Sepiapterin reductase (SPR) is an enzyme that acts in the third and final step of tetrahydrobiopterin (BH4) biosynthesis. The human
Spr gene locates within the region of 2.5
MB mapped to PARK3, an ...autosomal dominant form of familial Parkinson’s diseases. In order to explore the role of SPR in the metabolism of BH4, we produced and analyzed
Spr-deficient mice. Most of
Spr-null mice survived beyond two weeks. Whereas the BH4 contents in the homozygous mutant mice were greatly decreased than those in wild-type and heterozygous mice, the substantial amounts of BH4 were remained even 17 days after delivery.
Spr-null mice exhibited severe monoamine deficiencies and a tremor-like phenotype after weaning. The amount of TH protein in the brain of
Spr-null mice was less than 10% of wild-type, while TH protein in the adrenal, phenylalanine hydroxylase protein in the liver, and nNOS in the brain were not altered. These data suggest an essential role of SPR in the biosynthesis of BH4, and that the
SPR gene could be a candidate gene for PARK3.
Pharmacological studies have demonstrated antibody production and infection prevention with an intradermal coronavirus disease 2019 (COVID-19) DNA vaccine (AG0302-COVID-19). This clinical trial aimed ...to investigate the safety and immunogenicity of high doses of AG0302-COVID19 when injected intramuscularly and intradermally. Healthy adults were randomly divided into three intramuscular vaccination groups (2 mg, three times at 2-week intervals; 4 mg, twice at 4-week intervals; and 8 mg, twice at 4-week intervals) and two intradermal groups (1 mg, three times at 2-week intervals or twice at 4-week intervals). After a one-year follow-up, no serious adverse events were related to AG0302-COVID-19. At Week 52, the changes in the geometric mean titer (GMT) ratios of the anti-S antibodies were 2.5, 2.4, and 3.2 in the 2, 4, and 8 mg intramuscular groups, respectively, and 3.2 and 5.1 in the three times and twice injected intradermal groups, respectively. The number of INF-γ-producing cells responsive to S protein increased after the first dose and was sustained for several months. AG0302-COVID-19 showed an acceptable safety profile, but the induction of a humoral immune response was insufficient to justify progressing to a Phase 3 program.
We examined the renal pelvic urine culture (RPUC) and stone culture (SC) during ureteroscopy and evaluated their associations with postoperative systemic inflammatory response syndrome (SIRS). We ...prospectively collected data of 224 patients who underwent ureteroscopic laser lithotripsy from March 2015 to December 2017. We examined the bladder urine culture pre-operatively. If the patients had positive culture results, we treated them with antibiotics for 5–7 days before surgery based on the sensitivity profile. We collected RPUC and SC samples during surgery. After ureteroscopy, patients were closely monitored for any signs of SIRS. Using a logistic regression model, we analyzed how the clinical factors affected the incidence of SIRS. Pre-operative bladder urine culture (PBUC) was positive in 111 patients (49.6%). Intraoperative RPUC was positive in 43 patients (19.2%), and SC was positive in 34 patients (15.2%). Postoperatively, 23 patients (10.3%) were diagnosed with SIRS. A multivariate analysis revealed that female gender, struvite calculi and positive intraoperative RPUC results were significantly associated with postoperative SIRS. Among the 31 patients who were positive for both PBUC and intraoperative RPUC, the pathogens were not consistent in 11 patients (35.5%). Among the 25 patients who were positive for both PBUC and intraoperative SC, the pathogens were not consistent in 13 patients (52.0%). We recommend collecting RPUC and SC samples during ureteroscopy, especially for patients with high risk factors, including female gender, expected struvite calculi and positive PBUC results.
Effects of element substitutions on thermoelectric properties of Heusler Fe
2
VAl alloys were evaluated. By W substitution at the V site, the thermal conductivity is reduced effectively because of ...the enhancement of phonon scattering resulting from the introduction of W atoms, which have much greater atomic mass and volume than the constituent elements of Fe
2
VAl alloy. W substitution is also effective to obtain a large negative Seebeck coefficient and high electrical conductivity through an electron injection effect. To change the conduction type from
n
-type to
p
-type, additional Ti substitution at the V site, which reduces the valence electron density, was examined. A positive Seebeck coefficient as high as that of conventional
p
-type Fe
2
VAl alloy was obtained using a sufficient amount of Ti substitution. Electrical resistivity was reduced by the hole doping effect of the Ti substitution while maintaining low thermal conductivity. Compared with the conventional solo-Ti-substituted
p
-type Fe
2
VAl alloy, the
ZT
value was improved, reaching 0.13 at 450 K.
Background. A higher Ki-67 labeling index is associated with a poorer prognosis in gastroenteropancreatic neuroendocrine neoplasms. It has also been proposed that the Ki-67 labeling index may ...increase during disease progression from the primary site to metastatic sites. Although biopsy specimens are used to measure the Ki-67 labeling index, heterogeneity in lesions is thought to affect the assessment of the Ki-67 labeling index. To overcome tumor heterogeneity, we evaluated the variability in the Ki-67 labeling index between primary lesions and hepatic metastases by analyzing only surgically resected specimens. Methods. We conducted a single-center retrospective study to analyze the variability in the Ki-67 labeling index and the change in tumor grade between the primary site and metastatic hepatic sites in 19 patients diagnosed with gastroenteropancreatic neuroendocrine neoplasms at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 1998 to 2018. Both the primary site and metastatic hepatic sites were surgically resected. Results. Among the 19 patients with gastroenteropancreatic neuroendocrine neoplasms, 12 patients (63%) showed higher levels of the Ki-67 labeling index at metastatic hepatic sites than at the primary site. The median Ki-67 labeling index levels for the primary lesion and metastatic hepatic lesions were 5% and 10%, respectively. The Ki-67 labeling index levels were significantly elevated in the metastatic hepatic lesions compared to the primary lesion (P = .002). Conclusions. This study addressed the heterogeneity of the Ki-67 labeling index by analyzing only surgically resected specimens. We observed a statistically significant increase in the Ki-67 labeling index in hepatic metastases compared to the primary lesion.
Hypertension (HTN) is the single greatest cardiovascular risk factor worldwide. HTN management is usually guided by brachial cuff blood pressure (BP), but questions have been raised regarding ...accuracy.
This comprehensive analysis determined the accuracy of cuff BP and the consequent effect on BP classification compared with intra-arterial BP reference standards.
Three individual participant data meta-analyses were conducted among studies (from the 1950s to 2016) that measured intra-arterial aortic BP, intra-arterial brachial BP, and cuff BP.
A total of 74 studies with 3,073 participants were included. Intra-arterial brachial systolic blood pressure (SBP) was higher than aortic values (8.0 mm Hg; 95% confidence interval CI: 5.9 to 10.1 mm Hg; p < 0.0001) and intra-arterial brachial diastolic BP was lower than aortic values (-1.0 mm Hg; 95% CI: -2.0 to -0.1 mm Hg; p = 0.038). Cuff BP underestimated intra-arterial brachial SBP (-5.7 mm Hg; 95% CI: -8.0 to -3.5 mm Hg; p < 0.0001) but overestimated intra-arterial diastolic BP (5.5 mm Hg; 95% CI: 3.5 to 7.5 mm Hg; p < 0.0001). Cuff and intra-arterial aortic SBP showed a small mean difference (0.3 mm Hg; 95% CI: -1.5 to 2.1 mm Hg; p = 0.77) but poor agreement (mean absolute difference 8.0 mm Hg; 95% CI: 7.1 to 8.9 mm Hg). Concordance between BP classification using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure cuff BP (normal, pre-HTN, and HTN stages 1 and 2) compared with intra-arterial brachial BP was 60%, 50%, 53%, and 80%, and using intra-arterial aortic BP was 79%, 57%, 52%, and 76%, respectively. Using revised intra-arterial thresholds based on cuff BP percentile rank, concordance between BP classification using cuff BP compared with intra-arterial brachial BP was 71%, 66%, 52%, and 76%, and using intra-arterial aortic BP was 74%, 61%, 56%, and 65%, respectively.
Cuff BP has variable accuracy for measuring either brachial or aortic intra-arterial BP, and this adversely influences correct BP classification. These findings indicate that stronger accuracy standards for BP devices may improve cardiovascular risk management.
In individuals with hypertrophic obstructive cardiomyopathy, elongated anterior mitral leaflets are commonly associated with systolic anterior motion. In patients with mild septal hypertrophy, a ...myectomy is considered insufficient to relieve systolic anterior motion and left ventricular outflow tract obstruction.
In the patient, who had relatively mild septal hypertrophy, the section of the anterior leaflet protruding into the left ventricular outflow tract was resected, concomitant with septal myectomy and the relocation of the papillary muscles. An edge-to-edge stitch was placed at the uppermost segment of the coaptation zone. Using these manoeuvres, systolic anterior motion, left ventricular outflow tract obstruction and mitral regurgitation were successfully resolved postoperatively.
We describe a surgical technique with an edge-to-edge suture for the resection of an elongated anterior mitral leaflet. In combination with septal myectomy and relocation of the papillary muscles, this technique is a simple and viable option, especially when septal hypertrophy is not severe.
An even factor in a digraph, introduced by Cunningham and Geelen (Vertex-disjoint dipaths and even dicircuits. manuscript, 2001), is a collection of vertex-disjoint dipaths and even dicycles, which ...generalizes a path-matching of Cunningham and Geelen (Combinatorica 17, 315–337, 1997). In a restricted class of digraphs, called odd-cycle-symmetric, Pap (Integer Programming and Combinatorial Optimization. Lecture Notes in Computer Science, 3509, pp. 66–80, Springer, Heidelberg, 2005) presented a combinatorial algorithm to find a maximum even factor. For odd-cycle-symmetric weighted digraphs, which are odd-cycle-symmetric digraphs accompanied by a weight vector satisfying a certain property, Király and Makai (Integer Programming and Combinatorial Optimization. Lecture Notes in Computer Science, 3064, pp. 416–430, Springer, Heidelberg, 2004) provided a linear program that describes the maximum weight even factor problem, and proved the dual integrality. In this paper, we present a primal-dual algorithm to find a maximum weight even factor for an odd-cycle-symmetric weighted digraph. This algorithm is based on the weighted matching algorithm of Edmonds and the maximum even factor algorithm of Pap. The running time of the algorithm is O(
n
3
m
), where
n
and
m
are the numbers of the vertices and arcs, respectively, which is better than that of the existing algorithms for the special cases. The algorithm also gives a constructive proof for the dual integrality.
Discoid lateral meniscus tear leads to large chondral defect in the lateral compartment of the knee joint. There are few effective treatments for large chondral defect in both the tibial and femoral ...sides with severe degenerative lateral meniscus. We have developed a combined autologous chondrocyte implantation and meniscus reconstruction technique using hamstring tendon. This technique allows biological reconstruction and avoids knee arthroplasty.
•Discoid lateral meniscus tear leads to large chondral defect.•A combination of autologous chondrocyte implantation and meniscus reconstruction technique using hamstring tendon is introduced.•This novel method allows biological reconstruction.
Previous studies have indicated that athletes' anti-doping knowledge is inadequate. Athletes' willingness to learn about anti-doping (
willingness to learn
) may influence their anti-doping ...knowledge, but the actual situation is unclear. This study aimed to determine the relationship between athletes'
willingness to learn
about anti-doping and their objective measurement knowledge and explore directions for educational interventions. The eligible participants were 971 male and 802 female university athletes. We used the ALPHA test (12 questions/four choices; passing index: ≥10 points/80% correct answer rate) to assess objective anti-doping knowledge. The
willingness to learn
question was, “Would you like to learn more about anti-doping?” Responses were given on a 4-point scale ranging from 1: strongly disagree to 4: strongly agree. An ANCOVA was conducted with four levels of
willingness to learn
as the independent variable and ALPHA correct answer rate as the dependent variable, adjusting for confounding factors (years of athletic experience and anti-doping education experience). The percentage of athletes (%) and each ALPHA correct answer rate (%) by the level of
willingness to learn
was 1: strongly disagree,
n
= 1.64%, 61.78%; 2: somewhat disagree,
n
= 13.14%, 62.38%; 3: somewhat agree,
n
= 62.94%, 64.08%; 4: strongly agree,
n
= 22.28%, 67.11%. The ALPHA correct answer rates showed significant differences in the main effect by the level of
willingness to learn
F
(3, 1767)
= 2.873,
p
< 0.05, η
2
= 0.01, although the effect size was small, and multiple comparisons showed no significant differences between the levels. The results indicated that the ALPHA correct answer rate did not reach 80% even for the “strongly agree” level of
willingness to learn
, suggesting that information on anti-doping may be inadequate. The need to provide sufficient educational content to improve knowledge was evident.
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