bluuebunny/crossref_metadata_2025 huggingface dataset:
Menaquinone benefits weight control and improves inflammatory biomarkers in high‐fat diet‐induced obese rats (815.1)
Authors: Kim Misung , Na Woori , Sohn Cheongmin
Published: June 2021

Vitamin K is a co‐factor for γ‐glutamic carboxylase, which is an essential enzyme for the γ‐carboxylation of vitamin K‐dependent proteins. Menaquinone (vitamin K2) has been reported to have favorable effects on bone metabolism and energy metabolism. In the present study we investigated the effects of the long‐term supplementation effects of menaquinone on inflammatory status and weight control in high‐fat diet (HFD)‐induced obese mice. A total of twenty‐one male, 4‐week‐old C57BL/6 mice were fed and randomly divided into 3 groups (7 animals in each group; randomized block design), a normal diet (ND), 45% HFD and a 45% HFD + menaquinone (HFD ‐K2) for 3 months. Weight change, adipose tissue weight and serum proinflammatory cytokines were determines.Compared with the ND, the HFD increased total fat mass, leptin, osteoprotogerine, and fasting blood glucose levels. Consumption of HFD containing menaquinone resulted in significantly less weight gain (12% less, p<0.05). Interestingly, menaquinone supplementation significantly decreased the total fat accumulation (p<0.05) and leptin levels (p<0.05) and reduced serum glucose by 17% compared with the HFD group.

In conclusion, the present study demonstrates that menaquinone supplementation had favorable effects on weight control and body composition possibly through suppressing inflammation.

Further studies on the mechanism of menaquinone supplementation in the regulation of body fat accumulation would provide valuable data on the prevention of lifestyle related disorders, including diabetes and obesity.

Grant Funding Source: Funded by the Ministry of Education, Science and Technology in Korea(project no:2012R1A1A3012499
Propionate is a dominant inducer of bovine cytosolic phosphoenolpyruvate carboxykinase (PCK1) expression (818.11)
Authors: Zhang Qian , Koser Stephanie , Donkin Shawn
Published: June 2021

Expression of PCK1 is a critical control point for gluconeogenesis. Our objective was to determine the effects of propionate, insulin, and 8 Br‐cAMP (cAMP) on the bovine PCK1 promoter. Five promoter segments from ‐1238 to +221 relative to transcription initiation and nested 5’ truncation deletions at ‐815, ‐409, ‐281 and ‐85 to +221 were ligated to pGL3 Luciferase Reporter Vector and transfected into H4IIE cells. Following 5 h transfection, cells were exposed to treatments consisting of 2.5 mM propionate in combinations with insulin and cAMP for 23 h. Propionate induced (P<0.001) expression of all PCK1 promoter constructs (up to 8‐fold) over the control, and the induction was further enhanced for the promoter ‐1238 to +221 construct. In the presence of 0.1 mM cAMP, activity of the ‐1238 to +221 PCK1 promoter was linearly induced (P<0.0001) with increasing propionate (0.25, 0.5, 1.0, 2.5 mM propionate induced PCK1 by 1.4, 1.8, 2.6, 6.2‐fold over 0 mM, respectively). With 1.0 mM cAMP, propionate (1.0 vs. 2.5 mM) did not increase PCK1 activity. Induction of the ‐409 to +221 PCK1 promoter construct with 0.1 mM cAMP, was repressed by 10 nM insulin but 2.5 mM propionate prevented this response (P<0.0001). The data demonstrate an inductive effect of propionate that is dominant to the repressive effects of insulin on the bovine PCK1 promoter.

Grant Funding Source: Supported by USDA‐CSREES NRI Grant no. 2006‐35206‐16646
Resistant starch significantly alters gut microbiota and liver metabolome in mice fed a high fat diet (822.13)
Authors: Kieffer Dorothy , Martin Roy , Marco Maria , Kim Eun , Keenan Michael , Dunn Tamara , Adams Sean
Published: June 2021

Resistant starch (RS) is a fermentable dietary fiber shown to alter gut hormones and modify the gut microbiome. Because RS impacts the gut microbiota, we hypothesize that RS changes gut‐derived signals reaching the liver by altering the gut microbiota and, in turn altering liver metabolism. To assess the effects of RS on the liver metabolome under obesogenic conditions, male C57Bl/6J mice were fed a 45% fat diet for 10 weeks supplemented with type 2 RS (10% by wt) or maltodextrin (n=15/group). As expected, increased cecal weights (by 55%, p<0.001) and significant changes in the cecal microbiome were observed. At the phylum level there was an increase in Bacteroidetes (by 53%, p<0.001) and decrease in Firmicutes (by 52%, p<0.001) in the RS‐fed group. Despite no differences in food intake, adiposity, liver weights and liver triglycerides, RS mice displayed markedly altered liver metabolites, in particular reduced liver amino acids (reduced 15‐52% for all measured amino acids except Gln), creatinine (by 40%, p<0.001) and urea (by 28%, p<0.001). These metabolites were equivalent in RS plasma vs. controls, suggesting that RS effects were due to changes specific to liver AA biochemistry or transport, and not simply due to lower blood AA. Reductions in these nitrogenous metabolites by RS may have implications in the dietary treatment of chronic kidney disease, and should provide important clues about gut‐derived signaling pathways that impact the liver.

Grant Funding Source: Supported by: Danish Council for Strategic Research, USDA‐ARS Intramural Project 5306‐51530‐019‐00
Nine months of dietary supplementation of Omani fruits (pomegranate, figs and dates) improves the memory, anxiety and learning skills in Alzheimer's disease transgenic mice (845.1)
Authors: Subash Selvaraju , Essa Musthafa , Al‐Adawi Samir , Al‐Asmi Abdullah , Vaishnav Ragini , Guillemin Gilles
Published: June 2021

Active components present in the fruits have been shown to be neuro‐protective in different disease states including Alzheimer’s disease (AD). We have studied the comparative effect of 9 month dietary supplementation of pomegranate, figs and dates on the memory, anxiety and learning skills in AD mouse model. The experimental groups of APP‐transgenic mice from the age of 4 months were fed custom‐mix diets (pellets) containing 4% pomegranate or 4% figs or 4% dates. These experimental and control mice were examined at the age of 4‐5 months, 7‐8 months and 10‐11 months by Morris water maze test (for spatial memory & learning ability), T maze test (for position discrimination learning ability), rota rod test (for psychomotor coordination), elevated plus maze test (for anxiety‐related behavior) and open field test to analyze the effect of diet rich in pomegranate, figs and dates on memory, anxiety and learning skills. AD mice without fruits in diet showed memory deficit, anxiety‐related behavior, and severe impairment in spatial learning ability, position discrimination learning ability and motor coordination compared to the wild type mice on the same diet. All the diets rich in 4% pomegranate or 4% figs or 4% dates fed tg mice showed a significant improvement above factors compared to the AD tg mice on diet without pomegranate or figs. The more effect was found in the animals fed with 4% pomegranate compared to 4% figs and 4% date pal fruit diets. Our results suggest that dietary supplementation of pomegranate; figs and dates may have the beneficial effect in reducing the risk, delaying the onset or slowing the progression of AD. Supported by a research grant from The Research Council, Oman (RC/AGR/FOOD/11/01)

Grant Funding Source: Supported by a research grant from The Research Council, Oman (RC/AGR/FOOD/11/01).
Exercise tolerance in Gulf War veterans and relationship to deployment exposures (884.22)
Authors: Smith Webb , Klein Jacquelyn , Ndirangu Duncan , Chen Yang , Falvo Michael
Published: June 2021

Exercise intolerance and post‐exertional malaise are common findings that persist in veterans of the 1990 ‐ 1991 Gulf War. Previous work has suggested that these symptoms are related to exposure to airborne hazards during deployment. The objective of this study was to examine the relationship between self‐report measures of exposure and fatigue with cardiopulmonary exercise testing (CPET) performance. Ten male veterans (51.0±3.8 yrs; BMI: 30.0±5.1) completed health, exposure and fatigue questionnaires prior to a maximal exercise test to exhaustion on cycle ergometer. Exercise capacity was significantly reduced in this group and 40% had ventilatory limitations to exercise (i.e. ventilatory reserve < 30%). Exposure intensity was significantly associated with oxygen pulse (r = ‐0.69, p = 0.04), fatigue severity (r = 0.71, p = 0.03), and trends were observed for peak oxygen consumption (VO2) and uptake kinetics (p = 0.08). However, when categorized into low and high exposure groups, VO2 peak and uptake kinetics were significantly greater (p<0.05) in the low exposure group. Our preliminary findings in a small group of Gulf War veterans suggest that higher deployment‐related exposures may be associated with greater fatigue, reduced exercise capacity and slower VO2 kinetics. Future studies are necessary to better understand the health effects of airborne hazards exposures on cardiorespiratory function.

Grant Funding Source: VA Grants 1I21RX001079‐01, 1I21CX000797‐01
The histological structure of the medial patellofemoral ligament: implications in knee stability and pain generation (914.9)
Authors: Veteto Austin , Marberry Kevin , Kondrashov Peter
Published: June 2021

The histological structure of the knee joint capsule is not well understood. The aim of this study was to quantify the histological composition of the medial patellofemoral ligament (MPFL) in comparison with the lateral patellofemoral ligament (LPFL), quadriceps tendon (QT), anterior cruciate ligament (ACL), and medial collateral ligament (MCL). The MPFL is frequently damaged in lateral patellar dislocation injuries for which there are several surgical repair procedures. One of the side effects of these repairs is patellofemoral pain syndrome, which origin is unclear and might be due to the difference between in histological composition between the original ligament (MPFL) and the repair tissue. To better identify the role of MPFL in knee stability our comparison involved three ligaments with different known properties and QT to determine its validity as an autograft in MPFL and LPFL reconstruction. Samples of the MPFL, LPFL, QT, ACL, and MCL were excised from ten cadaveric knees and stained with H&E. The histological composition of each of the ligaments was quantified using the point‐counting system. Our data show that the MPFL and LPFL are composed of multiple elements including dense connective tissue, loose connective tissue, vasculature, and nerve fibers. Presence of these elements differentiates the MPFL and LPFL from the QT, ACL, and MCL, which are uniformly composed of dense regular connective tissue.
Human intestinal tract length and relationship with body height (916.4)
Authors: Minko Elizaveta , Pagano Anthony , Caceres Noel , Adar Tony , Márquez Samuel
Published: June 2021

Despite its great importance in surgical approaches to intestinal resection, little definitive information is available on human gut tract length. Previous studies have correlated various measures with sex, age, weight, height, and “ethnic background.” Better knowledge of these relationships may aid in avoidance of surgical complications such as the nutritional disorder “short bowel syndrome.” This study examined length of the intestinal tract and its components (small intestine and colon) in 10 donor bodies. The small intestine was measured from pyloric sphincter to ileocecal junction while the large intestine was measured from caecum to sigmoid colon. Results indicate strong correlation (r=0.827) between colon length and body height from cranial vertex to heel, likely a result of the colon's function in water absorption. This relationship was stronger than the ones among total gut length, small intestine length, and body height. In particular, the weakest correlation was between small intestine length and height (r=0.337), suggesting that the combined lengths of the duodenum, jejunum, and ileum are not closely related to body size. Indeed, this measure had the highest coefficient of variation (0.26) while colon length showed the lowest (0.085). Future research will test hypotheses related to population differences in gut length and its physiologic consequences.
Bedrest increases burden of mitochondrial DNA deletions in human muscle (956.1)
Authors: Cloutier Gregory , Kraytsberg Yevgenia , Khrapko Konstantin , Brooks Naomi , Safd Adeel , Roubenoff Ronnen , Castaneda‐Sceppa Carmen
Published: June 2021

We explored whether muscle disuse (i.e. bed rest) contributes to mitochondrial (mt)DNA deletions in skeletal muscle. mtDNA deletions have been associated with various degenerative processes (e.g. sarcopenia) and sedentary behavior. Human muscle tissue from a small sample (n=3) taken before and after a 28‐day bed rest were subjected to mutational analysis using, a restriction digestion / long range digital PCR approach. Total DNA was digested with SnaBI, an enzyme with a single restriction site located in an area commonly removed in deleted mtDNA molecules. DNA was exposed to long‐range PCR capable of amplifying most of the mitochondrial genome. Restriction digestion rendered mtDNA un‐amplifiable, except for molecules with deletions. The actual number of molecules with deletions and types thereof were determined using highly diluted DNA samples, reaching single molecule per reaction, in multiple independent PCR reactions, so that molecules could be directly counted (“digital PCR”). We found an increase in the fraction of molecules with mtDNA deletions after bedrest, relative to intact wild type molecules. This finding suggests that disuse results in skeletal muscle mtDNA deletions. Further studies are needed to determine the association of these deletions with physiological and metabolic changes seen with disuse or sedentary behavior.

Grant Funding Source: Supported by Ellison Medical Foundation, NSBRI‐NPFR00301, GCRC M01 RR00
Effect of Justicia spicigera extract plant on oxidative and nitrosative stress in hypertensive rat kidney mitochondria (960.2)
Authors: Esquivel‐Gutiérrez Edgar , Clemente‐Guerrero Mónica , Manzo‐Avalos Salvador , Salgado‐Garciglia Rafael , Saavedra‐Molina Alfredo
Published: June 2021

Hypertension is a major risk factor for cardiovascular, Reno vascular disease. Reduction of elevated blood pressure significantly reduces the risk of cardiovascular events. Kidney synthesizes reactive oxygen species (ROS), which under pathological conditions play an important role in renal dysfunction. Evidence indicates that increased oxidative and nitrosative stress are mediators of Reno vascular injury in cardiovascular pathologies. Herbal medicines are being used by about 80% of the world population for the primary health care including hypertension. Recent data demonstrated that Justicia spicigera (muicle) a Mexican medicinal plant, has a potential to reduce the blood pressure in L‐NAME rats through the chloroform extract, hence the main purpose of this work was to elucidate if the oxidative and nitrosative stress are related with the antihypertensive effect of Justicia spicigera, however our results indicate that the stress levels assayed by lipid peroxidation, nitric oxide and protein nitration (S‐nitrosylation) are no different in hypertensive and control groups. In conclusion, part of the mechanism by which muicle reduces blood pressure is not mediated by ROS. Acknowledgements: We appreciated the partial economic support from the grants of: CIC‐UMSNH (2.10 to RSG; 2.16 to ASM; 2.33 to SMA) and CONACYT (169093 to ASM). EEG is a CIC‐UMSNH Postdoctoral Fellow.
Different fluid intake patterns across the week can be identified in German adults (LB378)
Authors: Guelinckx Isabelle , Husson François , Perrier Erica , Kemgang Stella , Klein Alexis , Josse Julie
Published: June 2021

Food and fluid intake (FI) data are usually collected during one day with the assumption that this is representative of the daily intake of an individual. However, this assumption has never been validated. The aim of this analysis was to identify FI patterns of German adults using data of a Fluid Intake (FI) survey performed in spring 2012. FI of a national representative sample of German adults (N=1606; 18‐65 years; mean FI 2,5 ± 0,9 L/d) was recorded with a 24h fluid specific diary over 7 consecutive days. To identify FI pattern across the week an AMMI (additive main effect and multiplicative interactions) model was created and to cluster subjects with similar patterns a principle component analysis was performed. The results indicated 3 FI patterns, regardless of the mean weekly FI of an individual. The largest cluster of subjects (45% of total sample) consumed less fluid during the weekdays compared to the other clusters, however they increased their FI during the weekend. The 2nd cluster (31% of total sample) demonstrated the opposite behavior than the 1st cluster: after a high FI during the week they consumed less during the weekend. The FI pattern of the last cluster (24% of total sample) was stable during the beginning of the week, and then peaked on Friday to decrease again during the weekend. The identified FI patterns lead to conclude that individuals do change their FI behavior along the week, and FI of one day does not necessary reflect their daily FI. It remains to be determined if a specific behavior is more or less susceptible to health problems such as urinary tract infections and to behavior change programs.

Grant Funding Source: Supported by Danone Nutriticia Research
The association between Vitamin B6 and cognitive decline is modified by inflammatory state (LB425)
Authors: Reginaldo Christina , Sawaensgri Hathairat , Scott Tammy , Rosenberg Irwin , Selhub Jacob , Paul Ligi
Published: June 2021

Individuals with inflammatory conditions like CVD, diabetes, and cancer have low plasma pyridoxal 5’‐phosphate (PLP) levels, a marker of functional vitamin B6 deficiency. Prior studies suggest that during inflammation, PLP is mobilized to sites of inflammation to modulate immune response. This leads to low plasma PLP and reduces PLP available for neurotransmitter synthesis and their downstream signaling. These outcomes may affect cognition and depression.

We conducted a secondary data analysis of the Nutrition and Memory in Elders (NAME) study to determine whether plasma PLP is associated with cognitive decline and inflammation.

The NAME study includes cross‐sectional data on global cognition as measured by Mini‐Mental State Examination (MMSE) in a population of Boston‐area elderly (aged 60+).

Using multivariate analysis, cognition was directly associated with PLP (p=0.045); but not with CRP (p=0.71). Using logistic regression analysis, the odds of having cognitive decline for diabetics were 130% higher than that of non‐diabetics (p<0.05). Subjects with diabetes also have 28% higher CRP and 15% lower PLP levels than subjects without diabetes, (p=0.003 and 0.001, respectively).

Upon stratification by inflammatory state, cognition and PLP were directly associated in subjects without diabetes (p=0.049) and in subjects with CRP <3 mg/L (p=0.03).

Overall, cognition was positively associated with PLP but not with CRP. While this study found diabetes to be associated with higher CRP, lower PLP, and cognitive decline, the lack of an association between cognition and CRP suggests that mechanisms underlying the relation between PLP and disease likely involve a generalized trigger of inflammation and a secondary disease specific inflammatory response not well characterized by CRP. Further studies are needed to investigate the role of more specific inflammatory markers on the association between PLP and disease.

Grant Funding Source: Supported by USDA Cooperative Agreement 51520‐008‐045
Reduction of body weight by rutin is associated with an increase of brown adipose tissue mitochondrial biogenesis in high‐fat diet induced obese rat (LB430)
Authors: Seo Sangjin , Oh Soojung , Shin Yoonjin , Jung Sunyoon , Kim Yangha
Published: June 2021

Rutin is one of phenolic compounds found in variable plant species. This study investigated the effect of rutin on obesity in high‐fat diet induced obese rats. Three weeks of male Sprague‐Dawley rats were divided into three groups, and fed each experimental diets for 12 weeks: normal diet (NOR), 45% high‐fat diet (HF), and 45% high‐fat diet containing 0.1% rutin (HF+Rutin). Rutin reduced the final body weight by 7.9% compared to the HF group. The white adipose tissue (WAT) mass and the lipid‐droplet size were decreased, while the brown adipose tissue (BAT) mass was increased in rats supplemented with rutin when compared to the HF group. The serum levels of triglyceride (TG) and LDL‐cholesterol were lower, whereas the serum HDL‐cholesterol level was higher in the rutin supplemented group. Hepatic total lipid, TG and total cholesterol levels were decreased in the rutin group compared to the HF group. Electron microscopic analysis showed that the number and size of mitochondria in the BAT and muscle were increased by rutin. The mRNA expression of adipogenic genes including SREBP‐1c, PPARγ and aP2 was down‐regulated, whereas genes related with mitochondria biogenesis such as PGC‐1α and UCP2 were up‐regulated in the rutin group. These results suggested that rutin may have beneficial effect on obesity, which is partially mediated via regulation of mRNA expression related to adipogenesis and mitochondrial biogenesis.

Grant Funding Source: This work was supported by the Brain Korea 21 plus project funding (No.22A20130012143)
Decreasing the biological drive toward weight gain by increasing energy flux (LB431)
Authors: Foright Rebecca , Paris Hunter , Werth Kelsey , Larson Lauren , Beals Joseph , Wilburn Jessie , Davis Janelle , Bell Christopher , Melby Christopher
Published: June 2021

Introduction: Weight regain after weight loss is the experience of most obese dieters.

Metabolic adjustments characterized by decreased resting energy expenditure (REE) and increased hunger can prevent long‐term success. Possibly this energy gap could be attenuated by a high flux (HF) state (higher expenditure coupled with higher intake). Methods: 5 obese adults [age (x̅ ± SD) =46±10 BMI=35.0±3.7 kg/m2] underwent 7% weight loss and were stabilized at this weight for 3 weeks. REE via indirect calorimetry, and hunger via visual analog scale were then examined during two 4‐day conditions of energy balance in random order: Low Flux (LF)‐Sedentary with energy intake (EI)=REE x1.35; and HF‐Daily exercise net energy cost of ~500 kcal/d and EI= REE x1.7. Results: Average 5 day weight did not differ between HF (96.9kg) and LF (96.5kg) (p>0.10). Average daily REE was higher during HF (1816±227 kcal/day) compared to LF (1747±221 kcal/day) (p= 0.07). Average perceived hunger was lower during HF (93.9±24.1) compared to LF (93.8±7.0) (p= 0.056). Conclusion: These preliminary data suggest that high flux is associated with a greater REE and less hunger, which may protect against weight regain.

Grant Funding Source: Supported by the Colorado Agricultural Experiment Station
Physical Activity and Metabolic Risk Factors among Jamaican Adolescents (LB443)
Authors: Barrett Sheila , Huffman Fatma , Johnson Paulette , Campa Adriana , Magnus Marcia , Ragoobirsingh Dalip
Published: June 2021

The study examined relationships between physical activity (PA) and Metabolic Syndrome (METS) in Jamaican adolescents. A descriptive, cross‐sectional survey examined 276 students from 10 Jamaican high schools. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III and the International Diabetes Federation (IDF) criteria determined the metabolic risks. The Physical Activity Questionnaire for Children measured PA levels.

Mean age was 15.6 (±1.2). Percentage of subjects classified with METS varied by criterion used; IDF (6.9 %) and NCEP (12.4%). While 56% of the subjects classified with METS were physically inactive, logistic regression showed no relationships between PA and individual METS risk factors overall (p>0.05). Females were 15 times less physically active and had significantly (p<0.05) higher waist circumference (WC) than males, whereas, males had significantly (p<0.05) higher fasting blood glucose levels. Although urban adolescents had higher PA than rural adolescents, they had significantly (p<0.05) higher WC; one of the determinants of METS by IDF’s standard. Similarly, under the IDF’s classification, Blacks had significantly higher numbers of METS risk factors (p<0.05) compared to non‐Blacks.

Jamaican adolescents are at risk for METS irrespective of levels of PA. Living in urban areas, being female, and being Black increased the risk for METS. NCEP guidelines classified more subjects with METS compared with IDF’s. Intervention measures are needed to reduce METS risk factors among this population.

Grant Funding Source: Dissertation Year Fellowship, Florida International University
Food and nutrition insecurity among clients of anti‐retroviral therapy clinics in Accra, Ghana (LB451)
Authors: Aryeetey Richmond , Esi Colecraft , Wanke Christine
Published: June 2021

HIV‐infected persons have poorer treatment adherence and clinical outcomes if food insecure. Food insecurity and malnutrition was assessed in clients seeking routine ARV treatment in two hospitals in Accra. We surveyed 298 voluntarily‐participating ARV clients at Korle‐Bu and Police Hospitals in Accra using the Household Food insecurity assessment scale, a 24‐hr dietary recall tool, and measured weight and height of clients. About 53% of clients reported hunger or reduced food intake in the last month; 13% reported frequently going to bed hungry. A total of 56% were classified moderate‐ or severely food insecure. Eleven percent were chronically undernourished (BMI<18.5kg/m2) and 35% were overweight or obese (BMI>25kg/m2). Almost all clients had lower than RDA intake for iodine (97.7%), Vitamin A (85.6%), and folate (96%) in the last 24 hours. Food insecurity was significantly associated with low intake of zinc (p<0.01), folate (p=0.02), and vitamin C (p<0.01), and also low educational status, and quality of life. Sustainable interventions are needed to address food insecurity among PLHIV in Ghana to improve ART outcomes.

Grant Funding Source: Lifespan/Tufts/Brown Center for AIDS Research (CFAR):710‐9912‐8985
Metformin Reduces Inflammation and Lung Fibrosis in a Bleomycin‐Induced Lung Injury Model (LB505)
Authors: JANG AN‐HEE , KIM YOUNG WHAN
Published: June 2021

Idiopathic pulmonary fibrosis (IPF) is a progressive disorder characterized by the destruction of lung parenchyma together with deposition of extracellular matrix (ECM) in the interstitial and alveolar spaces. Metformin is developed as an oral anti‐diabetic drug in the biguanide class. Recently, it has been suggested to have anti‐inflammatory and anti‐tissue remodeling effects. Therefore, in this study, we investigated the roles of metformin in bleomycin‐induced lung fibrosis. C57BL/6 mice were intratracheally injected with bleomycin (BLM, 0.2 U/100 μl) on day 0. Metformin was administered orally to the mice once a day from day 1 to day 21. On day 21, the mice were sacrificed. We performed H&E and Masson’s trichrome (MT) staining to evaluate lung inflammation and collagen deposition and analyzed the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) by differential cell counts. From total RNA of lung tissue, the expression level of pro‐collagen, collagen‐1, fibronectin, and tumor growth factor‐β (TGF‐β) was determined by real‐time PCR. Metformin suppressed lung tissue inflammation in BLM‐instilled mice on day 21. Consistent with this, the number of inflammatory cells in BALF was diminished by metformin treatment. BLM increased the level of pro‐collagen, collagen‐1, fibronectin, and TGF‐β mRNA expression on day 21, which was suppressed in metformin‐treated mice. Metformin reduced peribronchial collagen deposition induced by BLM on day 21. Metformin has protective effects on BLM‐induced lung inflammation and remodeling.
Expression of Wnt5a and its effect on oxLDL uptake in THP‐1 cells (LB534)
Authors: Szymanski Candice , Kantake Noriko , McCall Kelly , Malgor Ramiro
Published: June 2021

Objective: To study Wnt5a expression and determine its effect on oxLDL uptake and foam cell development.

Introduction: Atherosclerosis is a chronic inflammatory disease involving plaque buildup in the arteries. This disease can lead to a heart attack and stroke, which are two of the biggest causes of death in this country. A key step in the pathogenesis of atherosclerosis is oxLDL uptake by macrophages and foam cell formation in the intima of the artery. Our group has been investigating the role of Wnt5a signaling in atherosclerosis. Previous results in the lab have shown that oxLDL up‐regulated Wnt5a mRNA expression in human monocyte‐derived macrophages and THP‐1 cells (an acute monocytic leukemia cell line). It was also found that Frizzled 5 (Fz5), a Wnt5a receptor, is highly expressed in foam cells present in human atherosclerotic plaques. Our hypothesis is that Wnt5a stimulates oxLDL uptake in macrophages.

Methods: THP‐1 cells were cultured in RPMI 1640 with 10% FBS. The cells were differentiated with Phorbol‐12‐Myristate‐13‐Acetate (PMA) for 24 hours. Cells were treated with oxLDL, nLDL, and rWnt5a in combinations to determine their effects on oxLDL uptake. Oil Red staining was used to assess lipid uptake in‐vitro. Expression of CD68, CD36, scavenger receptor, ROR2, Fz5, and Wnt5a were evaluated using immunofluorescence and western blot. RT‐PCR was done to evaluate mRNA expression.

Results: Oil Red staining showed a significant increase in the lipid uptake in macrophages treated with oxLDL. Immunofluorescence showed that oxLDL increased CD68 and Wnt5a expression in THP‐1 cells. Wnt5a also increased Fz5 and scavenger receptor expression in THP‐1 cells. Western blot showed that oxLDL significantly increased CD36 expression in THP‐1 cells. RT‐PCR showed that oxLDL induced Wnt5a expression in THP‐1cells.

Conclusions: The results show that oxLDL increases the expression of Wnt5a in THP‐1cells. Furthermore, Wnt5a increases the expression of receptors involved in the uptake of oxLDL. While the mechanism of this uptake is still unknown, our results suggest that Wnt5a plays a role in atherogenesis.
Renal denervation changes hemodynamic response to losartan in SHR rats (LB651)
Authors: Skrzypecki Janusz , Drapala Adrian , Sikora Mariusz , Ufnal Marcin
Published: June 2021

Efficacy of renal denervation in the treatment of drug‐resistant hypertension is currently under debate. Recently, SIMPLICITY III study showed that the combined therapy with renal denervation and antihypertensive drugs is not superior to appropriate pharmacotherapy alone. In this study we checked if renal denervation affects hypotensive effect of losartan, an angiotensin II type 1 receptor blocker, in Spontaneuosly Hypertensive Rats (SHR). We exposed renal arteries from extraperitoneal access. In the study group all visible nerves adjacent to renal arteries were dissected and then the arteries were wiped with 5% phenol in absolute ethanol. In controls renal arteries were left intact. In both groups we implanted subcutaneously osmotic minipumps releasing either losartan or 0,9% NaCl. One week later we measured mean arterial blood pressure (MABP) and heart rate (HR) in conscious rats. We found that losartan produced greater decrease in MABP than renal denervation. Rats treated with renal denervation and losartan exhibited similar decrease in MABP to rats treated with losartan alone. Interestingly, treatment with losartan alone significantly increased HR while renal denervation combined with losartan did not affect HR. In conclusion, this study shows that combined renal denervation and pharmacotherapy may produce different hemodynamic effects than pharmacotherapy alone.

Grant Funding Source: Supported by the Ministry of Science and Higher Education Republic of Poland, Diamond grant DI2012 008042
Exploring the Association Between USMLE Scores and ACGME Milestone Ratings: A Validity Study Using National Data From Emergency Medicine
Authors: Hamstra Stanley J. , Cuddy Monica M. , Jurich Daniel , Yamazaki Kenji , Burkhardt John , Holmboe Eric S. , Barone Michael A. , Santen Sally A.
Published: June 2021

Purpose

The United States Medical Licensing Examination (USMLE) sequence and the Accreditation Council for Graduate Medical Education (ACGME) milestones represent 2 major components along the continuum of assessment from undergraduate through graduate medical education. This study examines associations between USMLE Step 1 and Step 2 Clinical Knowledge (CK) scores and ACGME emergency medicine (EM) milestone ratings.

Method

In February 2019, subject matter experts (SMEs) provided judgments of expected associations for each combination of Step examination and EM subcompetency. The resulting sets of subcompetencies with expected strong and weak associations were selected for convergent and discriminant validity analysis, respectively. National-level data for 2013–2018 were provided; the final sample included 6,618 EM residents from 158 training programs. Empirical bivariate correlations between milestone ratings and Step scores were calculated, then those correlations were compared with the SMEs’ judgments. Multilevel regression analyses were conducted on the selected subcompetencies, in which milestone ratings were the dependent variable, and Step 1 score, Step 2 CK score, and cohort year were independent variables.

Results

Regression results showed small but statistically significant positive relationships between Step 2 CK score and the subcompetencies (regression coefficients ranged from 0.02 [95% confidence interval (CI), 0.01–0.03] to 0.12 [95% CI, 0.11–0.13]; all P < .05), with the degree of association matching the SMEs’ judgments for 7 of the 9 selected subcompetencies. For example, a 1 standard deviation increase in Step 2 CK score predicted a 0.12 increase in MK-01 milestone rating, when controlling for Step 1. Step 1 score showed a small statistically significant effect with only the MK-01 subcompetency (regression coefficient = 0.06 [95% CI, 0.05–0.07], P < .05).

Conclusions

These results provide incremental validity evidence in support of Step 1 and Step 2 CK score and EM milestone rating uses.
Farewell to the Step 2 Clinical Skills Exam: New Opportunities, Obligations, and Next Steps
Authors: Yudkowsky Rachel , Szauter Karen
Published: June 2021

The unexpected discontinuation of the United States Medical Licensing Examination Step 2 Clinical Skills (CS) exam in January 2021 carries both risks and opportunities for medical education in the United States. Step 2 CS had far-reaching effects on medical school curricula and school-based clinical skills assessments. Absent the need to prepare students for this high-stakes exam, will the rigor of foundational clinical skills instruction and assessment remain a priority at medical schools? In this article, the authors consider the potential losses and gains from the elimination of Step 2 CS and explore opportunities to expand local summative assessments beyond the narrow bounds of Step 2 CS.

The responsibility for implementing a rigorous and credible summative assessment of clinical skills that are critical for patient safety as medical students transition to residency now lies squarely with medical schools. Robust human simulation (standardized patient) programs, including regional and virtual simulation consortia, can provide infrastructure and expertise for innovative and creative local assessments to meet this need. Novel applications of human simulation and traditional formative assessment methods, such as workplace-based assessments and virtual patients, can contribute to defensible summative decisions about medical students’ clinical skills. The need to establish validity evidence for decisions based on these novel assessment methods comprises a timely and relevant focus for medical education research.
X-linked Malformation Deafness: Neurodevelopmental Symptoms Are Common in Children With IP3 Malformation and Mutation in POU3F4
Authors: Smeds Henrik , Wales Jeremy , Karltorp Eva , Anderlid Britt-Marie , Henricson Cecilia , Asp Filip , Anmyr Lena , Lagerstedt-Robinson Kristina , Löfkvist Ulrika
Published: June 2021

Objective:

Incomplete partition type 3 (IP3) malformation deafness is a rare hereditary cause of congenital or rapid progressive hearing loss. The children present with a severe to profound mixed hearing loss and temporal bone imaging show a typical inner ear malformation classified as IP3. Cochlear implantation is one option of hearing restoration in severe cases. Little is known about other specific difficulties these children might exhibit, for instance possible neurodevelopmental symptoms.

Material and methods:

Ten 2; 0 to 9; 6-year-old children with IP3 malformation deafness (nine boys and one girl) with cochlear implants were evaluated with a retrospective chart review in combination with an additional extensive multidisciplinary assessment day. Hearing, language, cognition, and mental ill-health were compared with a control group of ten 1; 6 to 14; 5-year-old children with cochlear implants (seven boys and three girls) with another genetic cause of deafness, mutations in the GJB2 gene.

Results:

Mutations in POU3F4 were found in nine of the 10 children with IP3 malformation. Children with IP3 malformation deafness had an atypical outcome with low level of speech recognition (especially in noise), executive functioning deficits, delayed or impaired speech as well as atypical lexical-semantic and pragmatic abilities, and exhibited mental ill-health issues. Parents of children with IP3 malformation were more likely to report that they were worried about their child’s psychosocial wellbeing. Controls, however, had more age-typical results in all these domains. Eight of 10 children in the experimental group had high nonverbal cognitive ability despite their broad range of neurodevelopmental symptoms.

Conclusions:

While cochlear implantation is a feasible alternative for children with IP3 malformation deafness, co-occurring neurodevelopmental anomalies, such as attention deficit hyperactivity or developmental language disorder, and mental ill-health issues require an extensive and consistent multidisciplinary team approach during childhood to support their overall habilitation.
Beyond Audition: Psychosocial Benefits of Music Training for Children With Hearing Loss
Authors: Lo Chi Yhun , Looi Valerie , Thompson William Forde , McMahon Catherine M.
Published: June 2021

Objectives:

Children with hearing loss tend to have poorer psychosocial and quality of life outcomes than their typical-hearing (TH) peers—particularly in the areas of peer relationships and school functioning. A small number of studies for TH children have suggested that group-based music activities are beneficial for prosocial outcomes and help develop a sense of belonging. While one might question whether perceptual limitations would impede satisfactory participation in musical activities, findings from a few studies have suggested that group music activities may have similar benefits for children with hearing loss as well. It is important to note that the effect of music on psychosocial outcomes has primarily been investigated at an anecdotal level. The objective of this study was to explore the effect of a music training program on psychosocial and quality of life outcomes for children with hearing loss. It was hypothesized that music training would provide benefits for domains centered upon peer relationships and prosocial measures.

Design:

Fourteen children aged 6 to 9 years with prelingual sensorineural hearing loss (SNHL) participated in a 12-week music training program that consisted of group-based face-to-face music therapy supplemented by online music apps. The design was a pseudorandomized, longitudinal study (9 participants were waitlisted, initially serving as a passive control group). Psychosocial wellbeing and quality of life were assessed using a questionnaire battery comprised of the Strengths and Difficulty Questionnaire (SDQ), the Pediatric Quality of Life Inventory, the Hearing Environments and Reflection on Quality of Life (HEAR-QL), and the Glasgow Children’s Benefit Inventory. For comparative purposes, responses were measured from 16 TH children that ranged in age from 6 to 9 years.

Results:

At baseline, children with SNHL had poorer outcomes for internalizing problems, and all measures of the HEAR-QL compared with the TH children. There were no differences for general psychosocial and physical health. After music training, SDQ internalizing problems such as peer relationships and emotional regulation were significantly reduced for the children with SNHL. There were no changes for any outcomes for the passive control group. Additional benefits were noted for emotional and learning factors on the Glasgow Children’s Benefit Inventory. However, there were no significant changes for any psychosocial and quality of life outcomes as measured by the Pediatric Quality of Life Inventory or HEAR-QL instruments.

Conclusions:

The present study provides initial evidence that music training has a positive effect on at least some psychosocial and quality of life outcomes for children with hearing loss. As they are at a greater risk of poorer psychosocial and quality of life outcomes, these findings are cause for cautious optimism. Children with hearing loss should be encouraged to participate in group-based musical activities.
Is Sacral Dysmorphism Protective Against Spinopelvic Dissociation? Multicenter Case Series
Authors: Obey Mitchel R. , Barnwell Jonathan , Routt M. L. Chip , Miller Anna N.
Published: June 2021

Objectives:

Investigate the incidence of sacral dysmorphism (SD) in patients with spinopelvic dissociation (SPD).

Design:

Retrospective case series.

Setting:

Two academic level 1 trauma centers.

Patients/Participants:

One thousand eight hundred fifty adult patients with sacral and pelvic fractures (OTA/AO 61-A, B, C).

Intervention:

Plain pelvic radiographs and CT scans.

Main Outcome Measurements:

Incidence of SD in patients with SPD. Secondary radiographic evaluation of fracture classification and deformity on sagittal imaging.

Results:

Eighty-two patients with SPD were identified, and 12.2% displayed features of SD, significantly less than reported in the literature. The S2 sacral body was the most common horizontal fracture location in patients with SD and nondysmorphic sacra (ND). Roy-Camille type I patterns were more common in ND (35%), versus type II in SD patients (40%). SD patients had lower body mass indexes (19.7 vs. 25.2, P = 0.001). Segmental kyphosis (22.5 degrees ND vs. 23.8 degrees SD, P = 0.838) and sacral kyphosis (26 degrees ND vs. 31 degrees SD, P = 0.605) were similar between groups. Percutaneous fixation was the most common surgical technique.

Conclusions:

We report a significantly lower prevalence of SD in patients with SPD than previously reported in the literature. This suggests that variations in sacral osseous anatomy alter force transmission across the sacrum during traumatic loading, which may be protective against certain high-energy fracture patterns. Preoperative evaluation of sacral anatomy is critical, not only in determining the size and orientation of sacral segment safe zones for screw placement, but also to better understand the pathomechanics involved in sacral trauma.

Level of Evidence:

Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
E-Health Decision Support Technologies in the Prevention and Management of Pressure Ulcers
Authors: Ting Justine Jeanelle , Garnett Anna
Published: June 2021

Pressure ulcers are problematic across clinical settings, negatively impacting patient morbidity and mortality while resulting in substantial costs to the healthcare system. E-health clinical decision support technologies can play a key role in improving pressure ulcer–related outcomes. This systematic review aimed to assess the impact of electronic health decision support interventions on pressure ulcer management and prevention. A systematic search was conducted in PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature, and Cochrane. Nineteen articles, published from 2010 to 2020, were included for review. The findings of this review showed promising results regarding the usability and accuracy of electronic health decision support tools to aid in pressure ulcer prevention and management. Evidence indicated improved clinician adherence to pressure ulcer prevention practices and decreased healthcare costs postimplementation of an electronic health decision support intervention. However, the studies included in this review did not consistently show reductions in pressure ulcer prevalence, incidence, or risk. Most of the articles included in the review were limited by small sample sizes drawn from single hospitals or long-term care homes. More high-quality studies are needed to determine the types of electronic health decision support tools that can drive sustainable improvements to patient outcomes.
Evolution of Dupilumab-Associated Cutaneous Atypical Lymphoid Infiltrates
Authors: Sokumbi Olayemi , Shamim Huma , Davis Mark Dennis P. , Wetter David A. , Newman Catherine C. , Comfere Nneka
Published: June 2021

Background:

Observations highlighting the “unmasking” of cutaneous T-cell lymphoma after treatment with dupilumab for atopic dermatitis (AD) have been recently reported. However, there remains a paucity of literature describing the evolution of clinical and histopathological features that characterizes this phenomenon.

Objective:

To define the clinical and histopathologic evolution of atypical lymphoid infiltrates after the administration of dupilumab for AD.

Methods:

A cross-sectional study of clinical and histopathologic features in 7 consecutive patients with a diagnosis of “atypical lymphoid infiltrate” or mycosis fungoides (MF) on dupilumab for AD was performed.

Results:

Seven patients with atypical lymphoid infiltrates or MF in evolution after dupilumab therapy (age range 27–74 years) were reviewed. Average duration of AD before MF diagnosis was 5.7 years, and the average duration on dupilumab treatment was 9.8 months. Notable histopathologic features across predupilumab and postdupilumab biopsies included progressive increase in the densities of the atypical lymphoid infiltrates (7/7), presence of atypical epidermotropic lymphocytes (6/7), and papillary dermal fibrosis (6/7).

Limitations:

Small retrospective cohort study.

Conclusion:

These cases highlight the transformation of lymphoid infiltrates after dupilumab treatment for AD and emphasize the importance of clinical and histopathologic evaluation before and during treatment with dupilumab for treatment-refractory presumed AD.
Kikuchi–Fujimoto Disease With Unusual Cutaneous Findings
Authors: Gates Gregory A. , Li Yunfeng , Magyar Clara , Sarantopoulos G. Peter
Published: June 2021

We present a case of the rare Kikuchi–Fujimoto disease (KFD) in a 14-year-old patient admitted to UCLA Medical Center with fever, weight loss, and pancytopenia. Physical examination revealed tender subcutaneous nodules and cervical lymphadenopathy. A lymph node biopsy showed findings consistent with KFD. The skin biopsy showed mild superficial dermal edema with neutrophil-predominant inflammation. In addition, rare atypical monocytoid cells were seen. This histologic finding of a Sweet-like morphology has not been reported previously in the literature in association with KFD. The differential diagnosis included Sweet syndrome arising in association with KFD, underlying connective tissue, and an infectious etiology.