Histone Acetylation Inhibits RSC and Stabilizes the +1 Nucleosome.

The +1 nucleosome of yeast genes, within which reside transcription start sites, is characterized by histone acetylation, by the displacement of an H2A-H2B dimer, and by a persistent association with the RSC chromatin-remodeling complex. Here we demonstrate the interrelationship of these characteristics and the conversion of a nucleosome to the +1 state in vitro. Contrary to expectation, acetylation performs an inhibitory role, preventing the removal of a nucleosome by RSC. Inhibition is due to both enhanced RSC-histone interaction and diminished histone-chaperone interaction. Acetylation does not prevent all RSC activity, because stably bound RSC removes an H2A-H2B dimer on a timescale of seconds in an irreversible manner.

Disruption of nucleosomes by DNA groove binders of clinical significance and implications for chromatin remodeling.

Small molecules that bind in the minor groove of DNA are in clinical use as antibiotics and antitumor drugs. Two members of this class of molecules, netropsin and chromomycin, are shown here to displace DNA from the nucleosome and promote transfer of the histone octamer to an acceptor protein. The effects of these groove-binding molecules are exploited to address an outstanding problem in the mechanism of the RSC chromatin remodeling complex. RSC and other remodeling complexes are DNA translocases, acting near the center of the nucleosomal DNA, but translocation is apparently impossible because DNA cannot slide across the histone surface in the nucleosome. Netropsin and chromomycin promote the release of DNA from the histone surface, enhance the formation of a RSC-nucleosome complex, and synergize with RSC in chromatin remodeling. These findings are in keeping with an involvement of bulge translocation in chromatin remodeling.

Role of the histone tails in histone octamer transfer.

The exceptionally high positive charge of the histones, concentrated in the N- and C-terminal tails, is believed to contribute to the stability of the nucleosome by neutralizing the negative charge of the nucleosomal DNA. We find, on the contrary, that the high positive charge contributes to instability, performing an essential function in chromatin remodeling. We show that the tails are required for removal of the histone octamer by the RSC chromatin remodeling complex, and this function is not due to direct RSC-tail interaction. We also show that the tails are required for histone octamer transfer from nucleosomes to DNA, and this activity of the tails is a consequence of their positive charge. Thus, the histone tails, intrinsically disordered protein regions, perform a critical role in chromatin structure and transcription, unrelated to their well-known role in regulation through posttranscriptional modification.

Revisiting frequencies of phonological sound classes in speech input: Change over time in child-directed speech.

The purpose of the current study was to revisit a controversial topic: whether frequencies of phonological consonant and vowel classes differ in speech directed to children and to adults. In addition, the current study investigated whether the frequency of phonological consonant and vowel classes changes with children's increasing chronological and/or developmental age. This study analyzed speech input from 44 adults to four different age groups of listeners (i.e., three groups of children at 6, 18, and 36 months of age and one group of adult listeners) in terms of frequency of occurrence of consonant and vowel classes. Results revealed that consonant stop, nasal, fricative and glide manner classes as well as all four consonant place classes were significantly different in speech directed to the four different age groups. A perspective is discussed to better understand the nature of frequency input of phonological sound classes.

Role of DNA sequence in chromatin remodeling and the formation of nucleosome-free regions.

AT-rich DNA is concentrated in the nucleosome-free regions (NFRs) associated with transcription start sites of most genes. We tested the hypothesis that AT-rich DNA engenders NFR formation by virtue of its rigidity and consequent exclusion of nucleosomes. We found that the AT-rich sequences present in many NFRs have little effect on the stability of nucleosomes. Rather, these sequences facilitate the removal of nucleosomes by the RSC chromatin remodeling complex. RSC activity is stimulated by AT-rich sequences in nucleosomes and inhibited by competition with AT-rich DNA. RSC may remove NFR nucleosomes without effect on adjacent ORF nucleosomes. Our findings suggest that many NFRs are formed and maintained by an active mechanism involving the ATP-dependent removal of nucleosomes rather than a passive mechanism due to the intrinsic instability of nucleosomes on AT-rich DNA sequences.

Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis.

Canine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology. We mapped the genomic landscape of canine melanoma through multi-platform analysis of 37 tumors (31 mucosal, 3 acral, 2 cutaneous, and 1 uveal) and 17 matching constitutional samples including long- and short-insert whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses. We identified novel predominantly truncating mutations in the putative tumor suppressor gene PTPRJ in 19% of cases. No BRAF mutations were detected, but activating RAS mutations (24% of cases) occurred in conserved hotspots in all cutaneous and acral and 13% of mucosal subtypes. MDM2 amplifications (24%) and TP53 mutations (19%) were mutually exclusive. Additional low-frequency recurrent alterations were observed amidst low point mutation rates, an absence of ultraviolet light mutational signatures, and an abundance of copy number and structural alterations. Mutations that modulate cell proliferation and cell cycle control were common and highlight therapeutic axes such as MEK and MDM2 inhibition. This mutational landscape resembles that seen in BRAF wild-type and sun-shielded human melanoma subtypes. Overall, these data inform biological comparisons between canine and human melanoma while suggesting actionable targets in both species.

Relationship between the target word form and children's productions: place of articulation in Consonant-Vowel-Consonant (C1VC2) words in American English.

The aim of the present study was to investigate relationships between characteristics of children's target words and their actual productions during the single-word period in American English. Word productions in spontaneous and functional speech from 18 children acquiring American English were analyzed. Consonant sequences in 3,328 consonant-vowel-consonant (C1VC2) target words were analyzed in terms of global place of articulation (labials, coronals, and dorsals). Children's actual productions of place sequences were compared between target words containing repeated place sequences (e.g., mom, map, dad, not) and target words containing variegated place sequences (e.g., mat, dog, cat, nap). Overall, when the target word contained two consonants at the same global place of articulation (e.g., labial-labial, map; coronal-coronal, not), approximately 50% of children's actual productions matched consonant place characteristics. Conversely, when the target word consisted of variegated place sequences (e.g., mat, dog, cat, nap), only about 20% of the productions matched the target consonant sequences. These results suggest that children's actual productions are influenced by their own production abilities as well as by the phonetic forms of target words.

Combined extracts of Moringa oleifera, Murraya koeingii leaves, and Curcuma longa rhizome increases energy expenditure and controls obesity in high-fat diet-fed rats.

BACKGROUND: LI85008F is a proprietary combination of leaf extracts of Moringa oleifera, Murraya koeingii, and extract of Curcuma longa rhizome. This herbal extract combination is an effective weight loss supplement for overweight and obese subjects. The present study aimed to investigate the thermogenic potential of the LI85008F in high-fat diet (HFD)-induced obese Sprague Dawley rats. METHODS: Seven rats received a regular diet (RD), and twenty-one rats received a high-fat diet (HFD) for 56 days. On day 28, the HFD-fed rats were randomized into three groups (n = 7). Starting from day 29 through day 56, one HFD-fed group received daily oral gavage of 0.5% Carboxymethylcellulose Sodium (CMC) alone (HFD), and the remaining two groups received 100 and 250 mg/kg LI85008F (LI85008F-100 and LI85008F-250, respectively). Body weight, fat mass, fat cell size, liver weight, liver triglyceride were measured. The energy metabolism parameters were measured using indirect calorimetry. In serum, the metabolic and endocrine markers were analyzed. The adipogenic and thermoregulatory proteins expression in the white adipose tissue (WAT) were analyzed using an immunoblot assay. RESULTS: Supplementation with both doses of LI85008F significantly increased resting energy expenditure (REE) in the obese rats. The LI85008F-250 rats showed significant up-regulation of uncoupling protein-1 (UCP-1) expression, as compared with the HFD rats. LI85008F significantly reduced body weight gain, fat mass, fat cell size, liver weight, and hepatic triglycerides. Serum triglyceride, total cholesterol, glucose, leptin, and fat cell markers were significantly reduced in LI85008F-supplemented rats compared to the HFD rats. CONCLUSION: The present data suggest that LI85008F reduces body fat mass and controls body weight gain via increasing energy metabolism in combination with reduced lipogenesis in diet-fed obese rats.

Inter-Institutional Partnerships to Develop Veterinarian-Investigators through the NIH Comparative Biomedical Scientist Training Program Benefit One Health Goals.

Limitations in workforce size and access to resources remain perennial challenges to greater progress in academic veterinary medicine and engagement between human and veterinary medicine (One Health). Ongoing resource constraints occur in part due to limited public understanding of the role veterinarians play in improving human health. One Health interactions, particularly through interdisciplinary collaborations in biomedical research, present constructive opportunities to inform resource policies and advance health care. To this end, inter-institutional partnerships between individual veterinary medical education programs (VMEPs) and several National Institutes of Health (NIH) intramural research programs have created synergies beyond those provided by individual programs. In the NIH Comparative Biomedical Scientist Training Program (CBSTP), interdisciplinary cross-training of veterinarians consisting of specialty veterinary medicine coupled with training in human disease research leading to a PhD, occurs collaboratively on both VMEP and NIH campuses. Pre-doctoral veterinary student research opportunities have also been made available. Through the CBSTP, NIH investigators and national biomedical science policy makers gain access to veterinary perspective and expertise, while veterinarians obtain additional opportunities for NIH-funded research training. CBSTP Fellows serve as de facto ambassadors enhancing visibility for the profession while in residence at NIH, and subsequently through a variety of university, industry, and government research appointments, as graduates. Thus, the CBSTP represents an inter-institutional opportunity that not only addresses critical needs for veterinarian-scientists in the biomedical workforce, but also simultaneously exposes national policy makers to veterinarian-scientists' specialized training, leading to more effective realization of One Health goals to benefit human and animal health.

iQOS: evidence of pyrolysis and release of a toxicant from plastic.

OBJECTIVE: To evaluate performance of the I quit original smoking (iQOS) heat-not-burn system as a function of cleaning and puffing topography, investigate the validity of manufacturer's claims that this device does not burn tobacco and determine if the polymer-film filter is potentially harmful. METHODS: iQOS performance was evaluated using five running conditions incorporating two different cleaning protocols. Heatsticks were visually and stereomicroscopically inspected preuse and postuse to determine the extent of tobacco plug charring (from pyrolysis) and polymer-film filter melting, and to elucidate the effects of cleaning on charring. Gas chromatography-mass spectrometry headspace analysis was conducted on unused polymer-film filters to determine if potentially toxic chemicals are emitted from the filter during heating. RESULTS: For all testing protocols, pressure drop decreased as puff number increased. Changes in testing protocols did not affect aerosol density. Charring due to pyrolysis (a form of organic matter thermochemical decomposition) was observed in the tobacco plug after use. When the manufacturer's cleaning instructions were followed, both charring of the tobacco plug and melting of the polymer-film filter increased. Headspace analysis of the polymer-film filter revealed the release of formaldehyde cyanohydrin at 90°C, which is well below the maximum temperature reached during normal usage. DISCUSSION: Device usage limitations may contribute to decreases in interpuff intervals, potentially increasing user's intake of nicotine and other harmful chemicals. This study found that the tobacco plug does char and that charring increases when the device is not cleaned between heatsticks. Release of formaldehyde cyanohydrin is a concern as it is highly toxic at very low concentrations.

Investigation of age-adjusted D-dimer using an uncommon assay.

BACKGROUND: Use of an age-adjusted D-dimer for the evaluation of acute pulmonary embolus (PE) has been prospectively validated in the literature and has become a practice recommendation from major medical societies. Most research on this subject involves the most common D-dimer assays reporting in Fibrinogen Equivalent Units (FEU) with a non-age-adjusted manufacturer-recommended cutoff of 500 ng/ml FEU. Limited research to date has evaluated age-adjustment in assays that report in D-Dimer Units (D-DU), which use a manufacturer-recommended cutoff of 230 ng/ml D-DU. Despite scant evidence, an age-adjusted formula using D-DU has been recently endorsed by the American College of Emergency Physicians (ACEP). This formula seems arbitrary in its derivation and unnecessarily deviates from existing thresholds, thus prompting the creation of our novel-age adjustment formula. The goal of this study was to retrospectively evaluate the test characteristics of our novel age-adjusted D-dimer formula using the D-DU assay in comparison to existing traditional and age-adjusted D-dimer thresholds for the evaluation of acute PE in the ED. METHODS: This was a retrospective chart review at an academic quaternary health system with three EDs and 195,000 combined annual ED visits. Only patients with D-dimer testing and CT PE protocol (CTPE) imaging were included. Admission and discharge diagnosis codes were used to identify acute PE. Outcome measures were sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of an unadjusted traditional threshold (230) compared with both novel and ACEP-endorsed age adjusted thresholds, (Age × 5) - 20 and Age × 5 if >50, respectively. Estimates with their exact 95% threshold were performed. RESULTS: 4846 adult patients were evaluated from January 2012 to July 2017. Group characteristics include a mean age of 52 and a frequency of acute PE diagnosis by CTPE of 8.25%. Traditional D-dimer cutoff demonstrated a sensitivity of 99.8% (95% CI 98.6-100), specificity of 16.7% (95% CI 15.6-17.8) and NPV of 99.9% (95% CI 99.3-100). Our novel age-adjusted D-dimer thresholds had a sensitivity of 97.0% (95% CI 94.8-98.4), specificity of 27.9% (95% CI 26.6-29.2) and NPV of 99.0% (95% CI 98.3-99.5) with the ACEP-endorsed formula demonstrating similar test characteristics. CONCLUSION: Use of an age-adjusted D-dimer on appropriately selected patients being evaluated for acute PE in the ED with a D-DU assay increases specificity while maintaining a high sensitivity and NPV. Both our novel formula and the ACEP-endorsed age-adjusted formula performed well, with our novel formula showing a trend towards improved testing characteristics.

Efficacy of a novel herbal formulation for weight loss demonstrated in a 16-week randomized, double-blind, placebo-controlled clinical trial with healthy overweight adults.

AIM: To re-evaluate the weight loss efficacy of LI85008F in healthy overweight adults via a 16-week randomized, double-blind, placebo-controlled clinical study. MATERIALS AND METHODS: One hundred and forty overweight participants (body mass index [BMI] 27-29.9 kg/m2 , 29.3% male; ages 21-50 years) were randomized into placebo (n =70) and LI85008F (n =70) groups. The participants received either 900 mg/d of LI85008F in two divided doses or two identical placebo capsules. In addition, participants were counselled to follow an ~1800 kcal/d diet and to engage in walking for 30 min, 5 d/wk throughout the study. RESULTS: At the end of the trial period, the LI85008F supplemented group showed significant reductions in body weight (5.36 ± 1.769 vs. 0.87 ± 1.381 kg; P < 0.0001) and BMI (2.05 ± 0.693 vs. 0.34 ± 0.559 kg/m2 ; P < 0.0001), compared with placebo. Significant reductions in waist and hip circumferences, and a 2.08-fold reduction of waist/hip ratio, were noted in the LI85008F supplemented group. LI85008F supplementation also resulted in significant improvements in lipid profiles, compared with the placebo; low-density lipoprotein (LDL) cholesterol decreased, while high-density lipoprotein (HDL) cholesterol increased, resulting in a significantly improved LDL/HDL ratio. No major adverse events were reported by the participants during the study. CONCLUSIONS: The unique herbal extract blend LI85008F, combined with modest calorie restriction and physical activity, is well tolerated, safe, and effective for weight management in overweight men and women.

Speech sound characteristics of early words: influence of phonological factors across vocabulary development.

This study investigates whether the earliest words children choose to say are mainly words containing sounds they can produce (cf. 'phonological dominance' hypotheses), or whether children choose words without regard to their phonological characteristics (cf. 'lexical dominance' hypotheses). Phonological properties of words in spontaneous speech from six children age 0;8 to 2;11 were analyzed by comparing sound distributions of consonant place and manner. Word-initial and word-final consonant patterns in children's Word Targets versus Actual Word Forms were analyzed as a function of vocabulary size. Word-initial results showed more overall evidence for phonological dominance. In word-final position, at lower vocabulary sizes, results showed several differences between Word Targets and Actual Word Forms, consistent with lexical dominance. These findings challenge an 'either-or' phonological versus lexical dominance approach, and support consideration of a multifactorial set of influences, including different phonological dimensions and word positions, on the words that young children choose to say.

Non-adjacent consonant sequence patterns in English target words during the first-word period.

The goal of this study was to investigate non-adjacent consonant sequence patterns in target words during the first-word period in infants learning American English. In the spontaneous speech of eighteen participants, target words with a Consonant-Vowel-Consonant (C1VC2) shape were analyzed. Target words were grouped into nine types, categorized by place of articulation (labial, coronal, dorsal) of initial and final consonants (e.g. mom, labial-labial; mat, labial-coronal; dog, coronal-dorsal). The results indicated that some consonant sequences occurred much more frequently than others in early target words. The two most frequent types were coronal-coronal (e.g. dad) and labial-coronal (e.g. mat). The least frequent type was dorsal-dorsal (e.g. cake). These patterns are consistent with phonotactic characteristics of English and infants' production capacities reported in previous studies. This study demonstrates that infants' expressive vocabularies reflect both ambient language characteristics and their own production capacities, at least for consonant sequences in C1VC2 word forms.

Design, Synthesis, and Characterization of Folate-Targeted Platinum-Loaded Theranostic Nanoemulsions for Therapy and Imaging of Ovarian Cancer.

Platinum (Pt) based chemotherapy is widely used to treat many types of cancer. Pt therapy faces challenges such as dose limiting toxicities, cumulative side effects, and multidrug resistance. Nanoemulsions (NEs) have tremendous potential in overcoming these challenges as they can be designed to improve circulation time, limit non-disease tissue uptake, and enhance tumor uptake by surface modification. We designed novel synthesis of three difattyacid platins, dimyrisplatin, dipalmiplatin, and distearyplatin, suitable for encapsulation in the oil core of an NE. The dimyrisplatin, dipalmiplatin, and distearyplatin were synthesized, characterized, and loaded into the oil core of our NEs, NMI-350, NMI-351, and NMI-352 respectively. Sequestration of the difattyacid platins was accomplished through high energy microfluidization. To target the NE, FA-PEG3400-DSPE was incorporated into the surface during microfluidization. The FA-NEs selectively bind the folate receptor α (FR-α) and utilize receptor mediated endocytosis to deliver Pt past cell surface resistance mechanisms. FR-α is overexpressed in a number of oncological conditions including ovarian cancer. The difattyacid platins, lipidated Gd-DTPA, and lipidated folate were characterized by nuclear magnetic resonance (NMR), mass spectrometry (MS), and elemental analysis. NEs were synthesized using high shear microfluidization process and characterized for size, zeta-potential, and loading efficiency. In vitro cytotoxicity was determined using KB-WT (Pt-sensitive) and KBCR-1000 (Pt-resistant) cancer cells and measured by MTT assay. Pharmacokinetic profiles were studied in CD-1 mice. NEs loaded with difattyacid platins are highly stable and had size distribution in the range of ∼120 to 150 nm with low PDI. Cytotoxicity data indicates the longer the fatty acid chains, the less potent the NEs. The inclusion of C6-ceramide, an apoptosis enhancer, and surface functionalization with folate molecules significantly increased in vitro potency. Pharmacokinetic studies show that the circulation time for all three difattyacid platins encapsulated in NE remained identical, thus indicating that chain length did not influence circulation time. A stable NMI-350 family of NEs were successfully designed, formulated, and characterized. The Pt-resistance in KBCR-1000 cells was reversed with the NMI-350 family. Dimyrisplatin loaded NE (NMI-350) was most potent in vitro. The NMI-350 family demonstrated identical pharmacokinetic profiles to one another and circulated much longer than cisplatin. These data indicate that NMI-350 warrants further preclinical and clinical development as a replacement for current Pt regimens especially for those afflicted with multi drug resistant cancers.

Importance of the Emergency Medicine Application Components: The Medical Student Perception.

BACKGROUND: The National Resident Matching Program (NRMP) application has several elements. With limited time and resources, students must prioritize the key application elements on which to focus. It is unclear if medical students applying to emergency medicine (EM) prioritize the same items as program directors. OBJECTIVE: We sought to determine medical student perception of the importance of each factor of the NRMP application to an EM residency. METHODS: This was a cross-sectional study approved by the Institutional Review Board at an academic tertiary care Level I trauma center. A pilot-tested and validated survey tool was given to all medical students rotating in EM during an 18-month period. The students ranked each application item on a 5-point scale (1 = not important and 5 = very important) with verbal anchors. RESULTS: Of 136 medical students, 85.3% responded. Excluded were 31% who were not planning to apply to EM, leaving 80 responses for analysis. Items ranked higher were EM rotation grade, interview, clinical rotation grades, and letters of recommendation. Less emphasis was placed on Alpha Omega Alpha (AOA) honor society status, publication in medical literature, and personal statement. Items most agreed upon and believed to be most important by the students were EM rotation grade, interviews, and clinical rotation grades. CONCLUSIONS: This is similar to previously reported rankings by program directors. Although medical students agreed on the importance of most aspects of the NRMP application, areas of discordance included emphasis on extracurricular activities and AOA. This can have implications for medical student mentoring and advising.

EGFR Targeted Theranostic Nanoemulsion for Image-Guided Ovarian Cancer Therapy.

PURPOSE: Platinum-based therapies are the first line treatments for most types of cancer including ovarian cancer. However, their use is associated with dose-limiting toxicities and resistance. We report initial translational studies of a theranostic nanoemulsion loaded with a cisplatin derivative, myrisplatin and pro-apoptotic agent, C6-ceramide. METHODS: The surface of the nanoemulsion is annotated with an endothelial growth factor receptor (EGFR) binding peptide to improve targeting ability and gadolinium to provide diagnostic capability for image-guided therapy of EGFR overexpressing ovarian cancers. A high shear microfludization process was employed to produce the formulation with particle size below 150 nm. RESULTS: Pharmacokinetic study showed a prolonged blood platinum and gadolinium levels with nanoemulsions in nu/nu mice. The theranostic nanoemulsions also exhibited less toxicity and enhanced the survival time of mice as compared to an equivalent cisplatin treatment. CONCLUSIONS: Magnetic resonance imaging (MRI) studies indicate the theranostic nanoemulsions were effective contrast agents and could be used to track accumulation in a tumor. The MRI study additionally indicate that significantly more EGFR-targeted theranostic nanoemulsion accumulated in a tumor than non-targeted nanoemulsuion providing the feasibility of using a targeted theranostic agent in conjunction with MRI to image disease loci and quantify the disease progression.

Nicotine concentrations in electronic cigarette refill and do-it-yourself fluids.

INTRODUCTION: We evaluated the accuracy of nicotine concentration labeling on electronic cigarette refill products. METHODS: The nicotine concentration of 71 electronic cigarette refill fluid products and 1 related do-it-yourself (DIY) product was quantified using high-performance liquid chromatography. Quantified data were compared with manufacturers labeled concentrations. Duplicate refill fluid products purchased at different times were evaluated by visual comparison of fluid coloration and quantified nicotine concentration. RESULTS: Thirty-five of the 54 nicotine-containing fluids had quantified nicotine concentrations that deviated by more than ± 10% from the manufacturer labels, with 46 of 50 being in excess of labeled values. Refill fluids labeled as 0 nicotine had no detectable nicotine. Of the 5 products that were unlabeled for nicotine concentration, 3 contained no detectable nicotine, whereas the remaining 2 contained nicotine in excess of 100mg/ml and may have been intended for DIY use. Sixteen of the 18 duplicate bottles of refill fluid varied greatly in their nicotine concentrations. One of the 5 companies showed significant improvement in labeling accuracy among the most recently purchased products. Of the 23 total duplicate pairs, 15 of 23 varied in coloration from their mates. CONCLUSIONS: Nicotine concentration labeling on electronic cigarette refill products was often inaccurate but showed improvement recently in products from 1 company. To ensure the safety of refill fluids and DIY products, it is necessary to establish quality control guidelines for the manufacturing and labeling and to monitor products longitudinally.

A novel pathogenic classification of cancers.

According to contemporary epidemiological and experimental evidence, we propose a novel classification of cancers based on pathogenesis instead of classifications based on histological appearance of cancer. This new scheme first defines cancers as either 1. inborn errors of development or 2. sporadic ones, and then sub-defines the former into 1A. inborn inherited errors of development, being those due to mutations contributed by one or both parents' gametes to the developing conceptus, and 1B. inborn induced errors of development when the malformations and/or cancers are due to environmental carcinogenic exposure during pregnancy. It is anticipated that the origin of an increasing number of so-called sporadic cancers will turn out to be linked to the inborn induced errors of development group.

Evaluation of Rhodiola rosea supplementation on skeletal muscle damage and inflammation in runners following a competitive marathon.

Adaptogens modulate intracellular signaling and increase expression of heat shock protein 72 (HSP72). Rhodiola rosea (RR) is a medicinal plant with demonstrated adaptogenic properties. The purpose of this study was to measure the influence of RR supplementation on exercise-induced muscle damage, delayed onset of muscle soreness (DOMS), plasma cytokines, and extracellular HSP72 (eHSP72) in experienced runners completing a marathon. Experienced marathon runners were randomized to RR (n=24, 6 female, 18 male) or placebo (n=24, 7 female, 17 male) groups and under double-blinded conditions ingested 600mg/day RR extract or placebo for 30days prior to, the day of, and seven days post-marathon. Blood samples were collected, and vertical jump and DOMS assessed the day before, 15min post- and 1.5h post-marathon. DOMS was also assessed for seven days post-marathon. Marathon race performance did not differ between RR and placebo groups (3.87±0.12h and 3.93±0.12h, respectively, p=0.722). Vertical jump decreased post-marathon (time effect, p<0.001) with no difference between groups (interaction effect, p=0.673). Post-marathon DOMS increased significantly (p<0.001) but the pattern of change did not differ between groups (p=0.700). Myoglobin (Mb), creatine phosphokinase (CPK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin (IL)-6, IL-8, IL-10, monocyte chemotactic protein-1 (MCP-1), granulocyte-colony-stimulating factor (G-CSF), C-reactive protein (CRP), and eHSP72 all increased post-marathon (all p<0.001), with no group differences over time (all p>0.300). In conclusion, RR supplementation (600mg/day) for 30days before running a marathon did not attenuate the post-marathon decrease in muscle function, or increases in muscle damage, DOMS, eHSP72, or plasma cytokines in experienced runners.