised the hypothesis that drugs targeting the IL-1βpathway, in addition to tumour necrosis factor (TNF), may be particularly effective for early RA treatment. We have recently identified gambogic acid as a promising therapeutic candidate to simultaneously block IL-1βand TNF secretion. Our main goal here was to investigate whether gambogic acid administration was able to attenuate inflammation in antigen-induced arthritis (AIA) rats.Methods. Gambogic acid was administered to AIA rats in the early and late phases of arthritis. The inflammatory score, ankle perimeter, and body weight were evaluated during the period of treatment. Rats were sacrificed after 19 days of disease progression and paw samples were collected for histological and immunohistochemical evaluation.Results. We found that inflammation in joints was significantly suppressed following gambogic acid administration. Histological and immunohistochemical evaluation of treated rats revealed normal joint structures with complete abrogation of the inflammatory infiltrate and cellular proliferation.Conclusions. Our results suggest that gambogic acid has significant anti-inflammatory properties and can possibly constitute a prototype anti-inflammatory drug with therapeutic efficacy in the treatment of inflammatory diseases such as RA.
Glix 13, a New Drug Acting on Glutamatergic Pathways in Children and Animal Models of Autism Spectrum Disorders
Authors: Santini Annamaria Chiara , Pierantoni Giovanna Maria , Gerlini Raffaele , Iorio Rosamaria , Olabinjo Yinka , Giovane Alfonso , Di Domenico Marina , Sogos Carla
Published: January 2014

Recently standardized diagnostic instruments have been developed in diagnostic and therapeutic procedures for Autism Spectrumv Disorders (ASD). According to the DSM-5 criteria, individuals with ASD must show symptoms from early childhood. These symptoms are communication deficits and restricted, repetitive patterns of behaviour. It was recently described by Bioinformatic analysis that 99 modified genes were associated with human autism. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes and the NMDA receptor gene family was identified among these. Using ultrasonic vocalizations, it was demonstrated that genetic variation has a direct impact on the expression of social interactions. It has been proposed that specific alleles interact with a social reward process in the adolescent mouse modifying their social interaction and their approach toward each other. In this review we report that the monoclonal antibody-derived tetrapeptide GLYX-13 was found to act as an N-methyl-D-aspartate receptor modulator and possesses the ability to readily cross the blood brain barrier. Treatment with the NMDAR glycine site partial agonist GLYX-13 rescued the deficit in the animal model. Thus, the NMDA receptor has been shown to play a functional role in autism, and GLYX-13 shows promise for the treatment of autism in autistic children.