bluuebunny/crossref_metadata_2025 huggingface dataset:
Massive Migration von Silikonöl in den subkonjunktivalen Raum: Ein Dilemma von Leckage-Mechanismen
Authors: Téllez Jesús , Vela José I. , Luna Sabina , Delgado Rubén
Published: September 2019

Zielsetzung: Wir berichten über einen Fall von früh aufgetretener massiver Migration von Silikonöl in den subkonjunktivalen Raum nach nahtloser Vitrektomie bei einem Patienten mit vorheriger Pars-plana-Implantation eines Glaukomdrainagesystems. Fallbericht: Ein 80-jähriger Mann stellte sich mit einem neovaskulären Glaukom aufgrund einer proliferativen diabetischen Retinopathie im linken Auge vor. Nach intrakameraler Injektion von Bevacizumab und panretinaler Photokoagulation wurde bei dem Patienten eine 23-Gauge Pars-plana-Vitrektomie (PPV) in Kombination mit einer superotemporalen Pars-plana-Implantation einer Ahmed Glaucoma Valve durchgeführt. Im weiteren Verlauf erfolgte eine erneute 23-Gauge-PPV wegen einer dichten Glaskörperblutung. Um wiederkehrende intraokuläre Blutungen zu verhindern, wurde intravitreal Silikonöl mit einer Viskosität von 1000 Zentistokes eingebracht. Es erfolgte kein Nahtverschluss. Im ersten postoperativen Monat kam es zu einer massiven Migration von Silikonöl in den 360° umfassenden subkonjunktivalen Raum, bis kein intraokuläres Silikonöl mehr nachweisbar war. Schlussfolgerungen: Wir erörtern die in diesem speziellen Fall möglichen Leckage-Mechanismen.
Surfactant Administration via Thin Catheter: A Practical Guide
Authors: Vento Maximo , Bohlin Kajsa , Herting Egbert , Roehr Charles Christoph , Dargaville Peter A.
Published: September 2019

Exogenous surfactant replacement is the most effective evidence-based therapy for respiratory distress syndrome in preterm infants. The mode of administration has evolved in the last decade towards less invasive techniques that aim to effectively provide an adequate dose of surfactant, while allowing spontaneous respiration to continue, and with the support of continuous positive airway pressure. Surfactant delivery via aerosolisation, pharyngeal instillation, and laryngeal mask are being actively pursued in research, but have not yet been adopted to any significant degree in clinical practice. Surfactant administration via thin catheter, on the other hand, is becoming more widely used in neonatal intensive care units worldwide and is now an acknowledged alternative to the standard mode of surfactant delivery. Different devices, including nasogastric tubes, vascular catheters, and purpose-built surfactant instillation catheters are used. We present here a contemporary review of surfactant administration via thin catheter, in a practical guide format that reflects the individual and collective scientific opinions of the clinicians who participated in formulating the guide.
Endoscopic Insertion of Nasojejunal Feeding Tube at Bedside for Critically Ill Patients: Relationship between Tube Position and Intragastric Countercurrent of Contrast Medium
Authors: Tatsumi Hiroomi , Akatsuka Masayuki , Kazuma Satoshi , Katayama Yoichi , Goto Yuya , Monma Kyoko , Yoshida Shinichiro , Masuda Yoshiki
Published: September 2019

Background and Oblectives: We evaluated the success rate of endoscopically positioned nasojejunal feeding tubes and the intragastric countercurrent of contrast medium thereafter. Method: This retrospective observational study investigated patients who were admitted to a single intensive care unit and required endoscopic placement of a post-pyloric feeding tube between January 2010 and June 2016. The feeding tube was grasped with forceps via a transoral endoscope and inserted into the duodenum or jejunum. Thereafter, we assessed the position of the tube and the intragastric countercurrent using abdominal radiography with contrast medium. Results: The tube tip was inserted at the jejunum and the duodenal fourth portion in 55.8 and 33.6% of patients, respectively. The tip of the inserted tube had moved into the jejunum of 71.7% of patients by the following day. The countercurrent rate was significantly lower among patients with a tube inserted into the duodenal fourth portion or more distal than among those with tubes inserted more proximally (8.4 vs. 45.4%, p = 0.0022). Conclusions: The endoscopic insertion and positioning of a nasojejunal feeding tube seemed effective because the rate of tube insertion into the duodenal fourth portion or more distal was about 90%. The findings of intragastric countercurrents indicated that feeding tubes should be inserted into the duodenal fourth portion or beyond to prevent vomiting and the aspiration of enteral nutrients.
The Link between Estradiol and Neuroplasticity in Transgender Women after Gender-Affirming Surgery: A Bimodal Hypothesis
Authors: Schneider Maiko A. , Spritzer Poli M. , Suh Jee Su , Minuzzi Luciano , Frey Benicio N. , Schwarz Karine , Costa Angelo B. , da Silva Dhiordan C. , Garcia Claudia C.G. , Fontanari Anna M.V. , Anes Mauricio , Castan Juliana U. , Cunegatto Fernanda R. , Picon Felipe A. , Luders Eileen , Lobato Maria I.R.
Published: September 2019

For transgender individuals, gender-affirming surgery (GAS) and cross-sex hormone therapy (CSHT) are part of the gender transition process. Scientific evidence supporting the maintenance of CSHT after GAS-related gonadectomy is accumulating. However, few data are available on the impact of CSHT on the brain structure following hypogonadism. Thus, we aimed to investigate links between estradiol and brain cortical thickness (CTh) and cognition in 18 post-gonadectomy transgender women using a longitudinal design. For this purpose, the participants underwent a voluntary period of CSHT washout of at least 30 days, followed by estradiol re-institution for 60 days. High-resolution T1-weighted brain images, hormonal measures, working and verbal memory were collected at 2 time points: on the last day of the washout (t1) and on the last day of the 2-month CSHT period (t2). Between these 2 time points, CTh increased within the left precentral gyrus and right precuneus but decreased within the right lateral occipital cortex. However, these findings did not survive corrections of multiple comparisons. Nevertheless, there was a significant negative correlation between changes in estradiol levels and changes in CTh. This effect was evident in the left superior frontal gyrus, the left middle temporal gyrus, the right precuneus, the right superior temporal gyrus, and the right pars opercularis. Although there was an improvement in verbal memory following hypogonadism correction, we did not observe a significant relationship between changes in memory scores and CTh. Altogether, these findings suggest that there is a link between estradiol and CTh.
Interconexões na integração lusófona
Authors: Valadares Flavio Biasutti
Published: September 2019

A pesquisa aborda as possibilidades de interconexão no espaço lusófono a partir da ideia de construção identitária por meio do uso de expressões idiomáticas, destacando-se a integração no mundo da lusofonia. Objetiva discutir a interconexão numa interface de integração relativa à constituição de uma identidade lusófona cujo espaço se organiza com a utilização de idiomatismos comuns em diversos ambientes de produção, ressaltando tal espaço como propício à discussão de interculturalidade. Baseia-se na Lusofonia e no conceito de expressões idiomáticas, além da perspectiva da interculturalidade. Como procedimentos metodológicos, recolhe textos de jornalísticos para a análise em sítios de países com língua portuguesa oficial. Conclui que a noção de que os efeitos de sentido são produzidos de modo consubstanciado a partir do que as expressões idiomáticas podem assumir quanto à significação que as metáforas inscritas em si promovem para a construção de uma interculturalidade.
Consciência lusófona em “Uma política do idioma”, de Celso Cunha
Authors: Nogueira Sônia Maria , Di Iório Patrícia Leite , Almeida Wemylla De Jesus
Published: September 2019

A história das políticas linguísticas de uma língua e de seu ensino pode ser observada pelas leis que as regiam, pelos materiais didáticos que circulavam e que direcionavam o ensino de certo momento, bem como por meio de conferências, discursos e documentos que apresentavam e/ou reivindicavam ações necessárias à constituição de uma política do idioma. Neste sentido, este trabalho busca analisar a proposta de política do idioma apresentada por Celso Cunha, em conferência no Ministério da Educação e Cultura, em 1963. Reproduzida, posteriormente, no livro Uma política do idioma (1964) e, segundo o autor, acrescida de notas e fundamentos linguísticos e filológicos. Trata-se de obra relevante para a compreensão da proposta de Cunha para a Educação Nacional e, portanto, documento importante para a compreensão do contexto político-linguístico-educacional, em que o discurso é proferido, bem como quais são as concepções de língua e de política do idioma que estão imanentes. Para estabelecer essas relações é necessário buscar fundamentos nos conceitos de Koerner (1996). Ainda por se tratar de ato de comunicação em uma cena política, buscamos, sob o olhar do discurso político (CHARAUDEAU, 2006), observar as estratégias de influência para a constituição do discurso político-linguístico de Celso Cunha.
O incipit na novelística histórica portuguesa e brasileira
Authors: Paolinelli Luisa Marinho Antunes
Published: September 2019

O incipit como partida para um lugar, origem de um itinerário narrativo desconhecido, é uma fórmula privilegiada que os autores possuem não só como mecanismo de sedução, como artifício que dita as regras do universo da história, mas também como expressão do seu posicionamento face ao que irão contar. Tratando-se do romance histórico, o autor tem ainda a responsabilidade de situar temporalmente o leitor, optando quer por descrições, segmentos narrativos ou por iniciar a história em medias res, sempre de forma a não desconfortar o leitor. O incipit neste género pode também funcionar como índice da forma como o autor faz uso da História na ficção: “écran” ideológico, com o intuito de intervenção no presente, evasão e catarse, ou, ainda, reflexão e clarificação de um determinado período. Se estas categorias são válidas na análise do incipit das obras dos autores lusos e de alguns textos de Alencar, os romances históricos de teor indianista alencarianos exigem uma outra categoria – a da elaboração ficcional da História com intenções mítico-lendárias. Com alguns piscar de olhos aos romancistas portugueses, numa verdadeira lição de ironia romântica, Alencar faz da descrição incipitaria uma verdadeira instituição que concentra em si objetivos ligados à construção da narrativa identitária.
Abstract 015: Maternal High Blood Pressure Control Persistently Alters Gut-Brain Communication and Attenuates Hypertension of Offspring
Authors: Yang Tao , Li Hongbao , Richards Elaine , Pepine Carl , Raizada Mohan
Published: September 2019

Objective:
Evidence suggests involvement of a dysfunctional gut-brain axis in hypertension. Maternal-fetal cross-talk is implicated in the long-term control of hypertension of offspring. Therefore, we tested the hypothesis that maternal factors influence gut-brain axis impacting hypertension in offspring.

Methods:
Pregnant female spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats, were treated with captopril (CAP) water (100 mg/kg/day) or sterile water throughout pregnancy and lactation. At weaning, the pups from dams drinking sterile water were continued until age 12 weeks. The pups from dams drinking CAP water were divided into two groups: offspring continuously drinking CAP and offspring withdrawn from CAP, then drinking sterile water until age 12 weeks (N=8-11/group).

Results:
Compared with SHR, maternal exposure of SHR to CAP lowered systolic BP in offspring at weaning (Δ=24mmHg, P<0.05). This was associated with amelioration of gut inflammation (decreased
Cd3
by 2.8-fold, P<0.01) and permeability (increased
Tjp1
by 4.3-fold, P<0.01;
Ocln
increased by 2.8-fold, P<0.01). At 12 week-old, SHR offspring exposed to maternal CAP demonstrated persistent decreased systolic BP (Δ=25mmHg, P<0.01), increased microbial Shannon diversity (Δ=1.25, P<0.001), altered β diversity, and growth of beneficial bacterial genera, compared with SHR (increased
Coprococcus
by 41-fold, P<0.001;
Oscillospira
by 4.9-fold, P<0.01;
Roseburia
by 83-fold, P<0.001;
Mucispirillum
by 26-fold, P<0.01). Decreases in activated microglia numbers per area (Δ=2.8, P<0.05) and neuroinflammation (decreased
Tnf
by 2.4-fold, P<0.001;
Il1b
by 2.7-fold, P<0.05) and improvement of gut inflammation (
Cd3
decreased by 1.8-fold, P<0.01) and permeability (increased
Tjp1
by 2.2-fold, P<0.1;
Ocln
by 1.8-fold, P<0.1) were also observed in these SHR offspring with maternal CAP, compared with SHR. These improvements were also found in the SHR with continuous CAP.

Conclusion:
Maternal decrease of BP by CAP improves dysregulated gut-brain axis in SHR offspring and long-term lowering of BP. Thus, it provides conceptual support that targeting of the gut-brain axis via the mother may be a relevant strategy for the control of hypertension in the offspring.
Abstract 018: Female Offspring of Polycystic Ovary Syndrome Rat Model Exhibit Insulin Resistance and Tendency Toward Increased Blood Pressure With Aging
Authors: Shawky Noha M , Vinson Ruth M , Reckelhoff Jane F
Published: September 2019

Background:
Polycystic ovary syndrome (PCOS) is associated with metabolic dysfunction and elevated blood pressure (BP). Whether daughters born to PCOS mothers exhibit a PCOS phenotype is controversial. In addition, whether daughters of PCOS women develop metabolic dysfunction and elevated BP with aging has not been reported.

Objectives:
The present study tested the hypothesis that aging causes an increase in MAP and metabolic dysfunction in female offspring of PCOS rats (F1
DHT
) along with changes in matrix metalloproteinase-9 (MMP-9) and transforming growth factor-β (TGF-β).

Methods:
PCOS was induced in SD females by implantation of 5α-dihydrotestosterone pellets (DHT; 7.5 mg/90 days, sc) starting at 4 wks of age. Rats were mated with SD males, and allowed to deliver and lactate. F1
DHT
were left untreated and were studied at 14-16 wks or 16-18 mos of age. Control dams were implanted with placebo pellets sc, allowed to mate, deliver and suckle their offspring (F1
PL
).

Results:
MAP (radiotelemetry) in 14-16 wk F1
DHT
females was not different from F1
PL,
nor did they exhibit other PCOS characteristics. With aging,

F1
DHT
rats showed a strong tendency for increased MAP compared to F1
PL
(107 ± 4 versus 93 ± 1 mmHg; p = 0.07 (n=2-4)). Plasma MMP-9 and TGF- β1, 2 and 3 were not different between groups. Fasting blood glucose was not different between groups (91 ± 2.6 vs 90 ± 1.6 mg/dl), but F1
DHT
rats showed significant hyperinsulinemia (0.9 ± 0.05 vs 0.78 ± 0.03 ng/ml, p ≤ 0.05) and insulin resistance (increased HOMA-IR index; 3.3 ± 0.2 vs 2.8 ± 0.1, p ≤ 0.05, (n = 5-6)). Lean mass (248.3 ± 5.5 vs 241.2 ± 2.5 g), fat mass (38.7 ± 4.8 vs 39.7 ± 2.2 g) and total water (185.8 ± 4.8 vs 179.9 ± 3 g) by Echo MRI, in addition to body weight (310.7 ± 7.7 vs 298.1 ± 4.6 g
;
(n = 6-8)) were also not different between groups.

Conclusion:
MAP in aging female offspring of PCOS rat model tends to be increased along with hyperinsulinemia and insulin resistance with no changes in fasting glucose, lean/fat mass, body weight, MMP9 or TGF-β. The data suggest that women whose mothers had PCOS may be at increased risk for hypertension and metabolic dysfunction with aging, although the mechanisms for the hypertension are not clear.
Abstract 019: Gut Microbiome Governs Independent Risks for Hypertension Comorbid With Depression, Hypertension Without Depression, and Depression Without Hypertension in Human Subjects
Authors: Stevens Bruce R , Pepine Carl , Raizada Mohan , Seungbum Kim , Richards Elaine
Published: September 2019

Objective:
Our hypothesis is that human patient gut microbiome dysbiosis determines independent risks for 1) comorbid hypertension plus depression, 2) hypertension without depression, or 3) depression without hypertension.

Methods:
After University of Florida Institutional Review Board approval, stool samples were collected from volunteers diagnosed with hypertension (HTN) and/or meeting
DSM-5
criteria for a depressive disorder (DEP), and from healthy human reference subjects without diagnosed HTN nor mental illness. Stool microbiome data were obtained by initial 16S rRNA gene amplicon sequence analyses followed by extensive whole genome metagenomic shotgun sequencing analyses.Subject metadata were analyzed for these risk interactions: 1) HTN/No DEP; 2) HTN/with DEP; 3) No HTN/No DEP; and 4) No HTN/with DEP.

Results:
KEGG ortholog metabolic pathways and gene analyses relating to systemic inflammasome induction and gut wall ACE components, multivariate PCA ordination, linear discriminant analysis effect size assessments, and network distance analyses collectively revealed significantly different (P<0.05) microbiome taxa and metabolic pathway patterns that differentiated the risk interactions.

Conclusions:
Human gut microbiome dysbiosis and attending pathologic metabolic pathways yielded discrete risk factors that discriminate patients comorbid with HTN plus DEP vs HTN without DEP vs DEP without HTN, in contrast to healthy reference subjects. These data collectively implicate the gut as a novel target for prevention, diagnosing, and treating HTN.
Abstract 021: Single Cell Multiplex Mass Cytometry Reveals Differential Abundance of Specific Memory and Regulatory T Cell Populations in Human Hypertension
Authors: Alexander Matthew R , Dale Bethany L , Elijovich Fernando , Wogsland Cara E , Irish Jonathan M , Madhur Meena S
Published: September 2019

Hypertension is the leading risk factor for morbidity and mortality worldwide. Emerging evidence in animal models demonstrates the importance of a variety of innate and adaptive immune cells in hypertension. We hypothesized that the abundance and phenotype of specific circulating immune cell subsets is altered in human hypertension reflecting disease pathophysiology. We performed unbiased high dimensional, single cell profiling of peripheral blood mononuclear cells in humans with a panel of 31 cell surface markers using mass cytometry. Unsupervised computational analysis from 11 control and 10 hypertensive individuals matched for age, gender, race, and body mass index revealed consistent increases in a novel memory helper T cell subset in hypertension. Manual two dimensional gating revealed that this CD4
+
CD45RO
+
CD62L
+
CCR7
-
CD161
lo
memory cell population is nearly 2-fold increased in hypertensive subjects (1.0 vs 1.9%). As an alternative to starting with unsupervised analysis, manual gating for major known immune cell populations revealed a 40% decrease in memory cytotoxic T cells and a 29% decrease in regulatory T cells in hypertensive individuals (3.2 vs 1.9% and 1.3 vs 0.93%, respectively). Unsupervised analysis of the cellular subsets of these populations using Phenograph revealed a selective 63% decrease in PD-1
+
memory cytotoxic T cells and 49% decrease in CCR10
+
regulatory T cells in hypertension (0.67 vs 0.25% and 0.37 vs 0.19%, respectively). Taken together, these results demonstrate that in human hypertension there are increases in a novel memory helper T cell subset and decreases in PD-1
+
memory cytotoxic and CCR10
+
regulatory T cell populations. These findings may provide new insights into hypertension pathogenesis and potential therapeutic targets.
Abstract 039: The
PDE3A
Gene Regulates Blood Pressure
Authors: Luft Friedrich C , Ercu Maria , Schächterle Carolin , Marko Lajos , Maass Philipp , Zühlke Kerstin , Kidd Alexa M , Gregersen Nerine , Hübner Norbert , Hodge Russell , Molé Illas Rosana , Walter Stephan , Preissner Robert , Heuser Arnd , Anistan Yoland-Marie , Tsvetkov Dmitry , Todiras Mihail , Popova Elena , Forslund Sofia , Müller Dominik N , Gollasch Maik , Aydin Atakan , Bähring Sylvia , Bader Michael , Klussmann Enno
Published: September 2019

Hypertension is the greatest driver of cardiovascular disease, the most common cause of death. Finding novel model mechanisms for blood-pressure (BP) regulation is an important goal. Autosomal-dominant hypertension with brachydactyly (HTNB) clinically resembles salt-resistant essential hypertension and causes death by stroke, commonly before age 50 years. We identified mutated phosphodiesterase 3A as responsible earlier; however, definitive mechanistic proof and animal models were lacking. We now describe new kindreds, one substituted within the earlier-described regulatory region (G449S), and another with a mutation causing an amino acid substitution within the PDE3A enzymatic pocket (R864C). Both exhibit the HTNB phenotype. Mutant PDE3A (T445N) overexpression in mouse vascular smooth muscle cells causes hypertension (mean telemetry BP 130/88 mm Hg vs littermate control 115/84 mm Hg, p<0.01). A 9 base-pair, three amino acid (3AA) deletion within the regulatory segment (using CRISPR-Cas9 technology), recapitulates HTNB in the rat, including the skeletal (with micro CT) phenotype. Three-weeks of radiotelemetry in homozygous 3AA+/+ rats at age 6 months revealed mean systolic BP 151, diastolic BP 119 mm Hg; heterozygous 3AA+/- (like the patients) showed 148/105 mm Hg; PDE3A knockout (frame-shift mutation) rats exhibited the lowest pressures at 115/87 mm Hg (all p<0.001) vs. BP of wild-type Sprague-Dawley rats at mean 126/90 mm Hg. R864C causes increased oligomerization. Furthermore, R864C, T445N, and 3AA all cause increased interactions at the scaffolding protein, 14-3-3 theta, compared to the wild-type (P<0.05). With two separate rodent models, our data not only direct mechanistic hypertension research along non-renal pathways, but also identify new areas of possible therapeutic intervention. We suggest that PDE3A could represent a generalizable novel therapeutic target in all instances of elevated blood pressure.
Abstract 041: Hypoxic Peripheral Chemoreceptor Activation Engages Sympathetic Brainstem and Hypothalamic Nuclei in Human Subjects
Authors: Gerlach Darius A , Manuel Jorge , Hoff Alex , Kronsbein Hendrik , Hoffmann Fabian , Heusser Karsten , Diedrich André , Ehmke Heimo , Jordan Jens , Tank Jens , Beissner Florian
Published: September 2019

Peripheral carotid chemoreceptors, which raise sympathetic activation at the brainstem level, may serve as targets for antihypertensive therapy. However, human peripheral chemoreflex regulation in the brainstem is poorly understood due to lack of suitable methodologies. Therefore, we combined measurements of beat-by-beat blood pressure and SpO
2
, and high-resolution functional magnetic resonance imaging (fMRI) to elucidate human brainstem circuits engaged through hypoxic peripheral chemoreceptor activation.

We submitted 12 healthy men (29.7 ±6.6 years; 24.0 ±1.86 kg/m
2
) to five hypoxic episodes by breathing 10% oxygen for 180 seconds followed by 90 seconds normoxia during multiband fMRI brain acquisitions. We monitored continuous finger arterial blood pressure using customized hardware, ECG, and SpO
2
. Brainstem and hypothalamus fMRI images were analyzed to identify nuclei involved in peripheral chemoreflex processing. Systolic blood pressure (SBP) and SpO
2
time courses were correlated with the blood-oxygen-level dependent signals with a general linear model.

With hypoxia, SpO
2
decreased by 12.32 ±3.68% (p < 0.01), heart rate increased 13.86 ±3.47 bpm (p < 0.01), and SBP decreased with hypoxia 5.45 ±5.5 mmHg (p < 0.01). In the brainstem, the nucleus tractus solitarii (t-values: SpO
2
: 5.9; SBP: 4.79), the caudal ventrolateral medulla (SpO
2
: 5.61; SBP: 5.59), intermediate reticular nucleus (SpO
2
: 4.7, SBP: 5.98), nucleus ambiguus (SpO
2
: 5.03, SBP: 5.59), dorsal motor nucleus of the vagal nerve (SBP: 4.79), and inferior olive (SpO
2
: 4.7, SBP: 6.16) were identified with high sensitivity and corrected for multiple comparisons (p < 0.01). Furthermore, we observed activation of the following hypothalamic nuclei: paraventricular nucleus (SpO
2
: 7.67), anterior and lateral hypothalamic area (SpO
2
: 7.67, SBP: 4.79), supraoptic nucleus, and tuberomammillary nucleus (SpO
2
: 7.07).

High-resolution brainstem fMRI during repeated hypoxia traces brainstem circuits engaged by peripheral chemoreceptors. The methodology can be applied to study peripheral chemoreceptor contributions to human cardiovascular disease and may have utility in identifying patients likely to respond to peripheral chemoreceptor modulation.
Abstract 044: High Sodium Intake Impairs Afferent Sympathodepressory Pathways in Rats
Authors: Rodionova Kristina , Ditting Tilmann , Fahrmeier Franziska , Loosen Sonja , Ott Christian , Schmieder Roland , Schiffer Mario , Amann Kerstin , Veelken Roland
Published: September 2019

Afferent renal nerve pathways are likely involved the development of salt sensitive hypertension. We recently reported that intrarenal NaCl elicited a long-lasting sympatho-depression via a neuro-humoral TRPV1 dependent and tachykinin mediated renal afferent nerve pathway. We now wanted to test the hypothesis that high sodium intake impairs this afferent sympatho-depressory mechanism. Respective groups were put on tap water, 0.9 % saline for drinking or chow containing 8% NaCl. Cultured dorsal root ganglion neurons (DRG Th11-L2) of rats with renal afferents were investigated in current clamp mode to assess action potential generation during current injection. Rats were equipped with femoral catheters for blood pressure (BP) & heart rate (HR) assessment, drug application, a renal arterial catheter for intrarenal administration (IRA) of NaCl boli (10 % NaCl, 10 μl) or Capsaicin (CAP 3.3, 6.6, 10, 33*10-7 M, 10 μl) and a bipolar electrode for renal sympathetic nerve activity (RSNA) recordings; eventually an intravenous (iv) bolus of the NK1-receptor blocker RP67580 (10*10-3M, 15 μl) was administered. Results are mean±SEM. In neurons from rats on high salt diet, but not on 0.9 % saline or controls the relation of tonic highly active neurons to less active neurons shifted towards less active units (tap water -tonic/phasic: 22/15; saline - tonic/phasic: 28/18; 8% high salt - tonic/phasic: 14/21* P<0.05). However, cultured tonic renal neurons from rats on 0.9% saline or on high salt diet exhibited increased action potential (AP) production upon stimulation (control 13,3+/4 APs/600ms vs. saline 19,8+/-2,33* APs/600ms vs. high salt diet 22,2*+/-4,54 APs/600ms, control vs. experimental *p<0.05, mean+/-SEM). ). 10% NaCl boli IRA induced decreases of RSNA from baseline 4.1±0.6 μV*sec to 2.2±0.8 μV*sec impaired in rats on 8% NaCl. (Suppressed RSNA unmasked in all groups by an i.v. NK1-inhibitor) In rats on high salt diet highly active tonic neurons with renal afferents
in vitro
decreased at the expense of less active phasic neurons in spite of tonic neurons producing more action potentials upon stimulation. The sodium inducible long-lasting sympatho-depression via a neuro-humoral tachykinin mediated afferent renal nerve pathway was eventually impaired.
Abstract 052: Rho Kinase and Endoplasmic Reticulum Stress Mediate Peripheral Vascular Dysfunction in a Model of Small Vessel Disease of the Brain
Authors: Neves Karla B , Morris Hannah , Alves-Lopes Rheure , Joutel Anne , Montezano Augusto C , Touyz Rhian M
Published: September 2019

CADASIL, a monogenic condition due to
Notch3
mutations is a small vessel disease of the brain resulting in premature vascular dementia and stroke. CADASIL patients have cerebral vascular narrowing, progressive SMCs loss and granular osmiophilic material (GOM) deposition, however it is unclear whether peripheral arteries also exhibit dysfunction. We studied mice harbouring the CADASIL-causing
Notch3
mutation (TgNotch3
R169C
), which recapitulates human CADASIL, to evaluate whether peripheral small arteries exhibit vascular dysfunction. Mesenteric arteries (MA) from male TgNotch3
R169C
and wildtype (TgNotch3
WT
) mice (6 months old) were investigated. Vascular structure and function were assessed by myography. No changes were observed in blood pressure and cardiac function in CADASIL mice, measured by tail cuff and echocardiography respectively. Expression of
Notch3
and target genes was augmented in MA from CADASIL mice (
Notch3
: 2.0±0.5 vs. 6.0±1.3; HeyL: 1.1±0.4 vs. 2.9±0.6, p<0.01). CADASIL mice exhibited impaired endothelium-dependent (Emax 109.9±7.4 vs. 81.3±5.4) and -independent (pD
2
7.8±0.1 vs 6.8±0.3) relaxation and increased reactivity in response to AngII (Emax 33.7±6.8 vs. 72.8±4.4), phenylephrine (Emax: 70.6±7.2 vs. 92.1±4.2), and U46619 (Emax: 123.4±4.4 vs. 215.1±24.4) (p<0.05 vs TgNotch3
WT
); effects attenuated by fasudil (Rho-kinase inhibitor) and 4-PBA (ER stress inhibitor) (p<0.05 vs. TgNotch3
R169C
). MA from CADASIL mice also had hypotrophic remodelling. U46619-induced calcium influx was increased in VSMCs (AUC: 1.3 fold increase) from TgNotch3
R169C
and gene expression of Rho GEFs (LARG: 1.1±0.1 vs. 2.1±0.3; PDZ: 0.9±0.1 vs. 2.9±0.4) was increased in MA from TgNotch3
R169C
vs. TgNotch3
WT
mice (p<0.05). eNOS phosphorylation (Thr
495
) and BiP expression (ER stress marker) were increased in vessels from CADASIL mice (eNOS: 1.8 fold increase; Bip: 1.7 fold increase; p<0.05 vs. TgNotch3
WT
). In conclusion, our data demonstrated that the vasculopathy associated with
Notch3
mutation is also present in peripheral small vessels where the interplay between Notch3, Rho-kinase and ER stress may be important. We identify potential new therapeutic targets in CADASIL, for which there are no disease-specific treatments.
Abstract 054: High Protein Diet-Induced Glomerular Hyperfiltration is Dependent on NOS1β
Authors: Wei Jin , Zhang Jie , Shan Jiang , Persson Erik , Liu Ruisheng
Published: September 2019

High protein diet is associated with glomerular hyperfiltration, but the mechanism has not been fully elucidated. In the present study, we tested a hypothesis that an increased intake of protein enhances the generation of neuronal nitric oxide synthase β (NOS1β)–dependent nitric oxide (NO) in the macula densa, which inhibits the tubuloglomerular feedback (TGF) response and promotes the rise in glomerular filtration rate (GFR). We used microperfusion, micropuncture, and renal clearance of FITC–sinistrin to examine the effects of high protein intake on NO generation at the macula densa, TGF, and GFR in C57BL/6, NOS1
flox/flox
and macula densa–specific NOS1 knockout (KO) mice. In C57BL/6 mice, a 4-weeks high protein diet increased kidney weight by 25.7±2.4 %, GFR by 33.6±3.7 % and renal blood flow (RBF) by 38.0±2.9 %, while reduced renal vascular resistance (RVR) by 25.8±3.1 % compared with a low protein diet. TGF response
in vivo
and
in vitro
were inhibited by 32.1±2.5 % and 31.7±4.2 % and NO generation by the macula densa was increased by 104.2±11.6 % following the high protein diet, associated with a 1.9±0.1-fold upregulation in NOS1β expression and a 2.4±0.1-fold upregulation in NOS1β phosphorylation at Ser1417 in renal cortex. The phenotype of the NOS1
flox/flox
mice in response to the high protein diet was similar to the C57BL/6 mice. In the KO mice, the high protein diet had no effect on the TGF-induced NO generation at the macula densa. The TGF response
in vivo
or
in vitro
was not significantly changed in the KO mice on the high protein diet. Furthermore, the increases of GFR and RBF, as well as kidney weight in response to the high protein diet were largely attenuated to 14.2±2.2 %, 16.1±2.4 %, and 10.9±1.9 % in the KO mice compared with the NOS1
flox/flox
mice.In conclusion, we identified a novel mechanism of high protein diet–induced hyperfiltration wherein an increase in protein intake upregulates the macula densa NOS1 β expression and activity via phosphorylation at Ser1417, which enhances the NO generation by the macula densa and blunts the TGF response, thereby promoting glomerular hyperfiltration.
Abstract 056: Racial Differences in Length of Stay and Hospital Expenses in Hypertension and Pregnancy
Authors: Grzeskowiak Michael Z , Berenji Navid , Pham Son , Oliveros Rene
Published: September 2019

Introduction:
Per a 2019 CDC report, pregnancy-related complications constituted approximately 700 deaths per year in the United States with cardiovascular disease being a primary driver of these deaths. Additionally, prior studies reveal known racial/ethnic disparities in treating cardiovascular disease. This epidemiological study analyzed the racial differences in length of stay and hospital expenses for women with hypertension and pregnancy at the three most populous states in the United States.

Methods:
The Healthcare Cost and Utilization Project database was used to gather statewide data. ICD-9 codes were used to collect data from 2014. ICD-9 codes were used that included both pregnancy and hypertension during in-patient admissions. The three most populous states in the United States were used to assess race/ethnicity in outcomes of length of stay (LOS) and mean hospital charges.

Results:
A total of 11,959; 6,726; 15,850 discharges were analyzed from California, New York, and Texas, respectively. LOS, in days, in California was 3.6, 3.3, and 3.1 for black, Asian/Pacific Islander, and white patients. LOS, in days, in New York was 3.9, 4.2, and 3.4 for black, Asian/Pacific Islander, and white patients. LOS, in days, in Texas was 3.8, 4.0, and 3.2 for black, Asian/Pacific Islander, and white patients. Mean hospital charges, in dollars, in California were 37,845, 39,502, and 33,406 for black, Asian/Pacific Islander, and white patients. Mean hospital charges, in dollars, in New York were 24,113, 28,777, and 17,711 for black, Asian/Pacific Islander, and white patients. Mean hospital charges, in dollars, in Texas were 21,890, 23,481, and 19,043 for black, Asian/Pacific Islander, and white patients.

Conclusion:
All three states revealed longer length of stay and higher hospital charges for black and Asian/Pacific Islander patients as compared to white patients. These results develop on those demonstrated by the CDC and underscore the importance of treating cardiovascular disease, specifically hypertension, in preventing pregnancy-related complications with an emphasis on treating black and Asian/Pacific Islander women. These preliminary results demonstrate how this would have a significant impact on length of stay and total hospital charges.
Abstract 059: Deficiency of Either Prebiotic Dietary Fibre or Prebiotic-Responsive Gut Microbiota Result in High Blood Pressure
Authors: Marques Francine , Shihata Waled , Jama Hamdi , Tsyganov Kirill , Ziemann Mark , Kiriazis Helen , Horlock Duncan , Giam Beverly , Vinh Antony , Johnson Chad , Fiedler April , Donner Daniel , Snelson Matthew , Phillips Sarah , Du Xiao-Jun , El-Osta Sam , Drummond Grant , Lambert Gavin , Mackay Charles , Kaye David
Published: September 2019

Background:
High fibre intake is associated with lower blood pressure (BP) in epidemiological and clinical studies. Prebiotic fibre resists digestion in the upper gastrointestinal tract and is fermented by gut microbiota in the intestine. The impact of lack of prebiotic dietary fibre in BP remains unknown.

Objectives:
To determine the consequences of lack of prebiotic dietary fibre to the development of hypertension through changes in the gut microbiome, associated receptors and immune-based mechanisms using a slow pressor angiotensin II (Ang II) model.

Methods:
C57BL/6 mice were fed a ‘no fibre’ or ‘high fibre’ diets for 3-weeks prior to sham or Ang II minipump implantation (n=4-21/group), and were followed for 4-weeks post-surgery. Gnotobiotic mice received faecal transplant from ‘no fibre’ sham or Ang II mice (n=5-6/group). Cardiac function, BP and gut microbiome (by 16S sequencing) were determined.

Results:
Ang II mice that received a ‘no fibre’ diet had significantly higher BP than sham (SBP mean±SEM: 143.7±3.5 vs 91.2±1.8, P<0.001) or ‘high fibre’ Ang II mice (143.7±3.5 vs 125.7±5mmHg, P<0.001). Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulates the prebiotic-deprived hypertensive phenotype (93.5±3 vs 107±3mmHg, P=0.017). Re-introduction of short-chain fatty acids (SCFAs; produced during fermentation of prebiotic fibre in the large intestine) acetate, propionate and butyrate to fibre-depleted mice had protective effects on the development of hypertension (143.7±3.5 vs 93±1.2, 112.8, 115.2mmHg, respectively), cardiac hypertrophy (cardiac weight index: 5.7 vs 5.2, 5.0, 4.9mg/g) and fibrosis (25.3 vs 8.9, 12.6, 12.5%) (all P<0.05). The anti-hypertrophic effect of SCFAs were mediated via cognate SCFA receptors GPR43/GPR109A (wild-type cardiac weight index 4.53 vs 6mg/g, 11.9% vs 24.4% perivascular fibrosis, P<0.01). Fibre increased the abundance of splenic T regulatory (Treg) cells (control 4.3 vs 6.2%, P<0.001) and acetate (4.3 vs 5.1, P=0.02).

Conclusions:
Lack of prebiotic dietary fibre leads to the development of a hypertensinogenic gut microbiome, hypertension and its complications. SCFA might represent new therapeutic opportunities through modulation of G-coupled protein receptors and Treg cells.
Abstract 080: Dietary Fructose Enhances Protein Kinase C Activation by Angiotensin II in Proximal Tubules via Changes in Intracellular Calcium
Authors: Garvin Jeffrey L , Hong Nancy , Yang Nianxin
Published: September 2019

Dietary fructose causes salt-sensitive hypertension. This is in part due to increasing the sensitivity of proximal nephron Na reabsorption to angiotensin II (Ang II) such that lower concentrations stimulate transport to a greater extent. Ang II stimulates Na transport in this segment by increasing protein kinase C (PKC) α, a calcium- and lipid-dependent kinase. We hypothesized that dietary fructose increases the ability of Ang II to elevate intracellular calcium (Cai) and, thereby, activate PKC α in proximal tubules. This, in turn, stimulates Na/H exchange activity, the primary transporter involved in Na reabsorption. To test our hypothesis rats were maintained on a diet of normal chow plus tap water or normal chow plus 20% fructose. The effect of Ang II on Cai was measured using Fura2 in perfused S2 segments. Na/H exchange (NHE) was measured in perfused tubules using the pH-sensitive dye BCECF. PKC α activity was measured by separating particulate and soluble fractions, performing Western blots and recording the particulate to soluble ratio. Basal Cai was 143±29 nM in proximal tubules from control rats while it was 160±30 nM in those given fructose, not significantly different. Ang II (1 nM) increased Cai by 43±10 nM in control tubules and by 148±53 nM in tubules from rats fed fructose (p < 0.03). A higher concentration of Ang II (100 nM) had a similar effect in tubules from both groups (Fructose: 237±100 nM vs. Control: 190±34 nM). Ang II increased the particulate to soluble ratio of PKC α, a measure of activation, by 0.134±0.026 in tubules from rats fed fructose (p <0.001) but not significantly in control tubules (0.060±0.061). Finally we measured NHE activity. Ang II (1 pM) increased NHE activity by 0.7±0.1 fluorescent units/s in tubules from rats given fructose but had no effect on NHE activity in control tubules (p<0.01). With Go6976, a PKC α/β1 inhibitor, Ang II was unable to stimulate NHE activity in tubules from rats fed fructose. We conclude that dietary fructose increases the ability of Ang II to elevate Cai, and consequently PKCα. This, in turn, stimulates NHE activity which likely contributes to fructose-induced salt-sensitivity of blood pressure.
Abstract 081: Ghrelin is Produced by the Kidney and Mediates Distal Tubular Sodium Reabsorption in Rats
Authors: Kemp Brandon A , Howell Nancy L , Padia Shetal H
Published: September 2019

Ghrelin is a 28-amino acid peptide hormone that exerts powerful appetite-stimulating effects. Ghrelin receptor expression has been reported in the collecting duct, but the role of ghrelin in the kidney is unknown. The present studies confirmed ghrelin mRNA expression in inner medullary collecting duct cells (N=6) using RT PCR and sequencing of the 320-bp PCR product. Ghrelin peptide expression was also confirmed in these cells using immunohistochemistry and flow cytometry. To test intrarenal ghrelin action, 12-week-old uninephrectomized female Sprague-Dawley rats (N=26) received 3 bolus injections of ghrelin siRNA (N=7) or scrambled siRNA (N=7) into the renal interstitial (RI) space of the remaining kidney, each injection 48h apart. Following the last injection, rats received three, 1h RI infusions of 5% dextrose in water. Mean arterial pressure (MAP), urine sodium (Na
+
) excretion (U
Na
V), glomerular filtration rate (GFR), fractional excretion of Na
+
(FE
Na
), and fractional excretion of lithium (FE
Li
) were calculated. In a separate set of rats, renal blood flow (RBF) was measured for 1h (N=6 for both ghrelin siRNA and scrambled siRNA). RI ghrelin siRNA-infused rats demonstrated significantly higher U
Na
V compared to scrambled siRNA-infused rats for all 3 periods (0.29±0.06 vs. 0.09±0.01, 0.35±0.09 vs. 0.11±0.03, and 0.27±0.07 vs. 0.09±0.02 μmol/min; P<0.01, P<0.05, and P<0.05 respectively) and significantly increased FE
Na
compared to scrambled siRNA infused rats (0.26±0.05 vs. 0.11±0.02, 0.35±0.06 vs. 0.11±0.03, and 0.24±0.04 vs. 0.10±0.03%; P<0.05, P<0.01, and P<0.05 respectively). There were no differences in in GFR, FE
Li
, MAP, or RBF. Since the increase in U
Na
V was not accompanied by similar increases in GFR, the effect of renal ghrelin inhibition suggested a tubular rather than hemodynamic, mechanism of action. To localize the specific tubular site, events distal to the renal proximal tubule were identified by changes in FE
Na
that occurred independently of changes in FE
Li
. RI ghrelin siRNA significantly increased FE
Na
without altering FE
Li
, suggesting distal nephron-dependent Na
+
reabsorption. Together, these data introduce ghrelin as a novel intrarenal peptide responsible for tonic Na
+
reabsorption at the level of the distal nephron.
Abstract 089: Role of Nox5 in Systemic Vascular Dysfunction in Ischemic Heart Disease
Authors: Montezano Augusto C , Sarafian Raquel D , Neves Karla B , Rios Francisco J , Passaglia Patricia , Camargo Livia L , Haddow Laura , Ford Thomas J , Dunne Michael , Alves-Lopes Rheure , MacQuaide Niall , Berry Colin , Smith Godfrey , Touyz Rhian M
Published: September 2019

Patients with coronary microvascular dysfunction (CMD), a potential cause of heart ischemia, have systemic vascular dysfunction, characterized by increased vascular contraction to ET-1 and a thromboxane A2 analogue (U46619). Nox5 regulates vascular contraction and is involved in cardiovascular diseases. In our study, we questioned whether Nox5 plays a role in systemic vascular dysfunction in heart ischemia. As Nox5 expression has been described in the cardiovascular system of rabbits, a model of ischaemic cardiomyopathy (IC) was used. Coronary artery ligation was performed in Male New Zealand White rabbits. After 8 weeks, skin and mesenteric arteries were isolated and vascular function assessed by wire myography. Vascular contraction to NA (EMax %KCl: 122±4 vs sham 97±3.7) and U46619 (EMax %KCl: 82±3 vs sham 67±4) were exacerbated in skin arteries from IC (p<0.05); an effect blocked by tiron (antioxidant, 10 μM) and melittin (nox5 inhibitor, 0.1 μM). In mesenteric arteries from IC animals, NA (EMax %KCl: 108±3 vs sham 98±7) and ET-1 (EMax %KCl: 103±3 vs sham 81±4) induced contraction were increased in a Nox5-ROS-dependent manner (p<0.05). No differences were observed in mRNA levels of Cav1.2 and IP3R Ca
2+
channels, but an increase in RyR was observed (2^-ddCT: 1.67±0.15 vs sham 0.98±0.08) in VSMCs isolated from IC animals. Peroxiredoxin (Prdx), antioxidant, mRNA was increased in IC (2^-ddCT: 1.95±0.4 vs sham 0.88±0.1, p<0.05). Conoidin A, an inhibitor of Prdx oxidation, reduced vascular contraction to NA in arteries from IC animals (EMax %KCl: 95±4, p<0.05). In subjects with CMD, we assessed total number of microparticles (MP) as biomarkers of vascular dysfunction. MPs were increased in CMD subjects (x10
11
/mL: 4.8±0.6 vs control 1.75±0.2), where Nox5 expression was also increased (AU: 0.11±0.02 vs control MP 0.03±0.006) (p<0.05). In separate studies, we exposed WT control arteries to MPs from WT and Nox5-expressing mice before assessing contraction. MPs from Nox5 mice increased contraction to a higher level of that observed with MPs from WT mice (EMax %KCl: 106±2 vs WT 96±2, p<0.05). In our study, we identify Nox5 as a regulator of systemic vascular dysfunction in ischemic heart diseases, through mechanisms that may involve ROS, Prdx oxidation and MPs.
Abstract 097: Megalin: A Novel Endocytic Receptor for Prorenin and Renin?
Authors: Sun Yuan , Garrelds Ingrid M , Lu Xifeng , Danser A.H. Jan
Published: September 2019

Disturbed renal handling of prorenin and renin [(pro)renin] may result in hypertension and renal damage. Megalin is a major endocytic receptor playing an essential role in nutrient reabsorption. Genetic mutations resulting in impaired expression or trafficking of megalin in patients with Dent’s disease or Lowe syndrome caused a 20-40-fold rise of urinary renin levels. Interestingly, the urine of such patients also contained prorenin, which normally is undetectable in urine. Moreover, inhibiting megalin in rodents massively upregulated urinary renin levels. The aim of this study was to investigate (pro)renin binding and internalization by megalin. Immortalized Brown Norway Rat yolk sac cells (BN16) were used, since they abundantly express megalin. To distinguish binding and internalization, cells were incubated at 4°C and 37°C, respectively, with 1000 U/L recombinant human (pro)renin for up to 24 hours. (Pro)renin levels were assessed using an immunoradiometric assay. At 4°C, BN16 cells bound 3 times more prorenin than renin (14184.0±2626.0 vs. 4795.0±986.5 pg/mg of protein, p=0.0155), suggestive for a higher affinity of prorenin. Similarly, at 37°C, prorenin accumulated at 3-fold higher levels than renin in BN16 cells. Consequently, depletion of medium prorenin (but not renin) content occurred after 24 hours. Mannose-6-phosphate (M6P), an antagonist of the (pro)renin-binding M6P receptor, did not affect cellular (pro)renin uptake. Yet, inhibiting megalin expression using siRNAs reduced (pro)renin binding and internalization by >50%. Furthermore, treating cells with albumin, an endogenous ligand of megalin, also decreased binding and internalization of (pro)renin. Exposing prorenin’s prosegment with the renin inhibitor aliskiren dramatically increased prorenin binding, while after prosegment cleavage with trypsin prorenin binding was identical to that of renin. In conclusion, megalin is a novel endocytic receptor for (pro)renin which determines urinary (pro)renin levels. Megalin displays selectivity towards prorenin in a prosegment-dependent manner, and this explains why urine normally does not contain prorenin, except under conditions where megalin trafficking is disturbed.