bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coronary Artery Disease–Associated
LIPA
Coding Variant rs1051338 Reduces Lysosomal Acid Lipase Levels and Activity in Lysosomes
Authors: Morris Gavin E. , Braund Peter S. , Moore Jasbir S. , Samani Nilesh J. , Codd Veryan , Webb Tom R. 
Published: March 2017

Objective—

Genome-wide association studies have linked variants at chromosome 10q23 with increased coronary artery disease risk. The disease-associated variants fall in
LIPA
, which encodes lysosomal acid lipase (LAL), the enzyme responsible for lysosomal cholesteryl ester hydrolysis. Loss-of-function mutations in
LIPA
result in accelerated atherosclerosis. Surprisingly, the coronary artery disease variants are associated with increased
LIPA
expression in some cell types. In this study, we address this apparent contradiction.

Approach and Results—

We investigated a coding variant rs1051338, which is in high linkage disequilibrium (
r
2
=0.89) with the genome-wide association study lead–associated variant rs2246833 and causes a nonsynonymous threonine to proline change within the signal peptide of LAL. Transfection of allele-specific expression constructs showed that the risk allele results in reduced lysosomal LAL protein (
P
=0.004) and activity (
P
=0.005). Investigation of LAL localization and turnover showed the risk LAL protein is degraded more quickly. This mechanism was confirmed in disease-relevant macrophages from individuals homozygous for either the nonrisk or risk allele. There was no difference in LAL protein or activity in whole macrophage extracts; however, we found reduced LAL protein (
P
=0.02) and activity (
P
=0.026) with the risk genotype in lysosomal extracts, suggesting that the risk genotype affects lysosomal LAL activity. Inhibition of the proteasome resulted in equal amounts of lysosomal LAL protein in risk and nonrisk macrophages.

Conclusions—
Our findings show that the coronary artery disease–associated coding variant rs1051338 causes reduced lysosomal LAL protein and activity because of increased LAL degradation, providing a plausible causal mechanism of increased coronary artery disease risk.
Newly Formed Reticulated Platelets Undermine Pharmacokinetically Short-Lived Antiplatelet Therapies
Authors: Armstrong Paul C. , Hoefer Thomas , Knowles Rebecca B. , Tucker Arthur T. , Hayman Melissa A. , Ferreira Plinio M. , Chan Melissa V. , Warner Timothy D. 
Published: March 2017

Objective—

Aspirin together with thienopyridine P2Y
12
inhibitors, commonly clopidogrel, is a cornerstone of antiplatelet therapy. However, many patients receiving this therapy display high on-treatment platelet reactivity, which is a major therapeutic hurdle to the prevention of recurrent thrombotic events. The emergence of uninhibited platelets after thrombopoiesis has been proposed as a contributing factor to high on-treatment platelet reactivity. Here, we investigate the influences of platelet turnover on platelet aggregation in the face of different dual-antiplatelet therapy strategies.

Approach and Results—
Traditional light transmission aggregometry, cytometry, advanced flow cytometric imaging, and confocal microscopy were used to follow the interactions of populations of platelets from healthy volunteers and patients with stable cardiovascular disease. Newly formed, reticulated platelets overproportionately contributed to, and clustered at, the core of forming aggregates. This phenomenon was particularly observed in samples from patients treated with aspirin plus a thienopyridine, but was absent in samples taken from patients treated with aspirin plus ticagrelor.

Conclusions—
Reticulated platelets are more reactive than older platelets and act as seeds for the formation of platelet aggregates even in the presence of antiplatelet therapy. This is coherent with the emergence of an uninhibited subpopulation of reticulated platelets during treatment with aspirin plus thienopyridine, explained by the short pharmacokinetic half-lives of these drugs. This phenomenon is absent during treatment with ticagrelor, because of its longer half-life and ability to act as a circulating inhibitor. These data highlight the important influences of pharmacokinetics on antiplatelet drug efficacies, especially in diseases associated with increased platelet turnover.
Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men
Authors: Goettsch Claudia , Iwata Hiroshi , Hutcheson Joshua D. , O’Donnell Christopher J. , Chapurlat Roland , Cook Nancy R. , Aikawa Masanori , Szulc Pawel , Aikawa Elena 
Published: March 2017

Objective—
Genome-wide association studies and preclinical studies demonstrated a role of sortilin in lipid metabolism, inflammation, and vascular calcification—all cardiovascular risk factors. We evaluated the association of serum sortilin levels with the risk of major adverse cerebrovascular and cardiovascular events (MACCE) and the severity of abdominal aortic calcification (AAC).

Approach and Results—

A cohort of community-dwelling men aged ≥50 years (n=830) was assessed. At baseline, sortilin levels were measured by ELISA, and AAC was assessed on lateral spine scans obtained by dual-energy X-ray absorptiometry. Men aged ≥60 years (n=745) were followed up prospectively for the incidence of MACCE. During the median follow-up of 7.9 years, 76 MACCE occurred. The unadjusted incidence of MACCE across increasing sortilin quartiles was 8.0, 7.4, 19.8, and 20.3 per 1000 person-years. In multivariate-adjusted analysis, sortilin associated with increased risk of MACCE (hazard ratio, 1.70 per SD; 95% confidence interval, 1.30–2.20;
P
<0.001). The third and fourth quartiles associated with 3.42-fold (95% confidence interval, 1.61–7.25;
P
<0.005) and 3.82-fold (95% confidence interval, 1.77–8.26;
P
<0.001) higher risk of MACCE compared with the first quartile. High sortilin also predicted MACCE independent of traditional Framingham risk factors. Higher sortilin associated with higher odds of severe AAC (score>5) after adjustment for confounders (odds ratio, 1.43 per SD; 95% confidence interval, 1.10–1.85;
P
<0.01). The highest sortilin quartile associated with 2-fold higher odds of severe AAC (versus 3 lower quartiles combined). After adjustment for low-density lipoprotein cholesterol, the odds of severe AAC remained significant.

Conclusions—
In older men, higher serum sortilin levels associated with higher MACCE risk and severe AAC independently of relevant confounders, including C-reactive protein and low-density lipoprotein cholesterol. This finding, however, needs to be validated in other cohorts.
Predicting Recovery Potential for Individual Stroke Patients Increases Rehabilitation Efficiency
Authors: Stinear Cathy M. , Byblow Winston D. , Ackerley Suzanne J. , Barber P. Alan , Smith Marie-Claire 
Published: March 2017

Background and Purpose—
Several clinical measures and biomarkers are associated with motor recovery after stroke, but none are used to guide rehabilitation for individual patients. The objective of this study was to evaluate the implementation of upper limb predictions in stroke rehabilitation, by combining clinical measures and biomarkers using the Predict Recovery Potential (PREP) algorithm.

Methods—
Predictions were provided for patients in the implementation group (n=110) and withheld from the comparison group (n=82). Predictions guided rehabilitation therapy focus for patients in the implementation group. The effects of predictive information on clinical practice (length of stay, therapist confidence, therapy content, and dose) were evaluated. Clinical outcomes (upper limb function, impairment and use, independence, and quality of life) were measured 3 and 6 months poststroke. The primary clinical practice outcome was inpatient length of stay. The primary clinical outcome was Action Research Arm Test score 3 months poststroke.

Results—

Length of stay was 1 week shorter for the implementation group (11 days; 95% confidence interval, 9–13 days) than the comparison group (17 days; 95% confidence interval, 14–21 days;
P
=0.001), controlling for upper limb impairment, age, sex, and comorbidities. Therapists were more confident (
P
=0.004) and modified therapy content according to predictions for the implementation group (
P
<0.05). The algorithm correctly predicted the primary clinical outcome for 80% of patients in both groups. There were no adverse effects of algorithm implementation on patient outcomes at 3 or 6 months poststroke.

Conclusions—
PREP algorithm predictions modify therapy content and increase rehabilitation efficiency after stroke without compromising clinical outcome.

Clinical Trial Registration—

URL:
http://anzctr.org.au
. Unique identifier: ACTRN12611000755932.
Effects of birth weight on profiles of dried blood amino-acids and acylcarnitines
Authors: Yang Lili , Zhang Yu , Yang Jianbin , Huang Xinwen 
Published: March 2017

Background Birth weight influences profiles of dried blood amino-acids and acylcarnitines in newborn screening. This study aimed to define a more appropriate cut-off value to reduce the false positive rate and the number of recalled patients in newborn screening. Methods All babies who underwent newborn screening in our center were included; they were divided into groups by birth weight: 2500–3999 g (comparator group), <1000 g (group 1), 1000–1499 g (group 2), 1500–2499 g (group 3), and >4000 g (group 4). The 0.5th and 99.5th percentiles were used as the cut-off values. Comparisons were done on amino acid and acylcarnitines concentrations between the groups. False positive rate, positive predictive value, corrected false positive rate by birth weights were determined. Results Data on a total of 578,287 newborn infants were included in the analysis. The total false positive rate was 0.75%, and positive predictive value 2.89%. The false positive rate was 0.69%, 0.54% and 5.31% in infants with normal birth weight, birth weight of >4000 (group 4) and low birth weight of < 2500 g (groups 1, 2 and 3), respectively. Low-birth weight infants had much higher phenylalanine, tyrosine, methionine, arginine, propionylcarnitine, isovalerylcarnitine and octadecanoylcarnitine concentrations. Free carnitines and palmitoylcarnitine concentrations were lower. After adjusting for birth weight, false positive rate of all indices decreased to 0.53%, and positive predictive value increased to 4.31%. Conclusions Amino acid and carnitine concentrations in low-birth weight newborn infants may differ from the normal term newborn infants. The cut-off values of individual metabolites should be adjusted based on birth weight, to reduce false positive rate and increase positive predictive value.
A genetic CLOCK variant associated with cluster headache causing increased mRNA levels
Authors: Fourier Carmen , Ran Caroline , Zinnegger Margret , Johansson Anne-Sofie , Sjöstrand Christina , Waldenlind Elisabet , Steinberg Anna , Belin Andrea Carmine 
Published: March 2017

Background Cluster headache is characterized by recurrent unilateral headache attacks of severe intensity. One of the main features in a majority of patients is a striking rhythmicity of attacks. The CLOCK ( Circadian Locomotor Output Cycles Kaput) gene encodes a transcription factor that serves as a basic driving force for circadian rhythm in humans and is therefore particularly interesting as a candidate gene for cluster headache. Methods We performed an association study on a large Swedish cluster headache case-control sample (449 patients and 677 controls) screening for three single nucleotide polymorphisms (SNPs) in the CLOCK gene implicated in diurnal preference (rs1801260) or sleep duration (rs11932595 and rs12649507), respectively. We further wanted to investigate the effect of identified associated SNPs on CLOCK gene expression. Results We found a significant association with rs12649507 and cluster headache ( p = 0.0069) and this data was strengthened when stratifying for reported diurnal rhythmicity of attacks ( p = 0.0009). We investigated the effect of rs12649507 on CLOCK gene expression in human primary fibroblast cultures and identified a significant increase in CLOCK mRNA expression ( p = 0.0232). Conclusions Our results strengthen the hypothesis of the involvement of circadian rhythm in cluster headache.
Influence of the Injury-to-Surgery Interval on the Healing Potential of Human Anterior Cruciate Ligament–Derived Cells
Authors: Inokuchi Takao , Matsumoto Tomoyuki , Takayama Koji , Nakano Naoki , Zhang Shurong , Araki Daisuke , Matsushita Takehiko , Kuroda Ryosuke 
Published: March 2017

Background: Vascular CD34+ cells in anterior cruciate ligament (ACL) tissue have the potential for high proliferation and multilineage differentiation that can accelerate tendon-bone healing. While patient characteristics, such as age, can affect tendon-bone healing, the influence of elapsed time after injury on the healing process is unclear. Hypothesis: Cells obtained during the early phase after injury will exhibit a greater tendon-bone healing potential compared with chronic phase counterparts when applied to an immunodeficient rat model of ACL reconstruction. Study Design: Controlled laboratory study. Methods: Adult human ACL-ruptured tissue was harvested from patients undergoing arthroscopic primary ACL reconstruction and classified into 2 groups based on the time elapsed between injury and surgery: (1) early group (≤3 months from injury) and (2) chronic group (>3 months from injury). In addition, 76 ten-week-old female immunodeficient rats underwent ACL reconstruction, followed by intracapsular administration of one of the following: (1) ACL-derived cells from the early group (n = 5), (2) ACL-derived cells from the chronic group (n = 5), or (3) phosphate-buffered saline (PBS) only (n = 5). During the 8 weeks after surgery, histological (weeks 2, 4, 8), immunohistochemical (week 2), radiographic (weeks 0, 2, 4, 8), and biomechanical (week 8) analyses were performed to evaluate tendon-bone healing. Results: In the early group, the histological evaluation showed early healing, induction of endochondral ossification–like integration, and mature bone ingrowth. Micro–computed tomography showed that the tibial bone tunnels at week 4 and week 8 were significantly reduced in the early group compared with those in the chronic group and PBS group ( P < .05). Moreover, biomechanical tensile strength was significantly greater in the early group than in the other groups ( P < .05). An accelerated healing potential in the early group was further demonstrated by the enhancement of intrinsic angiogenesis/osteogenesis and human-derived vasculogenesis/osteogenesis. Conclusion: Compared with human ACL-derived cells obtained during the chronic phase, cells obtained during the early phase after injury have a greater tendon-bone healing potential when used in an immunodeficient rat model of ACL reconstruction. Clinical Relevance: During ACL reconstruction surgery, transplanting ACL remnant tissue in the early phase after injury could accelerate and enhance tendon-bone healing.
Collagen Augmentation Improves the Quality of Cartilage Repair After Microfracture in Patients Undergoing High Tibial Osteotomy: A Randomized Controlled Trial
Authors: Kim Man Soo , Koh In Jun , Choi Young Jun , Pak Kyu Hyung , In Yong 
Published: March 2017

Background:The quality of cartilage repair after marrow stimulation is unpredictable. To overcome the shortcomings of the microfracture technique, various augmentation techniques have been developed. However, their efficacies remain unclear.Hypothesis:The quality of cartilage repair and clinical outcomes would be superior in patients undergoing high tibial osteotomy (HTO) with microfracture and collagen augmentation compared to those undergoing HTO with microfracture alone without collagen augmentation for the treatment of medial compartment osteoarthritis (OA) of the knee.Study Design:Randomized controlled trial; Level of evidence, 2.Methods:Twenty-eight patients undergoing HTO were randomized into 2 groups: microfracture alone (group 1, n = 14) or microfracture with collagen augmentation (group 2, n = 14). At 1 year postoperatively, second-look arthroscopic surgery and biopsy of repaired cartilage were performed at the time of HTO plate removal. Biopsy specimens were graded using the International Cartilage Repair Society Visual Assessment Scale II (ICRS II). In addition, imaging outcomes in terms of the magnetic resonance observation of cartilage repair tissue (MOCART) score were assessed based on magnetic resonance imaging (MRI). Finally, clinical outcomes in terms of the visual analog scale (VAS) for pain score, Knee Injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) score, and Tegner activity scale score were evaluated.Results:The mean ICRS II score in group 2 was significantly higher than that in group 1 (1053.2 vs 885.4, respectively; P = .002). Group 2 showed greater improvement in tissue morphology, cell morphology, surface architecture, middle/deep zone assessment, and overall assessment compared with group 1 ( P < .050 for all comparisons). Imaging outcomes based on the MOCART score were superior in group 2 compared to those in group 1 on MRI at 1 year postoperatively (64.6 vs 45.4, respectively; P = .001). The degree of defect repair was better in group 2 than in group 1 ( P = .040). Clinical outcomes in terms of the VAS for pain score, KOOS, IKDC score, and Tegner activity scale score were improved in both groups without between-group differences ( P > .100 for all comparisons).Conclusion:The quality of cartilage repair after microfracture with collagen augmentation was superior to that after microfracture alone in patients undergoing HTO. Clinical results after 1 year did not reflect this difference in tissue repair. Therefore, a longer follow-up of the cohort is needed to answer this question.
Anatomic and Histological Investigation of the Anterolateral Capsular Complex in the Fetal Knee
Authors: Sabzevari Soheil , Rahnemai-Azar Amir Ata , Albers Marcio , Linde Monica , Smolinski Patrick , Fu Freddie H. 
Published: March 2017

Background: There is currently disagreement with regard to the presence of a distinct ligament in the anterolateral capsular complex of the knee and its role in the pivot-shift mechanism and rotatory laxity of the knee. Purpose: To investigate the anatomic and histological properties of the anterolateral capsular complex of the fetal knee to determine whether there exists a distinct ligamentous structure running from the lateral femoral epicondyle inserting into the anterolateral tibia. Study Design: Descriptive laboratory study. Methods: Twenty-one unpaired, fresh fetal lower limbs, gestational age 18 to 22 weeks, were used for anatomic investigation. Two experienced orthopaedic surgeons performed the anatomic dissection using loupes (magnification ×3.5). Attention was focused on the anterolateral and lateral structures of the knee. After the skin and superficial fascia were removed, the iliotibial band was carefully separated from underlying structures. The anterolateral capsule was then examined under internal and external rotation and varus-valgus manual loading and at different knee flexion angles for the presence of any ligamentous structures. Eight additional unpaired, fetal lower limbs, gestational age 11 to 23 weeks, were used for histological analysis. Results: This study was not able to prove the presence of a distinct capsular or extracapsular ligamentous structure in the anterolateral capsular complex area. The presence of the fibular collateral ligament, a distal attachment of the biceps femoris, the entire lateral capsule, the iliotibial band, and the popliteus tendon in the anterolateral and lateral area of the knee was confirmed in all the samples. Histological analysis of the anterolateral capsule revealed a loose, hypocellular connective tissue with less organized collagen fibers compared with ligament and tendinous structures. Conclusion: The main finding of this study was that the presence of a distinct ligamentous structure in the anterolateral complex is not supported from a developmental point of view, while all other anatomic structures were present. Clinical Relevance: The inability to prove the existence of a distinct ligamentous structure, called the anterolateral ligament, in the anterolateral knee capsule may indicate that the other components of the anterolateral complex, such as the lateral capsule, the iliotibial band, and its capsule-osseous layer, are more important for knee rotatory stability.
Coagulase-Negative Staphylococci in Human Milk From Mothers of Preterm Compared With Term Neonates
Authors: Soeorg Hiie , Metsvaht Tuuli , Eelmäe Imbi , Metsvaht Hanna Kadri , Treumuth Sirli , Merila Mirjam , Ilmoja Mari-Liis , Lutsar Irja 
Published: March 2017

Background: Human milk is the preferred nutrition for neonates and a source of bacteria. Research aim: The authors aimed to characterize the molecular epidemiology and genetic content of staphylococci in the human milk of mothers of preterm and term neonates. Methods: Staphylococci were isolated once per week in the 1st month postpartum from the human milk of mothers of 20 healthy term and 49 preterm neonates hospitalized in the neonatal intensive care unit. Multilocus variable-number tandem-repeats analysis and multilocus sequence typing were used. The presence of the mecA gene, icaA gene of the ica-operon, IS 256, and ACME genetic elements was determined by PCR. Results: The human milk of mothers of preterm compared with term neonates had higher counts of staphylococci but lower species diversity. The human milk of mothers of preterm compared with term neonates more often contained Staphylococcus epidermidis mecA (32.7% vs. 2.6%), icaA (18.8% vs. 6%), IS 256 (7.9% vs. 0.9%), and ACME (15.4% vs. 5.1%), as well as Staphylococcus haemolyticus mecA (90.5% vs. 10%) and IS 256 (61.9% vs. 10%). The overall distribution of multilocus variable-number tandem-repeats analysis (MLVA) types and sequence types was similar between the human milk of mothers of preterm and term neonates, but a few mecA-IS 256-positive MLVA types colonized only mothers of preterm neonates. Maternal hospitalization within 1 month postpartum and the use of an arterial catheter or antibacterial treatment in the neonate increased the odds of harboring mecA-positive staphylococci in human milk. Conclusion: Limiting exposure of mothers of preterm neonates to the hospital could prevent human milk colonization with more pathogenic staphylococci.