bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic adjustments in response to graded exercise depends on central angiotensin AT1‐receptors
Authors: Leite Laura Hora Rios , Lacerda Ana Cristina R. , Balthazar Cláudio H. , Marubayashi Umeko , Coimbra Cândido C. 
Published: June 2021

To asses the influence of central angiotensin AT1 receptors on metabolic adjustments in rats during graded exercise on a treadmill, 2 μL of NaCl (Sal) or losartan (Los; 60 nmol) were intracerebroventricularly injected before running until fatigue (starting at 10 m/min, 1 m/min increment every 3 min until fatigue, 10% inclination). Oxygen consumption (VO2) was measured and mechanical efficiency (ME) calculated (n=6). The same protocol was used to collect blood samples through a jugular catheter (n=7). Plasmatic concentrations of glucose, lactate and free fatty acids (FFAs) were determined. During the first two steps of exercise, a similar increase in VO2 and equal ME were observed in both groups. Thereafter, VO2 continued to increase, but at a higher rate in Los‐treated animals, leading to a 34% reduction in ME in these animals (p<0.01). Los‐treated rats also showed a fast hyperglycemic response, already seen at low exercise intensities as 20% of maximal work. Higher lactate and FFAs levels followed this hyperglycemic response. The data shows that AT1‐receptor blockade during graded exercise increases metabolic cost, leading to decreased ME, hyperglycemia and higher FFA mobilization at lower levels of exercise intensities. We conclude that angiotensinergic blockade results in higher and premature sympathetic activation, shifting energy balance during graded exercise.Supported by CNPq, FAPEMIG
Metabolic Modeling of Acetate Transport and Metabolism in the Rat Brain
Authors: Shestov Alexander A , Deelchand Dinesh K , Henry Pierre‐Gilles 
Published: June 2021

The aims of this study were first to determine kinetic parameters for acetate transport and utilization in the brain and then use this information to perform 13C dynamic modeling in order to determine absolute cerebral metabolic fluxes.Previously measured in vivo 13C time courses obtained during infusion of [2‐13C] acetate in rat brain under morphine anesthetic at 9.4 T [1] were used for the modeling.Fitted values for transport and uptake kinetics were: Vtrmax= 0.96 ± 0.18 μmol/g/min and KtrM= 4.2 ± 0.8 mM for acetate transport through the BBB and Vutmax=0.50 ± 0.08 μmol/g/min with KMut= 0.01 ± 0.14 mM for acetate utilization through the mitochondrial inner membrane and acetyl‐CoA synthetase from acetate. The steady‐state cerebral metabolic flux of acetate (CMRace) was 0.49 ± 0.08 μmol/g/min (mean ± SD; n = 4).Metabolic fluxes determined from modeling of the 13C time courses were: VTCA(n)= 1.8 μmol/g/min, VTCA(g)= 0.27 μmol/g/min, VPC= 0.1 μmol/g/min, VX=1.4 μmol/g/min and VNT= 0.23 μmol/g/min.Maximum transport capacity of acetate through the BBB was two‐hold higher than the maximum rate of brain acetate utilization and KtrM was much higher than KMut, implying that the rate‐limiting step for acetate metabolism occurs after acetate enters the brain.[1] Deelchand et al. ISMRM 2006This work was supported by NIH P41 RR008079, P30 NS057091 and R01 NS038672
Functional Characterization of Ca2+ and K+ Channels in Human Embryonic Stem Cells
Authors: Firth Amy L. , Yuan Jason X.‐J. 
Published: June 2021

Human embryonic stem cell (hESC) expansion involves both self‐renewal and differentiation. Physiological properties of cell motility, migration and proliferation all require cytoplasmic Ca2+ and are regulated by a) membrane potential; b) spatial and temporal variations of intracellular Ca2+; and c) spatially‐ and temporally‐regulated expression of plasmalemmal receptors. Functional adaptation of Ca2+ and K+ channels in the plasma membrane may thus be an important prerequisite for hESCs to self‐renew, migrate into special niches or microenvironments and to differentiate into specific lineages. Using H9 hESC, changes in the voltage‐gated K+ (Kv) channels were closely related with the ability of hESC to differentiate into a smooth muscle like cell phenotype. The ion channel profile changed from a predominantly "A" type rapidly inactivating current to a delayed rectifier type current and correlated with an increase in expression of the Kv1 family of delayed rectifier K+ channels and a decrease in pluripotency markers OCT‐4 and NANOG. In addition, hESC express multiple transient receptor potential (TRP) channel subunits and passive depletion of Ca2+ from intracellular stores activated store‐operated Ca2+ entry. These data confirm that function and expression of certain ion channels in hESC differ from those in differentiated cell phenotypes such as smooth muscle cells and neurons, and the changes in channel activity are necessary for hESC to differentiate into functionally matured cells.Funded by the NIH/NHLBI and CIRM.
Increased arterial blood pressure and volume expansion in Atrap (angiotensin receptor‐associated protein) – deficient mice
Authors: Oppermann Mona , Castrop Hayo 
Published: June 2021

Atrap is an interacting protein of angiotensin AT1 receptors and was shown to facilitate AT1 receptor internalization in vitro. To further assess the in vivo function of Atrap, we generated Atrap‐deficient mice by gene targeting.Atrap‐deficient mice were viable, fertile and showed no gross abnormalities. Atrap protein in the kidney was localized to the proximal tubules. We found no Atrap expression in the renal vasculature or in JG cells. Systolic arterial blood pressure (telemetry) was elevated in Atrap‐/‐ compared to +/+ mice averaging 120.3±0.7 vs. 111.7±1.4 mm Hg (n=5, 72 hrs‐measurement, p=0.001). Dose‐response curves of arterial blood pressure after bolus angiotensin II infusion were similar in both genotypes. Plasma renin concentration (PRC) was markedly reduced in Atrap‐/‐ compared to +/+ (49±4 vs. 100±13 ng Ang I/mL/hr, n=40 and 37, respectively; p<0.001). After acute furosemide administration PRC increased 13.2±2 fold in Atrap‐/‐ and 9.9±1.8 fold in +/+ (p=0.34) indicating an intact renin secretory capacity in Atrap‐/‐ mice. Plasma volume was increased in Atrap‐/‐ compared to wild types (4.1±0.2 vs. 3.1±0.2% of body weight, n=18 and 13; p<0.002).In summary, Atrap‐deficient mice are hypertensive, volume expanded, and show a suppressed renin system. We suggest that Atrap acts as a negative regulator of AT1 receptors and that Atrap may be involved in the control of proximal tubular function.
Soluble guanylyl cyclase and phosphodiesterase 2A contribute to lung injury from intra‐tracheal LPS in mice
Authors: Rentsendorj Otgonchimeg , Schmid Eric P , D'Alessio Franco R , Aggarwal Neil R , Stephens R Scott , Servinsky Laura E , Pearse David P 
Published: June 2021

In animal models of lipopolysaccharide‐induced acute lung injury (LPS‐ALI), increased NO production from endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) contributes to alveolitis and epithelial barrier dysfunction. The toxic effects of NO have been attributed to peroxynitrite, but NO also generates cGMP through soluble guanylyl cyclase (sGC). Cytokines have been shown to increase human umbilical vein endothelial expression of phosphodiesterase 2A (PDE2A) in vitro (Surapisitchat et al. Circ Res 2007). PDE2A is a dual‐function PDE stimulated by cGMP to hydrolyze cAMP, a potent barrier‐protective molecule. We hypothesized that sGC and PDE2A contribute to LPS‐ALI. To test this, we administered intratracheal LPS (3.75 μg/g body weight) or diluent to anesthetized C57BL6 mice pretreated with the sGC inhibitor ODQ (10 mg/kg ip 1 hr before), the PDE2A inhibitor BAY 60‐7550 (3 mg/kg 1 hr before) or intraperitoneal (ip) diluent. At 6 hrs, the mice were reanesthetized for unilateral bronchoalveolar lavage (BAL) and lung harvesting. LPS increased BAL leukocytes, LDH and protein indicating alveolitis. LPS also increased lung Ser1177 eNOS phosphorylation, iNOS mRNA and PDE2A mRNA and protein expression. LPS did not alter sGC expression. sGC inhibition significantly attenuated the LPS‐induced increase in iNOS mRNA, BAL leukocytes and BAL LDH activity indicating an injurious role for sGC‐derived cGMP. PDE2A inhibition decreased iNOS mRNA and BAL LDH activity suggesting that PDE2A was also involved. We conclude that LPS‐induced activation of sGC in combination with LPS‐induced PDE2A expression contribute to LPS‐ALI in mice.Supported by AHA Grant‐In‐Aid
Characterization of Plasmepsin 10 from the Malaria Parasite P. falciparum
Authors: Machhar Raj P. , Marzahn Melissa R. , Johnson Zachary L. , Beyer Carl A. , Soni Ashik 
Published: June 2021

Malaria infection is caused by the protozoan parasite Plasmodium. Of the four forms of Plasmodium that infect humans, P. falciparum is the most deadly. Furthermore, chloroquine, the most popular anti‐malarial drug, is slowly becoming ineffective because of P. falciparum's growing resistance to it. This means that new anti‐malarial drugs need to be developed immediately to continue combating malaria across the globe and curb the perpetuation of P. falciparum.P. falciparum genome encodes for ten aspartic proteases known as plasmepsins. The primary objective of my research project is to obtain active and purified plasmepsin 10 that can be used in kinetic assays and x‐ray crystallographic studies.The protein was expressed in a recombinant bacterial system. Once the protein is purified, folded and active, kinetic assays can be performed to determine the kinetic parameters Km, Ki and Kcat. Next, optimal conditions for x‐ray crystallography are determined, and x‐ray crystallography is carried out to observe and analyze the enzyme‐inhibitor complex. This allows us to learn about the interactions between plasmepsin 10 and relevant inhibitors, along with the structural stability of the protein. This data will hopefully lead to a new anti‐malarial drug that could save the lives of millions of people every year.
Nitric Oxide Synthase: Catalytic Model for Reductase Function
Authors: Assan‐Mensah Issac B , Couser Laura M. , Dinsmore Natalie E. , Vogelien Dale L. , Lester Army , Smith Susan M.E. , Salerno John C. 
Published: June 2021

The NOS reductase unit, comprising three C terminal domains, is closely related to homologs studied intensively for many years. Several groups proposed ping‐pong and two state ping‐pong models for NADPH P450 reductase (e.g., Sem and Kasper, 1994). These proposals were adapted to NOS (Wolthers and Schimerlik, 2002) and shown to describe the kinetics of NADPH cytochrome c reductase activity at low substrate concentrations.We previously constructed a King‐Altman 'Ligand Restricted Conformational Shuttle' (LRCS) model based on an FMN domain shuttle in which cytochrome c interacts with FMN when the FMN binding domain is dissociated from the reductase complex. Here we show that this model explains details of NADPH cytochrome c reductase activity at high and low substrate concentrations without extra inhibitory weak binding sites. This includes potent substrate inhibition at high concentrations of cytochrome c as well as pseudo ping‐pong behavior at low substrate concentrations. The major effect of calmodulin binding on nNOS and eNOS reductase activities is to increase dissociation of the FMN binding domain, making it accessible to cytochrome c for electron transfer. Because of its size and specific interaction with the FMN binding domain, cytochrome c is a good model for NOS catalytic electron transfer. DCIP and ferricyanide reduction do not require similar large scale conformational change.
Outcomes of Various Antibiotic Cement–Coated Intramedullary Implants on the Treatment of Long Bone Septic Nonunion
Authors: Lopas Luke A. , Albertson Spencer , Solomon Eric , Watson David T. , Shah Anjan R. , Maxson Benjamin J. , Infante Anthony F. , Donohue David , Downes Katheryne L. , Sanders Roy W. , Mir Hassan R. 
Published: June 2021

Objective:
To determine the effectiveness of various types of antibiotic-coated intramedullary implants in the treatment of septic long bone nonunion.

Design:
Retrospective chart review.

Setting:
Level 1 trauma center.

Participants:
Forty-one patients with septic long bone nonunion treated with an antibiotic cement–coated intramedullary implant.

Intervention:
Surgical debridement and placement of a type of antibiotic-coated intramedullary implant.

Main Outcome Measurements:
Union and need for reoperation.

Results:
At an average 27-month follow-up (6–104), 27 patients (66%) had a modified radiographic union score of the tibia of 11.5 or greater, 12 patients (29%) a score lower than 11.5, and 2 patients (5%) underwent subsequent amputation. Six patients underwent no further surgical procedures after the index operation. Patients treated with a rigid, locked antibiotic nail achieved earlier weight-bearing (P = 0.001), less frequently required autograft (P = 0.005), and underwent fewer subsequent procedures (average 0.38 vs. 3.60, P = 0.004) than those treated with flexible core antibiotic rods.

Conclusions:
Antibiotic-coated intramedullary implants are successful in the treatment of septic nonunions in long bones. In our cohort, rigid, statically locked nails allowed faster rehabilitation, decreased the need for autograft, and decreased the number of additional surgical procedures. Further study is needed to confirm these findings.

Level of Evidence:
Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Efficacy of Percutaneous Retrograde Transphyseal Guided Growth Screw in Distal Femoral Angular Deformity Correction: A New Technique
Authors: Abdelaziz Ahmed , ElAshry Sameeh M. , Awadh Mohammad M. , Khaja Aliaa , Alsaifi Saleh 
Published: June 2021

Background:
We modified the original technique for percutaneous transphyseal screw which was described in 1998 by Metaizeau and colleagues for distal femoral coronal angular deformity correction; the modification is related to the screw direction, whereas the screw is administered in a retrograde pattern, starting from the epiphysis and directed toward the metaphysis. This technique opposes the original technique that was started with a metaphyseal entry point which aimed toward the epiphysis. This study evaluates the efficacy of the newly suggested surgical technique regarding the rate of correction and growth resumption after screw removal.

Methods:
This prospective study looked at 40 patients (65 distal femoral physes), who underwent a percutaneous retrograde transphyseal guided growth screw procedure, from October 2017 to September 2019. All the patients included had distal femoral coronal angular deformities; 52 in valgus and 13 in varus deformities. The study included 17 females with an average age of 11.75 (range: 8.4 to 14.5 y) for 29 femurs and 23 males with an average age of 13.75 (range: 11.75 to 15.6 y) for 36 femurs. The mechanical lateral distal femoral angle was measured initially, and then again was measured after reaching the desired corrected orientation. The patients were then followed up after the screw removal and followed up to maturity, if the physis had continued to grow postcorrection. The degree of correction per month was calculated, and the consequence of screw removal was detected. Follow-up average time was 12.6 months (range: 30 to 6 mo).

Results:
The average correction in the distal femur was 1.3 degrees per month (range: 0.5 to 1.857 degrees/mo). In all of the 65 segments (61 femurs had significant growth remaining and 4 femurs had reached skeletal maturity with suboptimal mechanical lateral distal femoral angle correction), the screws were removed at the time of angular correction. Rebound growth was observed in 15 physes with an average of 1.8 degrees (range: 2 to 3 degrees); they were stable in 42 physes and progressed in 4 physes with an average of 1.6 degrees (range: 1 to 2 degrees). Complications were minor and related to entrapment of soft tissue under the screw washer.

Conclusion:
Percutaneous retrograde transphyseal guided growth screw for distal femur coronal angular deformity is a minimally invasive procedure, with a statistically significant correction rate when compared with the original transphyseal screw technique. The new technique has proven to have growth resumption after screw removal with minimal complication risk.

Level of Evidence:
Level III—prospective observational study.
Comparison between capnodynamic and thermodilution method for cardiac output monitoring during major abdominal surgery
Authors: Sigmundsson Thorir S. , Öhman Tomas , Hallbäck Magnus , Suarez-Sipmann Fernando , Wallin Mats , Oldner Anders , Hällsjö-Sander Caroline , Björne Håkan 
Published: June 2021

BACKGROUND
Cardiac output (CO) monitoring is the basis of goal-directed treatment for major abdominal surgery. A capnodynamic method estimating cardiac output (CO

EPBF
) by continuously calculating nonshunted pulmonary blood flow has previously shown good agreement and trending ability when evaluated in mechanically ventilated pigs.

OBJECTIVES
To compare the performance of the capnodynamic method of CO monitoring with transpulmonary thermodilution (CO
TPTD) in patients undergoing major abdominal surgery.

DESIGN
Prospective, observational, method comparison study. Simultaneous measurements of CO

EPBF
and CO
TPTD were performed before incision at baseline and before and after increased (+10 cmH2O) positive end-expiratory pressure (PEEP), activation of epidural anaesthesia and intra-operative events of hypovolemia and low CO. The first 25 patients were ventilated with PEEP 5 cmH2O (PEEP5), while in the last 10 patients, lung recruitment followed by individual PEEP adjustment (PEEPadj) was performed before protocol start.

SETTING
Karolinska University Hospital, Stockholm, Sweden.

PATIENTS
In total, 35 patients (>18 years) scheduled for major abdominal surgery with advanced hemodynamic monitoring were included in the study.

MAIN OUTCOME MEASURES AND ANALYSIS
Agreement and trending ability between CO

EPBF
and CO
TPTD at different clinical moments were analysed with Bland--Altman and four quadrant plots.

RESULTS
In total, 322 paired values, 227 in PEEP5 and 95 in PEEPadj were analysed. Respectively, the mean CO

EPBF
and CO

TPTD
were 4.5 ± 1.0 and 4.8 ± 1.1 in the PEEP5 group and 4.9 ± 1.2 and 5.0 ± 1.0 l min−1 in the PEEPadj group. Mean bias (levels of agreement) and percentage error (PE) were −0.2 (−2.2 to 1.7) l min−1 and 41% for the PEEP5 group and −0.1 (−1.7 to 1.5) l min−1 and 31% in the PEEPadj group. Concordance rates during changes in CO

EPBF
and CO
TPTD were 92% in the PEEP5 group and 90% in the PEEPadj group.

CONCLUSION

CO

EPBF
provides continuous noninvasive CO estimation with acceptable performance, which improved after lung recruitment and PEEP adjustment, although not interchangeable with COTPTD. This method may become a tool for continuous intra-operative CO monitoring during general anaesthesia in the future.

TRIAL REGISTRATION
Clinicaltrials.gov identifier: NCT03444545.
State of the art: the role of citrulline as biomarker in patients with chemotherapy- or graft-versus-host-disease-induced mucositis
Authors: Dekker Ingeborg M. , Bruggink Hanneke , van der Meij Barbara S. , Wierdsma Nicolette J. 
Published: June 2021

Purpose of review
Serum or plasma citrulline levels are used as biomarker for a broad spectrum of intestinal functions. During high-dose chemotherapy, citrulline levels are decreased due to mucositis, a common side effect of chemotherapy. This may decrease intestinal function and result in diarrhea. In this review, most recent studies investigating citrulline as biomarker for intestinal function are discussed, with focus on patients with oncological diseases, specifically hematological malignancies with chemotherapy- or Graft-versus-Host-disease (GVHD)-induced mucositis.

Recent findings
Citrulline has recently been widely studied in relation to intestinal function and various clinical conditions. It seems therefore a promising noninvasive biomarker in clinical practice for more than intestinal function alone. The association between citrulline levels and intestinal function in patients with hematological malignancies, with or without mucositis remains unclear, as no other parameters of intestinal function for this purpose were assessed.

Summary
In conclusion, citrulline seems to be a promising noninvasive biomarker for various intestinal conditions in general, and potentially for intestinal function in patients with chemotherapy- or GVHD-induced mucositis. It is unclear from recent literature whether high fecal volume or diarrhea as side effect, results in impaired intestinal function and severe malabsorption and if citrulline biomarkers can be useful to detect this.
Gut microbiota and microbiome in schizophrenia
Authors: Samochowiec Jerzy , Misiak Błażej 
Published: June 2021

Purpose of review
Accumulating evidence indicates that there are bidirectional interactions between the gut microbiota and functioning of the central nervous system. Consequently, it has been proposed that gut microbiota alterations might play an important role in the pathophysiology of schizophrenia. Therefore, in this article, we aimed to perform a narrative review of studies addressing gut microbiota alterations in patients with schizophrenia that were published in the years 2019–2020.

Recent findings
Several studies have shown a number of gut microbiota alterations at various stages of schizophrenia. Some of them can be associated with neurostructural abnormalities, psychopathological symptoms, subclinical inflammation and cardiovascular risk. Experimental studies clearly show that transplantation of gut microbiota from unmedicated patients with schizophrenia to germ-free mice results in a number of behavioural impairments accompanied by altered neurotransmission. However, findings from clinical trials do not support the use of probiotics as add-on treatments in schizophrenia.

Summary
Gut microbiota alterations are widely observed in patients with schizophrenia and might account for various biological alterations involved in the cause of psychosis. However, longitudinal studies are still needed to conclude regarding causal associations. Well designed clinical trials are needed to investigate safety and efficacy of probiotics and prebiotics in schizophrenia.
Data-Driven Patterns in Protective Effects of Ibuprofen and Ketorolac on Hospitalized Covid-19 Patients
Authors: Lengerich Benjamin J. , Caruana Rich , Aphinayanaphongs Yin 
Published: June 2021

AbstractThe impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on patients with Covid-19 has been unclear. A major reason for this uncertainty is the confounding between treatments, patient comorbidities, and illness severity. Here, we perform an observational analysis of over 3000 patients hospitalized for Covid-19 in a New York hospital system to identify the relationship between in-patient treatment with Ibuprofen or Ketorolac and mortality. Our analysis finds evidence consitent with a protective effect for Ibuprofen and Ketorolac, with evidence stronger for a protective effect of Ketorolac than for a protective effect of Ibuprofen.