Ertugliflozin for Functional Mitral Regurgitation Associated With Heart Failure: EFFORT Trial.

BACKGROUND: The morbidity and mortality rates of patients with heart failure (HF) and functional mitral regurgitation (MR) remain substantial despite guideline-directed medical therapy for HF. We evaluated the efficacy of ertugliflozin for reduction of functional MR associated with HF with mild to moderately reduced ejection fraction. METHODS: The EFFORT trial (Ertugliflozin for Functional Mitral Regurgitation) was a multicenter, double-blind, randomized trial to examine the hypothesis that the sodium-glucose cotransporter 2 inhibitor ertugliflozin is effective for improving MR in patients with HF with New York Heart Association functional class II or III, 35%≤ejection fraction<50%, and effective regurgitant orifice area of chronic functional MR >0.1 cm2 on baseline echocardiography. We randomly assigned 128 patients to receive either ertugliflozin or placebo in addition to guideline-directed medical therapy for HF. The primary end point was change in effective regurgitant orifice area of functional MR from baseline to the 12-month follow-up. Secondary end points included changes in regurgitant volume, left ventricular (LV) volume indices, left atrial volume index, LV global longitudinal strain, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: The treatment groups were generally well-balanced with regard to baseline characteristics: mean age, 66±11 years; 61% men; 13% diabetes; 51% atrial fibrillation; 43% use of angiotensin receptor-neprilysin inhibitor; ejection fraction, 42±8%; and effective regurgitant orifice area, 0.20±0.12 cm2. The decrease in effective regurgitant orifice area was significantly greater in the ertugliflozin group than in the placebo group (-0.05±0.06 versus 0.03±0.12 cm2; P<0.001). Compared with placebo, ertugliflozin significantly reduced regurgitant volume by 11.2 mL (95% CI, -16.1 to -6.3; P=0.009), left atrial volume index by 6.0 mL/m2 (95% CI, -12.16 to 0.15; P=0.005), and LV global longitudinal strain by 1.44% (95% CI, -2.42% to -0.46%; P=0.004). There were no significant between-group differences regarding changes in LV volume indices, ejection fraction, or NT-proBNP levels. Serious adverse events occurred in one patient (1.6%) in the ertugliflozin group and 6 (9.2%) in the placebo group (P=0.12). CONCLUSIONS: Among patients with functional MR associated with HF, ertugliflozin significantly improved LV global longitudinal strain and left atrial remodeling, and reduced functional MR. Sodium-glucose cotransporter 2 inhibitors may be considered for patients with functional MR. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04231331.

Nanosensor-based monitoring of autophagy-associated lysosomal acidification in vivo.

Autophagy is a cellular process with important functions that drive neurodegenerative diseases and cancers. Lysosomal hyperacidification is a hallmark of autophagy. Lysosomal pH is currently measured by fluorescent probes in cell culture, but existing methods do not allow for quantitative, transient or in vivo measurements. In the present study, we developed near-infrared optical nanosensors using organic color centers (covalent sp3 defects on carbon nanotubes) to measure autophagy-mediated endolysosomal hyperacidification in live cells and in vivo. The nanosensors localize to the lysosomes, where the emission band shifts in response to local pH, enabling spatial, dynamic and quantitative mapping of subtle changes in lysosomal pH. Using the sensor, we observed cellular and intratumoral hyperacidification on administration of mTORC1 and V-ATPase modulators, revealing that lysosomal acidification mirrors the dynamics of S6K dephosphorylation and LC3B lipidation while diverging from p62 degradation. This sensor enables the transient and in vivo monitoring of the autophagy-lysosomal pathway.

Noncanonical PDK4 action alters mitochondrial dynamics to affect the cellular respiratory status.

Dynamic regulation of mitochondrial morphology provides cells with the flexibility required to adapt and respond to electron transport chain (ETC) toxins and mitochondrial DNA-linked disease mutations, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here, we show that pyruvate dehydrogenase kinase 4 (PDK4) is genetically required for cells to undergo rapid mitochondrial fragmentation when challenged with ETC toxins. Moreover, PDK4 overexpression was sufficient to promote mitochondrial fission even in the absence of mitochondrial stress. Importantly, we observed that the PDK4-mediated regulation of mitochondrial fission was independent of its canonical function, i.e., inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Phosphoproteomic screen for PDK4 substrates, followed by nonphosphorylatable and phosphomimetic mutations of the PDK4 site revealed cytoplasmic GTPase, Septin 2 (SEPT2), as the key effector molecule that acts as a receptor for DRP1 in the outer mitochondrial membrane to promote mitochondrial fission. Conversely, inhibition of the PDK4-SEPT2 axis could restore the balance in mitochondrial dynamics and reinvigorates cellular respiration in mitochondrial fusion factor, mitofusin 2-deficient cells. Furthermore, PDK4-mediated mitochondrial reshaping limits mitochondrial bioenergetics and supports cancer cell growth. Our results identify the PDK4-SEPT2-DRP1 axis as a regulator of mitochondrial function at the interface between cellular bioenergetics and mitochondrial dynamics.

Programming sp3 Quantum Defects along Carbon Nanotubes with Halogenated DNA.

Atomic defect color centers in solid-state systems hold immense potential to advance various quantum technologies. However, the fabrication of high-quality, densely packed defects presents a significant challenge. Herein we introduce a DNA-programmable photochemical approach for creating organic color-center quantum defects on semiconducting single-walled carbon nanotubes (SWCNTs). Key to this precision defect chemistry is the strategic substitution of thymine with halogenated uracil in DNA strands that are orderly wrapped around the nanotube. Photochemical activation of the reactive uracil initiates the formation of sp3 defects along the nanotube as deep exciton traps, with a pronounced photoluminescence shift from the nanotube band gap emission (by 191 meV for (6,5)-SWCNTs). Furthermore, by altering the DNA spacers, we achieve systematic control over the defect placements along the nanotube. This method, bridging advanced molecular chemistry with quantum materials science, marks a crucial step in crafting quantum defects for critical applications in quantum information science, imaging, and sensing.

Quantum Defect Sensitization via Phase-Changing Supercharged Antibody Fragments.

Quantum defects in single-walled carbon nanotubes promote exciton localization, which enables potential applications in biodevices and quantum light sources. However, the effects of local electric fields on the emissive energy states of quantum defects and how they can be controlled are unexplored. Here, we investigate quantum defect sensitization by engineering an intrinsically disordered protein to undergo a phase change at a quantum defect site. We designed a supercharged single-chain antibody fragment (scFv) to enable a full ligand-induced folding transition from an intrinsically disordered state to a compact folded state in the presence of a cytokine. The supercharged scFv was conjugated to a quantum defect to induce a substantial local electric change upon ligand binding. Employing the detection of a proinflammatory biomarker, interleukin-6, as a representative model system, supercharged scFv-coupled quantum defects exhibited robust fluorescence wavelength shifts concomitant with the protein folding transition. Quantum chemical simulations suggest that the quantum defects amplify the optical response to the localization of charges produced upon the antigen-induced folding of the proteins, which is difficult to achieve in unmodified nanotubes. These findings portend new approaches to modulate quantum defect emission for biomarker sensing and protein biophysics and to engineer proteins to modulate binding signal transduction.

Effects of intensive blood pressure control on left ventricular hypertrophy in aortic valve disease.

BACKGROUND: Hypertension adds to the pressure overload on the left ventricle (LV) in combination with aortic valve (AV) disease, but the optimal blood pressure (BP) targets for patients with AV disease remain unclear. We tried to investigate whether intensive BP control reduces LV hypertrophy in asymptomatic patients with aortic stenosis (AS) or aortic regurgitation (AR). METHODS: A total of 128 hypertensive patients with mild to moderate AS (n = 93) or AR (n = 35) were randomly assigned to intensive therapy, targeting a systolic BP <130 mm Hg, or standard therapy, targeting a systolic BP <140 mm Hg. The primary end point was the change in LV mass from baseline to the 24-month follow-up. Secondary end points included changes in severity of AV disease, LV volumes, ejection fraction and global longitudinal strain (GLS). RESULTS: The treatment groups were generally well balanced regarding the baseline characteristics. The mean (±SD) age of the patients was 68 ± 8 years and 48% were men. The mean BP was 145 ± 12/81 ± 10 mm Hg at baseline. Medication at baseline was similar between the 2 groups. The 2 treatment strategies resulted in a rapid and sustained difference in systolic BP (P < .05). At 24-month, the mean systolic BP was 129 ± 12 mm Hg in the intensive therapy group and 135 ± 14 mm Hg in the standard therapy group. No patient died or underwent AV surgery during follow-up in either of the groups. LV mass was changed from 189.5 ± 41.3 to 185.6 ± 41.5 g in the intensive therapy group (P = .19) and from 183.8 ± 38.3 to 194.0 ± 46.4 g in the standard therapy group (P < .01). The primary end point of change in LV mass was significantly different between the intensive therapy and the standard therapy group (-3.9 ± 20.2 g vs 10.3 ± 20.4 g; P = .0007). The increase in LV mass index was also significantly greater in the standard therapy group (P = .01). No significant differences in secondary end points (changes in severity of AV disease, LV volumes, ejection fraction and GLS) were observed between the treatment groups. CONCLUSIONS: Among hypertensive patients with AV disease, intensive hypertensive therapy resulted in a significant reduction in LV hypertrophy, although progression of AV disease was similar between the treatment groups. CLINICAL TRIAL REGISTRATION: http://ClinicalTrials.gov (Number NCT03666351).

Low- or standard-dose edoxaban versus antiplatelet therapy for leaflet thrombus and cerebral thromboembolism after TAVR: A prespecified analysis of randomized ADAPT-TAVR trial.

BACKGROUND: The risks of leaflet thrombosis and the associated cerebral thromboembolism are unknown according to different anticoagulation dosing after transcatheter aortic valve replacement (TAVR). The aim was to evaluate the incidence of leaflet thrombosis and cerebral thromboembolism between low-dose (30 mg) or standard-dose (60 mg) edoxaban and dual antiplatelet therapy (DAPT) after TAVR. METHODS: In this prespecified subgroup analysis of the ADAPT-TAVR trial, the primary endpoint was the incidence of leaflet thrombosis on 4-dimensional computed tomography at 6-months. Key secondary endpoints were new cerebral lesions on brain magnetic resonance imaging and neurological and neurocognitive dysfunction. RESULTS: Of 229 patients enrolled in this study, 118 patients were DAPT group and 111 were edoxaban group (43 [39.1%] 60 mg vs 68 [61.3%] 30 mg). There was a significantly lower incidence of leaflet thrombosis in the standard-dose edoxaban group than in the DAPT group (2.4% vs 18.3%; odds ratio [OR] 0.11; 95% confidence interval [CI], 0.01-0.55; P = .03). However, no significant difference was observed between low-dose edoxaban and DAPT (15.0% vs 18.3%; OR 0.79; 95% CI, 0.32-1.81; P = .58). Irrespective of different antithrombotic regiments, the percentages of patients with new cerebral lesions on brain MRI and worsening neurological or neurocognitive function were not significantly different. CONCLUSIONS: In patients without an indication for anticoagulation after TAVR, the incidence of leaflet thrombosis was significantly lower with standard-dose edoxaban but not with low-dose edoxaban, as compared with DAPT. However, this differential effect of edoxaban on leaflet thrombosis was not associated with a reduction of new cerebral thromboembolism and neurological dysfunction.

Midwave resonant cavity infrared detectors (RCIDs) with suppressed background noise.

We report a resonant cavity infrared detector (RCID) with an InAsSb/InAs superlattice absorber with a thickness of only ≈ 100 nm, a 33-period GaAs/Al0.92Ga0.08As distributed Bragg reflector bottom mirror, and a Ge/SiO2/Ge top mirror. At a low bias voltage of 150 mV, the external quantum efficiency (EQE) reaches 58% at the resonance wavelength λres ≈ 4.6 µm, with linewidth δλ = 19-27 nm. The thermal background current for a realistic system scenario with f/4 optic that views a 300 K scene is estimated by integrating the photocurrent generated by background spanning the entire mid-IR spectral band (3-5 µm). The resulting specific detectivity is a factor of 3 lower than for a state-of-the-art broadband HgCdTe device at 300 K, where dark current dominates the noise. However, at 125 K where the suppression of background noise becomes critical, the estimated specific detectivity D* of 5.5 × 1012 cm Hz½/W is more than 3× higher. This occurs despite a non-optimal absorber cut-off that causes the EQE to decrease rapidly with decreasing temperature, e.g., to 33% at 125 K. The present RCID's advantage over the broadband device depends critically on its low EQE at non-resonance wavelengths: ≤ 1% in the range 3.9-5.5 µm. Simulations using NRL MULTIBANDS indicate that impact ionization in the bottom contact and absorber layers dominates the dark current at near ambient temperatures. We expect future design modifications to substantially enhance D* throughout the investigated temperature range of 100-300 K.

Production of autolysis-proof Kex2 protease from Candida albicans in Saccharomyces cerevisiae for in vitro processing of fusion proteins.

Protein expression with a fusion partner followed by the removal of the fusion partner via in vitro processing with a specific endoprotease is a favored method for the efficient production of intact recombinant proteins. Due to the high cost of commercial endoproteases, this process is restricted to laboratories. Kex2p is a membrane-bound serine protease that cleaves after dibasic residues of substrates in the late Golgi network. Although Kex2p is a very efficient endoprotease with exceptional specificity, it has not yet been used for the in vitro processing of fusion proteins due to its autolysis and high production cost. In this study, we developed an alternative endoprotease, autolysis-proof Kex2p, via site-directed mutagenesis of truncated KEX2 from Candida albicans (CaKEX2). Secretory production of manipulated CaKex2p was improved by employing target protein-specific translational fusion partner in Saccharomyces cerevisiae. The mass production of autolysis-proof Kex2p could facilitate the use of Kex2p for the large-scale production of recombinant proteins. KEY POINTS: • A soluble and active CaKex2p variant was produced by autocatalytic cleavage of the pro-peptide after truncation of C-terminus • Autolysis-proof CaKex2p was developed by site-directed mutagenesis • Secretion of autolysis-proof CaKex2p was improved by employing optimal translational fusion partner in Saccharomyces cerevisiae.

Secretome-based screening of fusion partners and their application in recombinant protein secretion in Saccharomyces cerevisiae.

For the efficient production of heterologous proteins in the yeast Saccharomyces cerevisiae, we screened for a novel fusion partner from the yeast secretome. From twenty major proteins identified from the yeast secretome, we selected Scw4p, a cell wall protein with similarity to glucanase, and modified to develop a general fusion partner for the secretory expression of heterologous proteins in yeast. The optimal size of the SCW4 gene to act as an efficient fusion partner was determined by C-terminal truncation analysis; two of the variants, S1 (truncated at codon 115Q) and S2 (truncated at codon 142E), were further used for the secretion of heterologous proteins. When fused with S2, the secretion of three target proteins (hGH, exendin-4, and hPTH) significantly increased. Conserved O-glycosylation sites (Ser/Thr-rich domain) and hydrophilic sequences of S2 were deemed important for the function of S2 as a secretion fusion partner. Approximately 5 g/L of the S2-exendin-4 fusion protein was obtained from fed-batch fermentation. Intact target proteins were easily purified by affinity chromatography after in vitro processing of the fusion partner. This system may be of general application for the secretory production of heterologous proteins in S. cerevisiae. KEY POINTS : • Target proteins were efficiently secreted with their N-terminus fused to Scw4p. • O-glycosylation and hydrophilic stretches in Scw4p were important for protein secretion. • A variant of Scw4p (S2) was successfully applied for the secretory expression of heterologous proteins.

Fetal cardiac parameters for predicting postnatal operation type of fetuses with tetralogy of Fallot.

BACKGROUND: To assess fetal cardiac parameters predictive of postnatal operation type in fetuses with tetralogy of Fallot (TOF). METHODS: Echocardiographic data obtained in the second and third trimesters were retrospectively reviewed for fetuses diagnosed with TOF between 2014 and 2018 at Asan Medical Center. The following fetal cardiac parameters were analyzed: 1) pulmonary valve annulus (PVA) z-score, 2) right pulmonary artery (RPA) z-score, 3) aortic valve annulus (AVA) z-score, 4) pulmonary valve peak systolic velocity (PV-PSV), 5) PVA/AVA ratio, and 6) RPA/descending aorta (DAo) ratio. These cardiac parameters were compared between a primary corrective surgery group and a palliative shunt operation followed by complete repair group. RESULTS: A total of 100 fetuses with TOF were included. Only one neonatal death occurred. Ninety patients underwent primary corrective surgery and 10 neonates underwent a multistage surgery. The PVA z-score, RPA z-score, and RPA/DAo ratio measured in the second trimester and the PVA z-score, RPA z-score, and PVA/AVA raio measured in the third trimester were significantly lower in the multistage surgery group, while the PV-PSV as measured in both trimesters were significantly higher in the multistage surgery group. CONCLUSION: Fetal cardiac parameters are useful for predicting the operation type necessary for neonates with TOF.

A Prospective Study of Pressure Injury Healing Rate and Time and Influencing Factors in an Acute Care Setting.

OBJECTIVE: To determine pressure injury (PI) healing rate and time and identify influencing factors. METHODS: A prospective cohort research design was used. Data collection was performed between May 2015 and August 2018. The study participants were 77 inpatients who developed at least one PI during their stay in a university hospital. Researchers assessed participants' demographic (age, sex); physical (incontinence, activity of daily living, and nutrition status); physiologic (serum total protein, albumin, and creatinine, blood glucose, and hemoglobin levels); and disease- (diagnosis, number of comorbidities, and cardiovascular comorbidity), wound- (PI stage and size at first detection, and Pressure Ulcer Scale for Healing score), and treatment-related (IV nutrition supply and albumin infusion) factors. RESULTS: Across the 77 patients, 91 PIs developed. Of these, 54 (59.3%) healed with a mean healing time of 17.63 days. The healing rate was better, and the healing time was shorter for stage 2 PIs compared with unstageable or deep-tissue PIs. Factors influencing PI healing rate were number of comorbidities, cardiovascular comorbidity, incontinence, PI stage at first detection, IV nutrition supply, and mean serum creatinine level. Factors influencing PI healing time were number of comorbidities, cardiovascular comorbidity, and PI stage at first detection. CONCLUSIONS: To reduce hospital stays, PI-related complications, and mortality, evidence-based management strategies for PIs are needed. The findings of the present study may contribute to the development of such strategies.

V-9302 inhibits proliferation and migration of VSMCs, and reduces neointima formation in mice after carotid artery ligation.

Rapidly proliferating cells such as vascular smooth muscle cells (VSMCs) require metabolic programs to support increased energy and biomass production. Thus, targeting glutamine metabolism by inhibiting glutamine transport could be a promising strategy for vascular disorders such as atherosclerosis, stenosis, and restenosis. V-9302, a competitive antagonist targeting the glutamine transporter, has been investigated in the context of cancer; however, its role in VSMCs is unclear. Here, we examined the effects of blocking glutamine transport in fetal bovine serum (FBS)- or platelet-derived growth factor (PDGF)-stimulated VSMCs using V-9302. We found that V-9302 inhibited mTORC1 activity and mitochondrial respiration, thereby suppressing FBS- or PDGF-stimulated proliferation and migration of VSMCs. Moreover, V-9302 attenuated carotid artery ligation-induced neointima in mice. Collectively, the data suggest that targeting glutamine transport using V-9302 is a promising therapeutic strategy to ameliorate occlusive vascular disease.

Mid-infrared interband cascade light emitting devices grown on off-axis silicon substrates.

The high-quality growth of midwave infrared light emitters on silicon substrates will advance their incorporation into photonic integrated circuits, and also introduce manufacturing advantages over conventional devices grown on lattice-matched GaSb. Here we report interband cascade light emitting devices (ICLEDs) grown on 4 degree offcut silicon with 12% lattice mismatch. Four wafers produced functioning devices, with variations from wafer to wafer but uniform performance of devices from a given wafer. The full width at half maxima for the (004) GaSb rocking curves were as narrow as ∼ 163 arc seconds, and the root mean square surface roughness as small as 3.2 nm. Devices from the four wafers, as well as from a control structure grown to the same design on GaSb, were mounted epitaxial-side-up (epi-up). While core heating severely limited continuous wave (cw) emission from the control devices at relatively modest currents, efficient heat dissipation via the substrate allowed output from the devices on silicon to increase up to much higher currents. Although the devices on silicon had higher leakage currents, probably occurring primarily at dislocations resulting from the lattice-mismatched growth, accounting for differences in architecture the efficiency at high cw current was approximately 75% of that of our previous best-performing standard epi-down ICLEDs grown on GaSb. At 100 mA injection current, 200-µm-diameter mesas produced 184 µW of cw output power when operated at T = 25 °C, and 140 µW at 85°C. Epi-up mid-IR light emitters grown on silicon will be far simpler to process and much less expensive to manufacture than conventional devices grown on GaSb and mounted epi-down.

Methane detection using an interband-cascade LED coupled to a hollow-core fiber.

Midwave infrared interband-cascade light-emitting devices (ICLEDs) have the potential to improve the selectivity, stability, and sensitivity of low-cost gas sensors. We demonstrate a broadband direct absorption CH4 sensor with an ICLED coupled to a plastic hollow-core fiber (1 m length, 1500 µm inner diameter). The sensor achieves a 1σ noise equivalent absorption of approximately 0.2 ppmv CH4 at 1 Hz, while operating at a low drive power of 0.5 mW. A low-cost sub-ppmv CH4 sensor would make monitoring emissions more affordable and more accessible for many relevant industries, such as the petroleum, agriculture, and waste industries.

A novel protein fusion partner, carbohydrate-binding module family 66, to enhance heterologous protein expression in Escherichia coli.

BACKGROUND: Proteins with novel functions or advanced activities developed by various protein engineering techniques must have sufficient solubility to retain their bioactivity. However, inactive protein aggregates are frequently produced during heterologous protein expression in Escherichia coli. To prevent the formation of inclusion bodies, fusion tag technology has been commonly employed, owing to its good performance in soluble expression of target proteins, ease of application, and purification feasibility. Thus, researchers have continuously developed novel fusion tags to expand the expression capacity of high-value proteins in E. coli. RESULTS: A novel fusion tag comprising carbohydrate-binding module 66 (CBM66) was developed for the soluble expression of heterologous proteins in E. coli. The target protein solubilization capacity of the CBM66 tag was verified using seven proteins that are poorly expressed or form inclusion bodies in E. coli: four human-derived signaling polypeptides and three microbial enzymes. Compared to native proteins, CBM66-fused proteins exhibited improved solubility and high production titer. The protein-solubilizing effect of the CBM66 tag was compared with that of two commercial tags, maltose-binding protein and glutathione-S-transferase, using poly(ethylene terephthalate) hydrolase (PETase) as a model protein; CBM66 fusion resulted in a 3.7-fold higher expression amount of soluble PETase (approximately 370 mg/L) compared to fusion with the other commercial tags. The intact PETase was purified from the fusion protein upon serial treatment with enterokinase and affinity chromatography using levan-agarose resin. The bioactivity of the three proteins assessed was maintained even when the CBM66 tag was fused. CONCLUSIONS: The use of the CBM66 tag to improve soluble protein expression facilitates the easy and economic production of high-value proteins in E. coli.

Association between childhood obesity and familial salt intake: analysis of data from Korean National Health and Nutrition Examination Survey, 2014-2017.

High salt intake is known as a risk factor of childhood obesity. As family members share not only genes but also their diet habit, parents' salt intake may affect to their children's obesity. In this study, we investigated correlations between childhood obesity and parents' or children's sodium intakes based on a nationwide survey data. From the Korean National Health and Nutrition Examination Survey data from 2014 to 2017, 802 boys and 657 girls aged 10-18 years, and their parents were included. BMI z-score and 24-hour urinary sodium excretion, which is estimated through Tanaka's equation, were used to examine associations between obesity and sodium intakes. The BMI status and the prevalence of obesity between children and their parents showed strong positive correlations in both sexes (all p < 0.001). The urinary sodium excretion between children and their parents showed positive correlations in both sexes (all p < 0.05). Children with higher urinary sodium excretion showed higher BMI (in both sexes, p < 0.001) and higher parental obesity compared to those with lower urinary sodium excretion, however, statistical significances of the latter relationship were varied by sex. In conclusion, our study suggests close relationship between childhood obesity and their sodium intakes, which also correlate well with parental BMIs and diet behavior. Therefore, parental education and active participation could be crucial in regulating childhood obesity.

Gene polymorphisms in leptin and its receptor and the response to growth hormone treatment in patients with idiopathic growth hormone deficiency.

This study aimed to investigate the relationships between genetic polymorphisms of leptin/receptor genes and clinical/biochemical characteristics in children with growth hormone deficiency (GHD). Ninety-three GHD children and 69 age-matched normal controls were enrolled. Anthropometric measurements, bone age, and laboratory test results were obtained. Polymorphisms in the LEP gene promoter locus (LEP-2548, rs7799039) and LEPR genes (K109R, rs1137100 and Q223R, rs1137101) were analyzed using PCR-RFLP. The serum leptin levels were measured using an ELISA kit. The median height and BMI z-scores of all GHD subjects were -2.20 and -0.26, respectively, and those of normal controls were -0.30 and -0.13, respectively. The serum leptin levels were similar between GHD subjects and normal controls (p = 0.537), but those were different between the complete GHD (6.97 ng/mL) and partial GHD (4.22 ng/mL) groups (p = 0.047). There were no differences in the genotypic distributions of LEP-2548, LEPR K109R, and Q223R between GHD subjects and normal controls. However, GHD subjects with the G allele at LEP-2548 showed higher IGF-1 (p = 0.047) and IGFBP-3 SDSs (p = 0.027) than GHD subjects with the A allele. GHD subjects with the G allele at LEPR Q223R showed lower stimulated GH levels (p = 0.023) and greater height gain after 1 year of GH treatment (p = 0.034) than GHD subjects with the A allele. In conclusion, leptin/leptin receptor genes are suggested to have the role of growth-related factors, which can affect various growth responses in children who share the same disease entity.

Motorized Shaver Harvest Results in Similar Cell Yield and Characteristics Compared With Rongeur Biopsy During Arthroscopic Synovium-Derived Mesenchymal Stem Cell Harvest.

PURPOSE: To compare cell yield and character of synovium-derived mesenchymal stem cell (SDMSC) harvested by 2 different techniques using rongeur and motorized shaver during knee arthroscopy. METHODS: This study was performed in 15 patients undergoing partial meniscectomy. Two different techniques were used to harvest SDMSCs in each patient from the synovial membrane at 2 different locations overlying the anterior fat pad, each within 1 minute of harvest time. Cell yield and proliferation rates were evaluated. Cell surface marker analysis was done after passage 2 (P2). Trilineage differentiation potential was evaluated by real-time quantitative polymerase chain reaction and histology. Statistical analysis between the 2 methods was done using the Mann-Whitney U test. RESULTS: Wet weight of total harvested tissue was 69.93 (± 20.02) mg versus 378.91 (± 168.87) mg for the rongeur and shaver group, respectively (P < .0001). Mononucleated cell yield was 3.32 (± 0.89) versus 3.18 (± 0.97) × 103 cells/mg, respectively (P = .67). Fluorescence-activated cell sorting analysis revealed similar SDMSC-related cell surface marker expression levels in both groups, with positive expression for CD44, CD73, CD90, and CD105 and decreased expression for CD34 and CD45. Both groups showed similar trilineage differentiation potential in histology. Chondrogenic (SOX9, ACAN, COL2), adipogenic (LPL, PLIN1, PPAR-γ), and osteogenic (OCN, OSX, RUNX2) gene marker expression levels also were similar between both groups. CONCLUSIONS: No difference was observed between rongeur biopsy and motorized shaver harvest methods regarding SDMSC yield and cell characteristics. CLINICAL RELEVANCE: The current study shows that both rongeur and motorized shaver harvest are safe and effective methods for obtaining SDMSCs. Motorized shaver harvest results in higher volume of tissue acquisition per time, thereby leading to higher number of SDMSCs which may be useful during clinical application.

Operational Parameters for Sub-Nano Tesla Field Resolution of PHMR Sensors in Harsh Environments.

The resolution of planar-Hall magnetoresistive (PHMR) sensors was investigated in the frequency range from 0.5 Hz to 200 Hz in terms of its sensitivity, average noise level, and detectivity. Analysis of the sensor sensitivity and voltage noise response was performed by varying operational parameters such as sensor geometrical architectures, sensor configurations, sensing currents, and temperature. All the measurements of PHMR sensors were carried out under both constant current (CC) and constant voltage (CV) modes. In the present study, Barkhausen noise was revealed in 1/f noise component and found less significant in the PHMR sensor configuration. Under measured noise spectral density at optimized conditions, the best magnetic field detectivity was achieved better than 550 pT/√Hz at 100 Hz and close to 1.1 nT/√Hz at 10 Hz for a tri-layer multi-ring PHMR sensor in an unshielded environment. Furthermore, the promising feasibility and possible routes for further improvement of the sensor resolution are discussed.