bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased duodenal iron absorption through up‐regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis
Authors: Hoki Toshifumi , Miyanishi Koji , Tanaka Shingo , Takada Kohichi , Kawano Yutaka , Sakurada Akira , Sato Masanori , Kubo Tomohiro , Sato Tsutomu , Sato Yasushi , Takimoto Rishu , Kobune Masayoshi , Kato Junji
Published: March 2015

Increased hepatic iron accumulation is thought to be involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Hepatic iron accumulation, as well as oxidative DNA damage, is significantly increased in NASH livers. However, the precise mechanism of iron accumulation in the NASH liver remains unclear. In this study, 40 cases with a diagnosis of NASH (n = 25) or simple steatosis (SS; n = 15) by liver biopsy were enrolled. An oral iron absorption test (OIAT) was used, in which 100 mg of sodium ferrous citrate was administered to each individual. The OIAT showed that absorption of iron from the gastrointestinal (GI) tract was increased significantly in NASH patients, compared to SS and control subjects. Iron reduction therapy was effective in patients with NASH, who exhibited iron deposition in the liver and no alanine aminotransferase improvement after other therapies (n = 9). Serum hepcidin concentration and messenger RNA (mRNA) levels of divalent metal transporter 1 (DMT1) also were significantly elevated in patients with NASH. OIAT results were correlated with grade of liver iron accumulation and DMT1 mRNA levels. Then, we demonstrated that DMT1 mRNA levels increased significantly in Caco‐2/TC7 cell monolayers cultured in transwells with serum from NASH patients. An electrophoresis mobility shift assay showed activation of iron regulatory protein (IRP) in those cells, and IRP1 small interfering RNA clearly inhibited the increase of DMT1 mRNA levels. Conclusion: In spite of elevation of serum hepcidin, iron absorption from the GI tract increased through up‐regulation of DMT1 by IRP1 activation by humoral factor(s) in sera of patients with NASH. (Hepatology 2015) Hepatology 2015;62:751–761)
Contextual analysis of determinants of late diagnosis of hepatitis C virus infection in Medicare patients
Authors: Chirikov Viktor V. , Shaya Fadia T. , Howell Charles D.
Published: March 2015

Patient‐ and county‐level characteristics associated with advanced liver disease (ALD) at hepatitis C virus (HCV) diagnosis were examined in three Medicare cohorts: (1) elderly born before 1945; (2) disabled born 1945‐1965; and (3) disabled born after 1965. We used Medicare claims (2006‐2009) linked to the Area Health Resource Files. ALD was measured over the period of 6 months before to 3 months after diagnosis. Using weighted multivariate modified Poisson regression to address generalizability of findings to all Medicare patients, we modeled the association between contextual characteristics and presence of ALD at HCV diagnosis. We identified 1,746, 3,351, and 592 patients with ALD prevalence of 28.0%, 23.0%, and 15.0% for birth cohorts 1, 2, and 3. Prevalence of drug abuse increased among younger birth cohorts (4.2%, 22.6%, and 35.6%, respectively). Human immunodeficiency virus coinfection (prevalence ratio [PR] = 0.63; 95% confidence interval [CI]: 0.50‐0.80; P = 0.001), dual Medicare/Medicaid eligibility (PR = 0.89; 95% CI: 0.80‐0.98; P = 0.017), residence in counties with higher median household income (PR = 0.82; 95% CI: 0.71‐0.95; P = 0.008), higher density of primary care providers (PR = 0.84; 95% CI: 0.73‐0.98; P = 0.022), and more rural health clinics (PR = 0.90; 0.81‐1.01; P = 0.081) were associated with lower ALD risk. End‐stage renal disease (PR = 1.41; 95% CI: 1.21‐1.63; P = 0.001), alcohol abuse (PR = 2.57; 95% CI: 2.33‐2.84; P = 0.001), hepatitis B virus (PR = 1.32; 95% CI: 1.09‐1.59; P = 0.004), and Midwest residence (PR = 1.22; 95% CI: 1.05‐1.41; P = 0.010) were associated with higher ALD risk. Living in rural counties with high screening capacity was protective in the elderly, but associated with higher ALD risk among the disabled born 1945‐1965. Conclusions: ALD prevalence patterns were complex and were modified by race, elderly/disability status, and the extent of health care access and screening capacity in the county of residence. These study results help inform treatment strategies for HCV in the context of coordinated models of care. (Hepatology 2015;62:68‐78)
The Epidemiology of Nonsurgical Hypoparathyroidism in Denmark: A Nationwide Case Finding Study
Authors: Underbjerg Line , Sikjaer Tanja , Mosekilde Leif , Rejnmark Lars
Published: March 2015

Nonsurgical hypoparathyroidism (HypoPT) is a rare disorder most often caused by mutations in different genes. It is characterized by hypocalcaemia with inappropriately low PTH levels. Knowledge about this group of patients, including their mortality and morbidity, is very sparse. The aim was to identify all patients diagnosed with nonsurgical HypoPT in Denmark and assess their mortality and risk of complications. Through registers and review of individual patient hospital charts we identified all patients diagnosed with nonsurgical HypoPT in Denmark between 1977 and 2012. We assessed their mortality and morbidity by comparing them with a group of age- and gender-matched population-based controls. We identified a total of 180 patients with nonsurgical HypoPT among whom 123 (68%) were alive at the date of follow-up (prevalence of 2.3/100,000 inhabitants). Compared with controls, mortality was not increased, but patients had a significantly increased risk of renal insufficiency (hazard ratio [HR] 6.01), cardiovascular diseases (HR 1.91), neuropsychiatric complications (HR 2.45), infections (HR 1.94), seizures (HR 10.05), cataract (HR 4.21), and fractures at the upper extremities (HR 1.93). In contrast patients had significantly reduced risk of malignant diseases (HR 0.44). In conclusion, nonsurgical HypoPT is a rare disease associated with a number of complications that should be considered when taking care of these patients. © 2015 American Society for Bone and Mineral Research.
Fluocinolone Acetonide Is a Potent Synergistic Factor of TGF-β3–Associated Chondrogenesis of Bone Marrow–Derived Mesenchymal Stem Cells for Articular Surface Regeneration
Authors: Hara Emilio Satoshi , Ono Mitsuaki , Pham Hai Thanh , Sonoyama Wataru , Kubota Satoshi , Takigawa Masaharu , Matsumoto Takuya , Young Marian F , Olsen Bjorn R , Kuboki Takuo
Published: March 2015

Articular cartilage repair remains a challenging problem. Based on a high-throughput screening and functional analysis, we found that fluocinolone acetonide (FA) in combination with transforming growth factor beta 3 (TGF-β3) strongly potentiated chondrogenic differentiation of human bone marrow–derived mesenchymal stem cells (hBMSCs). In an in vivo cartilage defect model in knee joints of immunocompromised mice, transplantation of FA/TGF-β3–treated hBMSCs could completely repair the articular surface. Analysis of the intracellular pathways revealed that FA enhanced TGF-β3–induced phosphorylation of Smad2 and Smad3. Additionally, we performed a pathway array and found that FA activates the mTORC1/AKT pathway. Chemical inhibition of mTORC1 with rapamycin substantially suppressed FA effect, and inhibition of AKT completely repressed chondrogenesis of hBMSCs. Inhibition of glucocorticoid receptor with mifepristone also suppressed FA effect, suggesting that FA involves binding to the glucocorticoid receptor. Comparative analysis with other glucocorticoids (triamcinolone acetonide [TA] and dexamethasone [DEX]) revealed the unique ability of FA to repair articular cartilage surgical defects. Analysis of intracellular pathways showed that the mTORC1/AKT pathway and the glucocorticoid receptor was highly activated with FA and TA, but to a lesser extent with DEX. Collectively, these results show a unique ability of FA to enhance TGF-β3–associated chondrogenesis, and suggest that the FA/TGF-β3 combination may be used as major inducer of chondrogenesis in vitro. Additionally, FA/TGF-β3 could be potentially applied in a clinical setting to increase the efficiency of regenerative approaches based on chondrogenic differentiation of stem cells. © 2015 American Society for Bone and Mineral Research.
The trouble with quality filtering based on relative Cramér‐Rao lower bounds
Authors: Kreis Roland
Published: March 2015

Cramér Rao Lower Bounds (CRLB) have become the standard for expression of uncertainties in quantitative MR spectroscopy. If properly interpreted as a lower threshold of the error associated with model fitting, and if the limits of its estimation are respected, CRLB are certainly a very valuable tool to give an idea of minimal uncertainties in magnetic resonance spectroscopy (MRS), although other sources of error may be larger. Unfortunately, it has also become standard practice to use relative CRLB expressed as a percentage of the presently estimated area or concentration value as unsupervised exclusion criterion for bad quality spectra. It is shown that such quality filtering with widely used threshold levels of 20% to 50% CRLB readily causes bias in the estimated mean concentrations of cohort data, leading to wrong or missed statistical findings—and if applied rigorously—to the failure of using MRS as a clinical instrument to diagnose disease characterized by low levels of metabolites. Instead, absolute CRLB in comparison to those of the normal group or CRLB in relation to normal metabolite levels may be more useful as quality criteria. Magn Reson Med 75:15–18, 2016. © 2015 Wiley Periodicals, Inc.
The effect of dissolved oxygen on the susceptibility of blood
Authors: Berman Avery J.L. , Ma Yuhan , Hoge Richard D. , Pike G. Bruce
Published: March 2015

Purpose

It has been predicted that, during hyperoxia, excess O2 dissolved in arterial blood will significantly alter the blood's magnetic susceptibility. This would confound the interpretation of the hyperoxia‐induced blood oxygenation level‐dependent signal as arising solely from changes in deoxyhemoglobin. This study, therefore, aimed to determine how dissolved O2 affects the susceptibility of blood.

Theory and Methods

We present a comprehensive model for the effect of dissolved O2 on the susceptibility of blood and compare it with another recently published model, referred to here as the ideal gas model (IGM). For validation, distilled water and samples of bovine plasma were oxygenated over a range of hyperoxic O2 concentrations and their susceptibilities were determined using multiecho gradient echo phase imaging.

Results

In distilled water and plasma, the measured changes in susceptibility were very linear, with identical slopes of 0.062 ppb/mm Hg of O2. This change was dramatically less than previously predicted using the IGM and was close to that predicted by our model. The primary source of error in the IGM is the overestimation of the volume fraction occupied by dissolved O2.

Conclusion

Under most physiological conditions, the susceptibility of dissolved O2 can be disregarded in MRI studies employing hyperoxia. Magn Reson Med 75:363–371, 2016. © 2015 Wiley Periodicals, Inc.
Free‐breathing, motion‐corrected, highly efficient whole heart T2 mapping at 3T with hybrid radial‐cartesian trajectory
Authors: Yang Hsin‐Jung , Sharif Behzad , Pang Jianing , Kali Avinash , Bi Xiaoming , Cokic Ivan , Li Debiao , Dharmakumar Rohan
Published: March 2015

Purpose

To develop and test a time‐efficient, free‐breathing, whole heart T2 mapping technique at 3.0T.

Methods

ECG‐triggered three‐dimensional (3D) images were acquired with different T2 preparations at 3.0T during free breathing. Respiratory motion was corrected with a navigator‐guided motion correction framework at near perfect efficiency. Image intensities were fit to a monoexponential function to derive myocardial T2 maps. The proposed 3D, free breathing, motion‐corrected (3D‐FB‐MoCo) approach was studied in ex vivo canine hearts and kidneys, healthy volunteers, and canine subjects with acute myocardial infarction (AMI).

Results

Ex vivo T2 values from proposed 3D T2‐prep gradient echo were not different from two‐dimensional (2D) spin echo (P = 0.7) and T2‐prep balanced steady‐state free precession (bSSFP) (P = 0.7). In healthy volunteers, compared with 3D‐FB‐MoCo and breath‐held 2D T2‐prep bSSFP (2D‐BH), non–motion‐corrected (3D‐FB‐Non‐MoCo) myocardial T2 was longer, had a larger coefficient of variation (COV), and had a lower image quality (IQ) score (T2 = 40.3 ms, COV = 38%, and IQ = 2.3; all P < 0.05). Conversely, the mean and COV and IQ of 3D‐FB‐MoCo (T2 = 37.7 ms, COV = 17%, and IQ = 3.5) and 2D‐BH (T2 = 38.0 ms, COV = 15%, and IQ = 3.8) were not different (P = 0.99, P = 0.74, and P = 0.14, respectively). In AMI, T2 values and edema volumes from 3D‐FB‐MoCo and 2D‐BH were closely correlated (R2 = 0.88 and 0.96, respectively).

Conclusion

The proposed whole heart T2 mapping approach can be performed within 5 min with similar accuracy to that of the 2D‐BH T2 mapping approach. Magn Reson Med 75:126–136, 2016. © 2015 Wiley Periodicals, Inc.
Disambiguating the optic nerve from the surrounding cerebrospinal fluid: Application to MS‐related atrophy
Authors: Harrigan Robert L. , Plassard Andrew J. , Bryan Frederick W. , Caires Gabriela , Mawn Louise A. , Dethrage Lindsey M. , Pawate Siddharama , Galloway Robert L. , Smith Seth A. , Landman Bennett A.
Published: March 2015

Purpose

Our goal is to develop an accurate, automated tool to characterize the optic nerve (ON) and cerebrospinal fluid (CSF) to better understand ON changes in disease.

Methods

Multi‐atlas segmentation is used to localize the ON and sheath on T2‐weighted MRI (0.6 mm3 resolution). A sum of Gaussian distributions is fit to coronal slice‐wise intensities to extract six descriptive parameters, and a regression forest is used to map the model space to radii. The model is validated for consistency using tenfold cross‐validation and for accuracy using a high resolution (0.4 mm2 reconstructed to 0.15 mm2) in vivo sequence. We evaluated this model on 6 controls and 6 patients with multiple sclerosis (MS) and a history of optic neuritis.

Results

In simulation, the model was found to have an explanatory R‐squared for both ON and sheath radii greater than 0.95. The accuracy of the method was within the measurement error on the highest possible in vivo resolution. Comparing healthy controls and patients with MS, significant structural differences were found near the ON head and the chiasm, and structural trends agreed with the literature.

Conclusion

This is a first demonstration that the ON can be exclusively, quantitatively measured and separated from the surrounding CSF using MRI. Magn Reson Med 75:414–422, 2016. © 2015 Wiley Periodicals, Inc.
Pulse sequence programming in a dynamic visual environment: SequenceTree
Authors: Magland Jeremy F. , Li Cheng , Langham Michael C. , Wehrli Felix W.
Published: March 2015

Purpose

To describe SequenceTree, an open source, integrated software environment for implementing MRI pulse sequences and, ideally, exporting them to actual MRI scanners. The software is a user‐friendly alternative to vendor‐supplied pulse sequence design and editing tools and is suited for programmers and nonprogrammers alike.

Methods

The integrated user interface was programmed using the Qt4/C++ toolkit. As parameters and code are modified, the pulse sequence diagram is automatically updated within the user interface. Several aspects of pulse programming are handled automatically, allowing users to focus on higher‐level aspects of sequence design. Sequences can be simulated using a built‐in Bloch equation solver and then exported for use on a Siemens MRI scanner. Ideally, other types of scanners will be supported in the future.

Results

SequenceTree has been used for 8 years in our laboratory and elsewhere and has contributed to more than 50 peer‐reviewed publications in areas such as cardiovascular imaging, solid state and nonproton NMR, MR elastography, and high‐resolution structural imaging.

Conclusion

SequenceTree is an innovative, open source, visual pulse sequence environment for MRI combining simplicity with flexibility and is ideal both for advanced users and users with limited programming experience. Magn Reson Med 75:257–265, 2016. © 2015 Wiley Periodicals, Inc.
Assessment of lymphatic impairment and interstitial protein accumulation in patients with breast cancer treatment‐related lymphedema using CEST MRI
Authors: Donahue Manus J. , Donahue Paula C.M. , Rane Swati , Thompson Christopher R. , Strother Megan K. , Scott Allison O. , Smith Seth A.
Published: March 2015

Purpose

Lymphatic impairment is known to reduce quality of life in some of the most crippling diseases of the 21st century, including obesity, lymphedema, and cancer. However, the lymphatics are not nearly as well‐understood as other bodily systems, largely owing to a lack of sensitive imaging technologies that can be applied using standard clinical equipment. Here, proton exchange‐weighted MRI is translated to the lymphatics in patients with breast cancer treatment‐related lymphedema (BCRL).

Methods

Healthy volunteers (N = 8) and BCRL patients (N = 7) were scanned at 3 Tesla using customized structural MRI and amide proton transfer (APT) chemical exchange saturation transfer (CEST) MRI in sequence with the hypothesis that APT effects would be elevated in lymphedematous tissue. APT contrast, lymphedema stage, symptomatology, and histology information were evaluated.

Results

No significant difference between proton‐weighted APT contrast in the right and left arms of healthy controls was observed. An increase in APT contrast in the affected arms of patients was found (P = 0.025; Cohen's d = 2.4), and variability among patients was consistent with documented damage to lymphatics as quantified by lymphedema stage.

Conclusion

APT CEST MRI may have relevance for evaluating lymphatic impairment in patients with BCRL, and may extend to other pathologies where lymphatic compromise is evident. Magn Reson Med 75:345–355, 2016. © 2015 Wiley Periodicals, Inc.
Comparison of ultrashort echo time sequences for MRI of an ancient mummified human hand
Authors: Özen Ali Caglar , Ludwig Ute , Öhrström Lena Maria , Rühli Frank Jakobus , Bock Michael
Published: March 2015

Purpose

To compare the three different short‐echo time (TE) pulse sequences ultrashort echo time (UTE), point‐wise encoding time reduction with radial acquisition (PETRA), and single point imaging (SPI) for MRI of ancient remains.

Methods

MRI of mummies is challenging due to the extremely low water content and the very short transverse relaxation times T2*. To overcome the signal loss associated with the short T2*, three pulse sequences with very short TEs were compared. MR images of an ancient mummified human hand were acquired at field strengths of 1.5 Tesla (T) and 3T using home‐made solenoid Tx/Rx radiofrequency (RF) coils.

Results

In all MR images, tissues could be differentiated and anatomical structures such as bones and tendons were clearly identified. Skin with embalming resin was hyperintense in MRI, whereas it appeared iso‐intense in computed tomography. PETRA has the highest signal to noise ratio. With UTE, short scan times and a homogeneous RF excitation can be achieved, and blurring is less pronounced than with PETRA. SPI shows no blurring artifacts; however, it requires long scan times.

Conclusion

This work provided an initial analysis for the optimization of imaging protocols for paleoradiology studies with MRI, and, ultimately, for MRI of tissue with extremely short T2*. Magn Reson Med 75:701–708, 2016. © 2015 Wiley Periodicals, Inc.
Sliding‐slab three‐dimensional TSE imaging with a spiral‐In/Out readout
Authors: Li Zhiqiang , Wang Dinghui , Robison Ryan K. , Zwart Nicholas R. , Schär Michael , Karis John P. , Pipe James G.
Published: March 2015

Purpose

T2‐weighted imaging is of great diagnostic value in neuroimaging. Three‐dimensional (3D) Cartesian turbo spin echo (TSE) scans provide high signal‐to‐noise ratio (SNR) and contiguous slice coverage. The purpose of this preliminary work is to implement a novel 3D spiral TSE technique with image quality comparable to 2D/3D Cartesian TSE.

Methods

The proposed technique uses multislab 3D TSE imaging. To mitigate the slice boundary artifacts, a sliding‐slab method is extended to spiral imaging. A spiral‐in/out readout is adopted to minimize the artifacts that may be present with the conventional spiral‐out readout. Phase errors induced by B0 eddy currents are measured and compensated to allow for the combination of the spiral‐in and spiral‐out images. A nonuniform slice encoding scheme is used to reduce the truncation artifacts while preserving the SNR performance.

Results

Preliminary results show that each of the individual measures contributes to the overall performance, and the image quality of the results obtained with the proposed technique is, in general, comparable to that of 2D or 3D Cartesian TSE.

Conclusion

3D sliding‐slab TSE with a spiral‐in/out readout provides good‐quality T2‐weighted images, and, therefore, may become a promising alternative to Cartesian TSE. Magn Reson Med 75:729–738, 2016. © 2015 Wiley Periodicals, Inc.
Fitness is a determinant of the metabolic response to endurance training in adolescents at risk of type 2 diabetes mellitus
Authors: Sénéchal Martin , Rempel Meaghan , Duhamel Todd A. , MacIntosh Andrea C. , Hay Jacqueline , Wicklow Brandy , Wittmeier Kristy , Shen Garry X. , McGavock Jonathan M.
Published: March 2015

Objective

The purpose of this prospective cohort study was to determine whether changes in cardiorespiratory fitness are associated with the metabolic response to endurance training in adolescents at risk of type 2 diabetes mellitus (T2DM).

Methods

Seventy‐three overweight and obese adolescents completed a 6‐month endurance exercise intervention. Total fat mass, trunk fat mass, visceral adipose tissue, and liver fat were assessed with dual energy X‐ray absorptiometry and magnetic resonance imaging spectroscopy.

Results

The change in cardiorespiratory fitness with training was independently associated with reductions in BMI z‐score (β = −0.09; P = 0.006), total fat mass (β = −1.40; P = 0.007), trunk fat mass (β = −0.70; P = 0.01), and liver fat (β = −1.80; P = 0.053). Adolescents within the highest tertile of change in fitness were 4.67 (95% CI: 1.15‐13.73; P = 0.03), 11.90 (95% CI: 2.37‐59.77; P = 0.002), and 6.21 (95% CI: 1.14‐33.99; P = 0.035) times more likely to experience decreases in body weight, BMI, and liver fat compared with adolescents in the lowest tertile.

Conclusions

The changes in adiposity and hepatic triglyceride content in response to endurance training are significantly related to the increase in cardiorespiratory fitness in adolescents at risk of T2DM.
Hyperammonemic syndrome after Roux‐en‐Y gastric bypass
Authors: Fenves Andrew Z. , Shchelochkov Oleg A. , Mehta Ankit
Published: March 2015

Objective

Hyperammonemic encephalopathy is an uncommon but severe complication of the Roux‐en‐Y gastric bypass surgery for obesity. Mechanisms underlying this complication are incompletely understood, resulting in delayed recognition and management. This study evaluated common laboratory findings and possible etiology of hyperammonemic encephalopathy after successful Roux‐en‐Y gastric bypass surgery.

Methods

A retrospective review of 20 patients identified through our own clinical practice was conducted, with the addition of similar cases from other institutions identified through the review of literature.

Results

Patients presenting with hyperammonemic encephalopathy after Roux‐en‐Y gastric bypass surgery presented with overlapping clinical and laboratory findings. Common features included: (1) weight loss following successful Roux‐en‐Y gastric bypass for obesity; (2) hyperammonemic encephalopathy accompanied by elevated plasma glutamine levels; (3) absence of cirrhosis; (4) hypoalbuminemia; and (5) low plasma zinc levels. The mortality rate was 50%. Ninety‐five percent of patients were women. Three patients were diagnosed with proximal urea cycle disorders. One patient experienced improvement in the hyperammonemia after surgical correction of spontaneous splenorenal shunt.

Conclusions

Hyperammonemic encephalopathy after Roux‐en‐Y gastric bypass surgery is a newly recognized, potentially fatal syndrome with diverse pathophysiologic mechanisms encompassing genetic and nongenetic causes.
Association of UCP‐3 rs1626521 with obesity and stomach functions in humans
Authors: Acosta Andres , Camilleri Michael , Shin Andrea , Vazquez‐Roque Maria I. , Iturrino Johanna , Lanza Ian R. , Nair K. Sreekumaran , Burton Duane , O'Neill Jessica , Eckert Deborah , Carlson Paula , Vella Adrian , Zinsmeister Alan R.
Published: March 2015

Objective

To examine the association of gene variants of uncoupling proteins (UCP)‐2 and −3 with obesity and gastrointestinal (GI) traits.

Methods

In 255 overweight or obese adults, the associations of gene variants in UCP‐2 (−3474, rs659366) and UCP‐3 (rs1626521, rs2075577, rs15763) with body weight (BW) and GI traits were studied. Gene variants were genotyped by TaqMan® assay. The associations of genotypes with BW and GI traits (gastric emptying, gastric volume, satiety by buffet meal, satiation by nutrient drink test and GI hormones) were assessed using ANOVA corrected for false detection rate (FDR).

Results

A novel UCP‐3 gene variant, rs1626521, was identified; it was associated with BW (P = 0.039), waist circumference (P = 0.035), and significantly higher postprandial gastric volume (P = 0.003) and calories ingested at buffet meal (P = 0.006, both significant with FDR). In a subgroup of 11 participants, rs1626521 was also associated with reduced mitochondrial bioenergetics efficiency in skeletal muscle (P = 0.051). In an in vitro study in HEK293 cells, rs1626521 reduced UCP‐3 protein expression (P = 0.049). Associations detected between other genotypes and GI traits were nonsignificant with FDR.

Conclusions

A newly identified functional variant (rs1626521) in UCP‐3 affects postprandial gastric functions and satiety and may contribute to weight gain and alter human mitochondrial function.
Maternal prepregnancy obesity and achievement of infant motor developmental milestones in the upstate KIDS study
Authors: Wylie Amanda , Sundaram Rajeshwari , Kus Christopher , Ghassabian Akhgar , Yeung Edwina H.
Published: March 2015

Objective

Maternal prepregnancy obesity is associated with several poor infant health outcomes; however, studies that investigated motor development have been inconsistent. Thus, maternal prepregnancy weight status and infants' gross motor development were examined.

Methods

Participants consisted of 4,901 mother–infant pairs from the Upstate KIDS study, a longitudinal cohort in New York. Mothers indicated dates when infants achieved each of six gross motor milestones when infants were 4, 8, 12, 18, and 24 months old. Failure time modeling under a Weibull distribution was utilized to compare time to achievement across three levels of maternal prepregnancy BMI. Hazard ratios (HR) below one indicate a lower “risk” of achieving the milestone and translate to later achievement.

Results

Compared to infants born to thin and normal‐weight mothers (BMI < 25), infants born to mothers with obesity (BMI > 30) were slower to sit without support (HR = 0.91, P = 0.03) and crawl on hands and knees (HR = 0.86, P < 0.001), after adjusting for maternal and birth characteristics. Increased gestational age was associated with faster achievement of all milestones, but additional adjustment did not impact results.

Conclusions

Maternal prepregnancy obesity was associated with a slightly longer time for infant to sit and crawl, potentially due to a compromised intrauterine environment or reduced physically active play.
Insulin response to oral stimuli and glucose effectiveness increased in neuroglycopenia following gastric bypass
Authors: Patti Mary Elizabeth , Li Ping , Goldfine Allison B.
Published: March 2015

Objective

Hyperinsulinemic hypoglycemia with neuroglycopenia is a rare complication following Roux‐en‐Y gastric bypass (RYGB) surgery for weight management. Insulin secretion and action in response to oral and intravenous stimuli in persons with and without neuroglycopenia following RYGB are evaluated in this study.

Methods

Cross‐sectional cohort studies were performed at a single academic institution to assess insulin secretion and action during oral mixed meal tolerance test and intravenous glucose tolerance test (IVGTT).

Results

Insulin secretion was increased more following oral mixed meal than intravenous glucose in individuals with neuroglycopenia compared to the asymptomatic group. Reduced insulin clearance did not contribute to higher insulinemia. Glucose effectiveness at zero insulin, estimated during the IVGTT, was also higher in those with neuroglycopenia. Insulin sensitivity did not differ between groups.

Conclusions

Increased beta‐cell response to oral stimuli and insulin‐independent glucose disposal may both contribute to severe hypoglycemia after RYGB.
Assembling the pieces of macromolecular complexes: Hybrid structural biology approaches
Authors: Politis Argyris , Borysik Antoni J.
Published: March 2015

Hybrid approaches in structural biology have gained considerable interest for uncovering the molecular architectures of large and transient biological systems. In particular, MS‐based methods and structural electron microscopy can complement conventional tools, such as X‐ray crystallography and NMR spectroscopy. However, bringing together the data derived from diverse sources requires sophisticated methods that can efficiently deal with intrinsic ambiguities and heterogeneities of the vast amount of data available. Here, we highlight hybrid approaches for studying dynamic assemblies, such as transient soluble and integral membrane protein complexes. In this review, we emphasize the integration of the wide range of emerging MS‐based methods, such as ion mobility, native MS, hydrogen–deuterium exchange MS and chemical cross‐linking MS, with data acquired from cryo electron microscopy and X‐ray crystallography and further provide a future outlook of hybrid structural biology approaches.
Quantitative functional characterization of conserved molecular interactions in the active site of mannitol 2‐dehydrogenase
Authors: Lucas James E. , Siegel Justin B.
Published: March 2015

Enzyme active site residues are often highly conserved, indicating a significant role in function. In this study we quantitate the functional contribution for all conserved molecular interactions occurring within a Michaelis complex for mannitol 2‐dehydrogenase derived from Pseudomonas fluorescens (pfMDH). Through systematic mutagenesis of active site residues, we reveal that the molecular interactions in pfMDH mediated by highly conserved residues not directly involved in reaction chemistry can be as important to catalysis as those directly involved in the reaction chemistry. This quantitative analysis of the molecular interactions within the pfMDH active site provides direct insight into the functional role of each molecular interaction, several of which were unexpected based on canonical sequence conservation and structural analyses.
Correlation between electron delocalization and structural planarization in small water rings
Authors: Wang Bo , Wang Li , Dai Xing , Gao Yang , Jiang Wanrun , Han Jie , Wang Zhigang , Zhang Rui‐Qin
Published: March 2015

The discovery of the covalent‐like character of the hydrogen bonding (H‐bonding) system [Science 342, 611(2013)] has promoted a renewal of our understanding of the electronic and geometric structures of water clusters. In this work, based on density functional theory calculations, we show that the preferential formation of a stable quasiplanar structure of (H2O)n(n = 3–6) is closely related to three kinds of delocalized molecular orbitals (MOs; denoted as MO‐I, II, and III) of water rings. These originate from the 2p lone pair electrons of oxygen (O), the 2p bond electrons of O and the 1s electrons of H and the 2s electrons of O and 1s electrons of H, respectively. To maximize the orbital overlaps of the three MOs, geometric planarization is needed. The contribution of the orbital interaction is more than 30% in all the water rings according to our energy decomposition analysis, highlighting the considerable covalent‐like characters of H‐bonds. © 2015 Wiley Periodicals, Inc.
Introduction to the Special Issue: Public Health Genetics and Genomics
Authors: McWalter Kirsty , Gaviglio Amy
Published: March 2015

This special issue of the Journal of Genetic Counseling is dedicated to public health genetics and genomics. The seventeen papers featured in this issue span such topics as genetic counselors in public health roles, newborn screening, population screening, ethics, and health beliefs and behaviors. In this introduction to the special issue, we review some history of public health genetics and genomics, present the Centers for Disease Control and Prevention's “10 Essential Public Health Services” with associated geneticsspecificrecommendations and priorities, and briefly overview how each article ties into the world of public health genetics and genomics. We hope this issue encourages genetic counselors to visualize their everexpanding and important roles in public health genetics and genomics, as well as their contributions to improving population health.
The role of molecular imaging in the evaluation of myocardial and peripheral angiogenesis
Authors: Stacy Mitchel R. , Paeng Jin Chul , Sinusas Albert J.
Published: March 2015

Angiogenesis, or the formation of new microvasculature, is a physiological process that may occur in the setting of chronic tissue ischemia and can play an important role in improving tissue perfusion and blood flow following myocardial infarction or in the presence of peripheral vascular disease (PVD). Molecular imaging of angiogenesis within the cardiovascular system is a developing field of study. Targeted imaging of angiogenesis has the potential for non-invasive assessment of the underlying molecular signaling events associated with the angiogenic process and, when applied in conjunction with physiological perfusion imaging, may be utilized to predict and evaluate clinical outcomes in the setting of ischemic heart disease or PVD. This review discusses the developing radiotracer-based imaging techniques and technology currently in use that possess potential for clinical translation, with specific focus on PET and SPECT imaging of myocardial and peripheral angiogenesis.
Estudio de Monte Carlo para comparar 8 pruebas de normalidad sobre residuos de mínimos cuadrados ordinarios en presencia de procesos autorregresivos de primer orden
Authors: Montenegro Sebastián , Alonso Julio César
Published: March 2015

Este estudio tiene como objetivo evaluar el poder y tamaño de 8 pruebas de normalidad en la presencia de errores autorregresivos de orden uno y diferentes tamaños de muestra. Para lograr este objetivo se emplean simulaciones de Monte Carlo evaluando las siguientes pruebas: Cramér-von Mises, Anderson-Darling, Lilliefors, Pearson, Shapiro-Wilk, Shapiro-Francia, Jarque-Bera y D’Agostino-Pearson. Los resultados muestran 4 aspectos importantes: primero, el efecto de la autocorrelación sobre el tamaño y el poder de las pruebas es asimétrico. Segundo, el tamaño de todas las pruebas se distorsionan en presencia de autocorrelación fuerte. Tercero, ninguna de las pruebas tiene un mejor poder que las demás. Cuarto, cuando la muestra es pequeña, las pruebas de normalidad estudiadas tienen un poder muy bajo.
Scaffolding the retina: The interstitial extracellular matrix during rat retinal development
Authors: Taylor Linnéa , Arnér Karin , Engelsberg Karl , Ghosh Fredrik
Published: March 2015

Purpose

To examine the expression of interstitial extracellular matrix components and their role during retinal development.

Material and methods

Fibronectin (FN), collagen IV (Coll IV) and laminin 5 (Lam 5) expression in rat retinas from developmental stages E17 to adult were studied. In addition, PN5 full‐thickness retinas were cultured for 7 days with dispase, which selectively cleaves FN and Coll IV, at either 0.5 U/ml or 5.0 U/ml for 3 or 24 h. Eyecups and retinal cultures were examined morphologically using hematoxylin and eosin staining and immunohistochemistry.

Results

Coll IV, Lam 5 and FN were all transiently expressed in the interstitial matrix of the retinal layers during development. The retinal layers in dispase treated explants was severely disturbed in a dose and time dependent manner.

Conclusions

FN, Lam 5 and Coll IV, are present in the interstitial extracellular matrix during rat retinal development. Enzymatic cleavage of FN and Coll IV early in the lamination process disrupts the retinal layers implicating their pivotal role in this process.
Medial and Lateral Heel Whips: Prevalence and Characteristics in Recreational Runners
Authors: Souza Richard B. , Hatamiya Nicolas , Martin Carly , Aramaki Andrew , Martinelli Brian , Wong Jamie , Luke Anthony
Published: March 2015

Objective

To investigate the prevalence and characteristics of recreational runners with medial and lateral heel whips.

Design

Observational cohort study.

Setting

Clinical research laboratory.

Participants

A total of 256 recreationally active runners and joggers participated.

Main Outcome Measures

High‐definition video was acquired from a posterior view while runners ran at a self‐selected pace on a treadmill. Heel whips, defined as the medial or lateral rotation of the foot in the transverse plane during initial swing, were measured with Dartfish software. Subjects were stratified by direction (medial and lateral) and severity (W_5‐10 = 5‐10 degrees; W_10+ = >10 degrees) of heel whip. Body mass index and gender comparisons, as well as measurement reliability, also were explored.

Results

Mean heel whip angle across runners was 0.4 degrees (medial) with a standard deviation of 9.2 degrees. Of the 512 feet analyzed, 274 (54%) demonstrated a 5 degree whip or greater. There was a similar number of medial and lateral heel whips observed (27% each). Female runners were twice as likely to demonstrate a lateral heel whip of greater than 8.9 degrees. Overweight runners had more medially directed whips when compared with normal and underweight runners.

Conclusions

More than half of the recreational runners studied were observed to have a medial or lateral heel whip of greater than 5 degrees. These data reveal the age, body mass index, and gender distribution of recreational runners with and without heel whips.
A Survey of Runners' Attitudes Toward and Experiences With Minimally Shod Running
Authors: Cohler Marissa H. , Casey Ellen
Published: March 2015

Objective

To investigate the characteristics, perceptions, motivating factors, experiences, and injury rates of runners who practice minimally shod running.

Design

Survey.

Setting

web‐based questionnaire.

Participants

Five‐hundred sixty‐six members of the Chicago Area Runner's Association.

Methods

A link to a 31‐question online survey was e‐mailed to members of Chicago Area Runner's Association. Questions covered demographic information, use of minimalist‐style running shoes (MSRS), injury rates, and change in pain.

Main Outcome Measures

Use of MSRS, occurrence or improvement of injury/pain, regions of injury/pain, reasons for or for not using MSRS.

Results

One‐hundred seventy‐five (31%) respondents had practiced minimally shod running, and the most common motivating factor was to decrease injuries and/or pain. Fifty‐one respondents (29%) suffered an injury or pain while wearing MSRS, with the most common body part involved being the foot. Fifty‐four respondents (31%) had an injury that improved after adopting minimally shod running; the most common area involved was the knee. One‐hundred twenty respondents (69%) were still using MSRS. Of those who stopped using MSRS, the main reason was development of an injury or pain. The most common reason that respondents have not tried minimally shod running is a fear of developing an injury.

Conclusion

This survey‐based study demonstrated that the use of MSRS is common, largely as the result of a perception that they may reduce injuries or pain. Reductions and occurrences of injury/pain with minimally shod running were reported in approximately equal numbers. The most common site of reported injury/pain reduction was the knee, whereas the most common reported site of injury/pain occurrence was the foot. Fear of developing pain or injury is the most common reason runners are reluctant to try minimally shod running.
Influence of Knee Pain and Low Back Pain on the Quality of Life in Adults Older Than 50 Years of Age
Authors: Kim Won , Jin Young Soo , Lee Choon Sung , Bin Seong‐il , Lee Sang Yoon , Choi Kyoung Hyo
Published: March 2015

Objectives

To investigate the impact of knee pain and low back pain (LBP) on quality of life (QoL) in people ≥50 years of age.

Design

Cross‐sectional study.

Setting

A nationwide survey.

Participants

A total of 1295 men and 1658 women aged ≥50 years from the Fifth Korea National Health and Nutrition Examination Survey, conducted in 2010.

Methods

Knee pain and LBP were assessed by a questionnaire, and QoL was assessed by the EuroQol (EQ)‐5D, consisting of the EQ‐5D descriptive system and the EuroQol visual analogue scale (EQ‐VAS). Multiple linear regression models were used to evaluate associations between knee pain or LBP and the EQ‐5D index or EQ‐VAS score.

Main Outcome Measurements

Standardized coefficient (β) for QoL according to the presence of knee pain or LBP.

Results

Both men and women with knee pain or LBP had a lower QoL than those without them in all dimensions of the EQ‐5D, EQ‐5D index, and EQ‐VAS scores. Compared with most other chronic diseases, knee pain and LBP showed stronger negative correlations with the EQ‐5D index and EQ‐VAS score. In men, LBP showed a stronger negative correlation with the EQ‐VAS score than knee pain. The relative impact of LBP on knee pain was greater in people aged ≥65 years than in people aged 50–64 years, especially men.

Conclusions

These results suggest that knee pain and LBP are important factors affecting QoL in middle‐aged and elderly people and that LBP may be relatively more important than knee pain in elderly people, especially men. Proper management and prevention of these conditions can help to improve QoL.
Exploring the Relationship Between Mild Traumatic Brain Injury Exposure and the Presence and Severity of Postconcussive Symptoms Among Veterans Deployed to Iraq and Afghanistan
Authors: Baldassarre Megan , Smith Bridget , Harp Jordan , Herrold Amy , High Walter M. , Babcock‐Parziale Judith , Louise‐Bender Pape Theresa
Published: March 2015

Objective

The aim of this study was to describe the association between mild traumatic brain injury (mTBI) and persisting postconcussive symptoms according to symptom category, number, and severity.

Design

The study design was observational.

Participants

The study sample comprised veterans (≥18 years of age) deployed in Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) conflicts who had not received any treatment for mTBI in the 30 days preceding study enrollment.

Methods

Veterans were interviewed and completed testing in a single day. The Standard TBI Diagnostic Interview and the Clinician‐Administered PTSD Scale were used. Testing included the Neurobehavioral Symptom Inventory and a full neuropsychological battery. Gold standard classification methods were utilized to determine presence/absence of mTBI. For each of the 5 symptom outcomes, an adjusted multiple linear regression model (negative binomial count models) accounting for effects of socio‐demographic variables and behavioral health conditions was used.

Main Outcome Measures

Self‐report of neurobehavioral symptoms categorized as affective, cognitive, somatic, and vestibular symptoms, in addition to the instruments specified above.

Results

OEF/OIF veterans with mTBI, relative to veterans with no mTBI, were observed to have 30% more symptoms overall (P < .001), 34% more somatic symptoms (P < .001), 22% more cognitive symptoms (P = .008), 15% more affective symptoms (P = .017), and 59% more vestibular symptoms (P < .001). For adjusted models, variables significantly related to number of symptoms across all 4 symptom categories were anxiety (all P < .001) and insomnia (all P < .001). For the adjusted models, variables significantly related to symptom severity across all 4 symptom categories were insomnia (all P < .001), depression (P < .001‐.05) and anxiety (all, P < .001).

Conclusions

OEF/OIF veterans with mTBI, relative to veterans with no mTBI, have significantly more and significantly more severe persisting symptoms, with vestibular symptoms reported with the greatest frequency. After accounting for behavioral health conditions and socio‐demographic factors, OEF/OIF veterans with mTBI compared to veterans without mTBI had significantly more cognitive, affective, vestibular, and somatic symptoms persisting 4.8 years after the mTBI event(s).
Economics as energy framework: Complexity, turbulence, financial crises, and protectionism
Authors: Rutledge John
Published: March 2015

This paper presents a framework for thinking about economic growth, trade, and capital flows viewed as transformations of current and vintage solar energy, stored in the form of natural resources, human capital, physical capital and technology described by the laws of thermodynamics. Recent developments in nonequilibrium thermodynamics (NET) show how efficient global capital markets and high‐speed communications networks accelerate energy flow and growth but also create turbulence, financial crisis, protectionism and conflict. The paper discusses the role that NET can play in helping us understand stock market bubbles and financial crises.
Modeling fund and portfolio risk: A bi‐modal approach to analyzing risk in turbulent markets
Authors: Karagiannidis Iordanis , Sykes Wilford D.
Published: March 2015

Following the financial crisis of 2008, it has been argued that Value at Risk (VaR), and risk analysis in general, failed to alert risk managers of the turbulence on the horizon. This is a misguided view that should not have come as a surprise because many widely circulated academic papers and discussions suggested, well before the crisis, that simple VaR results could easily be misinterpreted if the circumstances for its proper use are not fully understood. This paper addresses some ways in which VaR concepts may be applied more effectively. Non‐standard Monte Carlo simulations are utilized. Whereas standard mean–variance defined methodologies using Monte Carlo analysis may not capture how “fat” a lower tail may actually be, a bi‐modal switching structure between assumed normal periods and possible turbulent economic periods may help resolve the problem. Lower boundaries (worst case paths) of the different (normal versus bi‐modal) processes are mapped to illustrate implied riskiness of portfolios if turbulence occurs. The analysis implies that no mechanical risk analysis is sufficiently divorced from a judgment call about possible market disruptions; however, a bi‐modal approach allows quantification of the said judgment in conjunction with empirical observations from history.