bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic heme promotes sustained elevations in CO excretion, anorexia, attenuated physical activity and circulatory collapse in rats
Authors: Johnson Robert A , McGloin Kayla E , Johnson Fruzsina K , Nicholson Susannah E , Stewart Ronald M 
Published: June 2021

Carbon monoxide (CO) is generated from the degradation of heme, in a reaction that is catalyzed by heme oxygenase, a heat shock protein (HSP32). Loss of appetite, confusion, lethargy, and systemic organ failure are all amongst the well documented adverse effects of chronic, subhypoxic, exogenous CO poisoning, and heme treatment has been shown to accelerate hemorrhage induced circulatory collapse. Accordingly, we wanted to determine if chronic elevations in endogenous CO, from heme alone, would affect appetite, activity and survival. Towards this end, rats (N=24) were treated with heme (15 or 45μmol/Kg heme as heme‐lysinate, IP q24h) for up to four weeks. Heme treatments produced up to a 3‐fold increase in expired CO, which was accompanied by a transient reduction in food intake, cessation of weight gain and a >95% decrease in wheel running activity. While both heme doses produced these adverse effects, heme administration of 45μmol/Kg per day also led to circulatory collapse and premature deaths in otherwise healthy unbled rats (50% at 14 days). Concurrent provision of high zinc diet (0.5%) ‐which promotes formation of ZnPP, a heme oxygenase inhibitor‐ conferred marked improvement against heme treatments. We conclude that heme drives heme oxygenase activity to increase endogenously formed CO and produce adverse effects which can promote circulatory collapse.Jointly supported by NIH/DOD grant HL64577 (RAJ) and National Trauma Institute
Interindividual variability in heart rate variability (HRV) and complexity (HRC) measurements
Authors: Ryan Kathy L , Rickards Caroline A , Muniz Gary W , Moralez Gilbert , Convertino Victor A 
Published: June 2021

Indices of HRV and HRC have been suggested as potential tools for assisting triage decisions in trauma patients (Aviat Space Environ Med 77:1107, 2007; J Trauma 63:512, 2007). Determination of intersubject variability in these measurements in normal individuals has not been performed. We hypothesized that common indices of HRV and HRC are not highly variable in healthy human subjects, thereby allowing the establishment of “normal” values. ECG was collected for 5 min in 31 supine, resting subjects. Time domain variables included RRISD, RMSSD, pNN50, and SD1 and SD2 from Poincaré plot analysis. Frequency domain variables (LF, 0.04–0.15 Hz; HF, 0.15–0.4Hz) were calculated using Fourier transform. HRC analyses included entropy (SampEn), fractal nature (FD‐L and FD‐DA), stationarity (StatAv), symbol dynamics (SymDyn) and detrended fluctuation analysis (DFA). Data are below:Against expectations, many parameters demonstrated high interindividual variability. Since application of clinical vital signs depends on comparison to a “normal” value, a single measurement of HRV or HRC may not be beneficial for determining patient status. However, tracking changes in continuously‐measured HRV or HRC parameters over time might be more useful.
Transient Increase in P2Y2 Receptor Expression after Spinal Cord Injury in Rat Model
Authors: Rodríguez Ana E. , Torrado Aranza , Figueroa Johnny D. , González Fernando A. , Miranda Jorge D. 
Published: June 2021

Spinal cord injury (SCI) increases inhibitory molecules release and reactive astrocytes proliferation at injury site producing nonpermissive environment for axonal regeneration. Reactive astrogliosis mechanism is unknown, but the release of nucleotides has been linked to this hypertrophic state. Our goal is to investigate the spatio‐temporal profile of P2Y2 after SCI. Molecular biology and immunohistochemical (IHC) studies were used to evaluate the expression and role of these receptors in rats injured at the T‐10 level using the NYU impactor device. P2Y2 gene temporal profile using standardized RT‐PCR showed a two‐fold increase after 4–7 days post‐injury (DPI) and returned to basal levels by 14 DPI. Double labeling IMH localized P2Y2 in cells bodies, axons, macrophages, oligodendrocytes and astrocytes. Also, levels of P2Y2 immunoreactivity were increased after injury in astrocytes. Therefore, the gene profile of P2Y2 after SCI showed that the levels of this mRNA and protein increased after trauma, suggesting a role in the establishment of the restrictive environment for axonal regeneration after SCI.Support by NIH‐MRISP 2R2MH48190‐14, NIH‐SNRP NS39405, MBRS‐SCORE S06‐GM008224, MBRS‐RISE GM‐68138, PR‐EPSCOR EPS‐9874782
Is microglial activation necessary for phrenic long‐term facilitation following acute intermittent hypoxia?
Authors: Vinit Stephane , Mitchell Gordon S. 
Published: June 2021

Microglial activation is critical for some forms of neuroplasticity in the spinal dorsal horn, such as the induction of chronic pain (Coull et al., 2005). Microglia regulate neuronal function in multiple ways, including the production of growth/trophic factors such as Brain Derivated Neurotrophic Factor (BDNF). BDNF is also critical for respiratory plasticity in the phrenic motor nucleus, such as phrenic long‐term facilitation (pLTF) following acute intermittent hypoxia (Baker‐Herman et al., 2004). Thus, we wondered if microglial activation plays a role in the induction and/or maintenance of pLTF. Since the antibiotic minocycline prevents microglial activation, we tested the hypothesis that minocycline would block pLTF following acute intermittent hypoxia in anesthetized rats. In anesthetized (urethane), paralyzed, vagotomized and ventilated rats, integrated phrenic nerve activity was measured in rats: 1) pretreated with minocycline (3 hrs before protocol; 10 mg i.v.) or 2) pretreated with a vehicle injection. 60 min post‐intermittent hypoxia, similar pLTF was observed in both sham and minocycline treated rats (~45% baseline in both groups). Thus, our data provide no evidence for microglial involvement in pLTF following acute intermittent hypoxia, although these findings do not rule out microglial involvement in longer‐lasting forms of respiratory plasticity.Supported by NIH HL69064 and HL80209.
A Phase I/II Dose‐Escalation Trial of Vitamin D3 with Calcium Supplementation in Patients with Multiple Sclerosis
Authors: Kimball Samantha M , Burton Jodie , Vieth Reinhold , O'Connor Paul 
Published: June 2021

There is evidence to suggest that vitamin D nutritional status may influence the development and progression of multiple sclerosis (MS). To characterize the safety profile of high‐dose oral vitamin D3 in MS, we conducted a phase I/II dose‐escalation trial of vitamin D3 with calcium supplementation in patients with MS.In 52‐week trial patients with MS were matched (age, gender, disease duration, Expanded Disability Status Scale, disease modifying therapy, and MS subtype), stratified, and randomized to treatment or control. The treatment group received escalating doses of vitamin D3 (4,000â 40,000 IU/d) and calcium (1200mg/d). The primary endpoint was change in serum calcium concentrations in the treatment group. Baseline and end‐of‐trial measures of disease progression will be compared. Immune system biomarkers will be compared between baseline and end‐of‐study within the treatment group and between treatment and control subjects. Interim analysis: 9/25 treatment patients remain in‐study while 15/25 have finished. Serum and urine calcium levels have remained within normal ranges (2.2â 2.6mmol/L) for all participants with no incidence of hypercalcemia or hypercalciura. There was no significant difference between control and treatment groups. Mean serum 25(OH)D concentrations have increased significantly from 73.5 to 402.1 nmol/L (p<0.001) at the highest dose (n=14). Further results to follow.
Gamma Delta T Cell Dependent Inflammation and Wound Healing in the Mouse Corneal Epithelium
Authors: Byeseda Sarah Elizabeth , Tawil Ahmad , Li Zhijie , Burns Alan , Smith C. Wayne 
Published: June 2021

We found that γδ T cells migrate into murine corneal epithelium in response to epithelial wounding, and wound healing and inflammation are significantly reduced in TCRδ −/− mice (Am. J. Pathol 171:838–845, 2007). The current work is to define mechanisms for migration of γδ T cells into corneal epithelium. Limbal and paralimbal corneal epithelium was collected at 0 and 3 hrs after central abrasion in female C57BL/6 mice for qrtPCR, and immunocytology. Results: ICAM‐1 mRNA was increased 26 fold at 3 hrs. Anti‐ICAM‐1 staining was negative at 0 hr, but strongly positive over the limbal and paralimbal epithelium at 3 hrs. γ/δ T cells increased at 3 hrs after injury, but ICAM‐1−/− mice failed to show an increase. Of 11 chemokine receptors probed, only CCR3 and CCR5 were significantly increased in wildtype mice at 3 hrs. mRNA for chemokines recognized by these receptors was significantly increased: CCL3 (MIP‐1α), CCL4 (MIP‐1β), CCL5 (RANTES) and CCL7 (MCP‐3). Further, CXCL10 (IP‐10) mRNA was also significantly increased. CXCL10 is known to attract some γδ T cells, but its receptor (CXCR3) was not evident here. Conclusion: The migration of γδ T cells into murine corneal epithelium in response to epithelial abrasion appears to depend on ICAM‐1 expression, and since CCR5 is reported on some γδ T cells, our observations suggest a mechanism for attraction into corneal epithelium.Source of research support: General Clinical Research Centers
A clinicopathological correlation study of cognitive status and senile plaques and neurofibrillary tangles in clinically well‐characterized individuals of extreme old age
Authors: Purohit Dushyant , Batheja Nirmala , Haroutunian Vahram , Sano Mary , Grossman Hillel , Perl Daniel 
Published: June 2021

We describe the distribution of senile plaques (SP) and neurofibrillary tangles (NFT) in a series of 34 brain specimens derived from 90+ year‐old individuals (see table below) who had been systematically evaluated for cognitive function with the final assessments expressed using the Clinical Dementia Rating score (CDR; mean 2.62, SD ±1.27, range 0–5). We determined the extent of SP as a mean density of 5 neocortical areas and of NFT using aggregate density assessments in neocortex, hippocampus and entorhinal cortex. Due to the relatively small sample, we grouped the cases into normal to mild/moderate dementia and severe dementia as follows, and used the Wilcoxon Two‐Sample Test to compare the two groups.Although our sample size is relatively small, there was a statistically significant positive correlation between the extent of dementia (in CDR scores) and SP density score (one sided p=0.011), but not for the NFT density score (one sided p=0.076). This study is ongoing with the hope providing further insights on correlates for both normal cognitive function and dementia in additional prospectively evaluated subjects of extreme old age.Supported by NIH grants PO1 AG‐02219 and P50 AG‐05138
MGMT Promoter Methylation Status Predicts Survival in Pediatric Glioblastoma
Authors: Zhang Wenyong William , Mehta Vidya , Courteau Girard R , Su Jack , Lau Ching , Webb Renee , Adesina Adekunle M 
Published: June 2021

Pediatric glioblastoma (pGBM) represents 15% of pediatric brain tumors with a 3‐year survival rate of < 20%. Effective DNA repair is an important cellular mechanism for resistance to chemotherapy and radiation. The role of this mechanism in pGBM remains poorly understood. We evaluated the expression pattern of proteins (by immunohistochemistry) involved in the repair of DNA damage induced by alkylating agents, as well as, mismatch and base excision repairs including hMLH1, hMSH2 and PARP in fifteen pGBMs. MGMT promoter methylation was analyzed using methylation specific PCR and pyrosequencing. The relationship between DNA repair pathway alteration and survival was analyzed.MGMT promoter methylation was detected in 33% of tumors. Loss of hMLH1 and hMSH2 protein expression was seen in 47% and 53% of tumors, respectively. PARP expression was seen in 100% of pGBMs. hMLH1, hMSH2 and PARP expressions did not correlate with either event free survival or overall survival (p > 0.05). MGMT promoter methylation correlated significantly with better overall survival (p = 0.035). We conclude that MGMT promoter methylation status is a predictor of better survival in treated pGBM.
DNA Replication and Latency in Herpes Simplex Viruses
Authors: Lehman I. Robert 
Published: June 2021

The 152‐kbp herpes simplex virus type 1 (HSV‐1) genome encodes 75 genes of which seven are indispensable for DNA replication. During lytic infection, the HSV‐1 genome circularizes and replication proceeds in two phases: The first is a theta type mechanism initiated at one of the three origins. The product of one of the essential seven genes, the UL 9 protein, serves as the replication initiator, which binds to and unwinds DNA at a viral origin. The Theta phase is followed by rolling circle replication, the predominant mode of HSV‐1 replication. The rolling circle phase has been reconstituted with the six remaining essential gene products which include a DNA polymerase with its associated processivity factor, a single stranded DNA binding protein and a heterotrimeric helicase – primase. The UL 9 protein is the limiting component in DNA replication and is the site at which HSV‐1 DNA replication is regulated.After replication in infected epithelial cells of the skin or bucal mucosa, HSV‐1 gains entrance to sensory nerve termini and establishes a latent infection. The mechanism that leads to the establishment of latency is not understood. We have found that the phosphorylated form of the UL9 protein interacts with the human neural F‐box‐42kDa protein (NFB 42) a neuron specific component of the E3 ubiquitin ligase complex. It is polyubiquinated and then degraded via the 26 S proteosome pathway. NFB 42 is found primarily in the cytosol, whereas the UL 9 protein is located predominantly in the nucleus. We have identified an HSV‐1 dependent shuttling of NFB 42 between the cytosol and the nucleus which mediates the nuclear export of the UL 9 protein. These results suggest a mechanism by which the latency of HSV‐1 can be established in neuronal cells.Supported by NIH Grant AI 26538
Lipids as ligands of nuclear receptor mediated gene expression
Authors: Repa Joyce J. , Clarke Stephen L. , McDonald Jeffrey G. 
Published: June 2021

The liver X receptors (LXRalpha and LXRbeta) are members of the nuclear hormone receptor family of ligand‐activated transcription factors. LXRs have been identified as cellular sterol sensors that are activated by cholesterol‐derived oxysterols to increase the expression of genes that contribute to cholesterol catabolism, efflux and elimination. These qualities make the LXRs attractive therapeutic targets for intervention in atherosclerosis. The majority of studies defining the actions of LXRs have been performed in the mouse model, taking advantage of genetically modified mouse strains devoid of LXRs. When an LXRalpha‐null mouse is fed dietary cholesterol, it fails to increase the expression of LXR target genes and consequently accumulates plasma and hepatic cholesterol and shows no increase in plasma and liver triglycerides. Interestingly, the Golden Syrian hamster also shows this dietary cholesterol‐induced phenotype, and fails to exhibit upregulation of hepatic LXR target genes such as CYP7A1 and SREBP‐1c. These observations prompted us to ask if the LXR‐signaling pathway is intact in the hamster, and whether we could use these qualities to further investigate LXR biology using the cholesterol‐fed hamster.We have cloned and characterized hamster LXRalpha, evaluated the promoter motifs of LXR target genes, and compared the effects of dietary cholesterol and synthetic LXR ligands on cholesterol homeostasis and hepatic gene regulation to define this differential response to dietary cholesterol in this valuable animal model.Supported by a grant from the American Heart Association (JJR)
Structural models of inhibition in neurotransmitter sodium symporters
Authors: Singh Satinder Kaur , Gouaux J. Eric 
Published: June 2021

Neurotransmitter sodium symporters (NSS) play a critical role in terminating synaptic transmission by utilizing preexisting ion gradients to catalyze the thermodynamically unfavorable movement of small molecules, including the biogenic amines, from the synapse to neuronal and glial cytoplasms. Their dysfunction has been implicated in many neuropsychiatric diseases, and they are the target of a broad array of therapeutic and addictive compounds. Steady‐state kinetic data have revealed the existence of both competitive and noncompetitive modes of inhibition. Despite these strides, atomic‐level insight into inhibitor action has remained elusive. To address this dearth of knowledge, we employed LeuT, a leucine transporter and prokaryotic NSS homologue, as a structural paradigm. Through a combination of steady‐state kinetics, radioligand binding, dissociation assays, and X‐ray crystallography, we have pinpointed an allosteric antagonist binding site in an extracellular‐facing vestibule located approximately 11 Å above the substrate binding site. More importantly, we have defined molecular principles that may be germane to noncompetitive inhibition in eukaryotic NSS members and permit the rational design of novel noncompetitive inhibitors with therapeutic potential.Research was supported by NIH and HHMI.
Prevalence of Oxidative Stress and Metabolic Syndrome in Adults with and without spinal cord injury
Authors: Nelson Mindy J Dopler , Burri Betty Jane , Neidlinger Terry R , Stanhope Kimber , Havel Peter J 
Published: June 2021

Objectives: To investigate the extent of oxidative stress and metabolic syndrome (MetS) in people with spinal cord injuries (SCI) and to identify the major factors associated with oxidative stress and MetS in this population.Methods: Twenty‐four subjects with paraplegia (PARA), 26 subjects with tetraplegia (TETRA), and 28 able‐bodied controls (CNTL) were recruited from Northern California. MetS was defined as having ≥ 3 of the following components: (a) BMI ≥ 30.0 kg/m2; (b) fasting plasma high‐density lipoprotein <40 mg/dL for males; <50 mg/dL for females; (c) fasting plasma triglyceride >150 mg/dL; (d) ≥ 130mmHg systolic (SBP) or ≥ 85mmHg diastolic blood pressure (DBP) (e) fasting plasma glucose 100–125 mg/dL, fasting plasma insulin ≥ 20uU /mL, or homeostasis model assessment of insulin resistance ≥ 4.0. Antioxidant activity was measured using vitamin E and TBARS.Results: Subjects with SCI had greater incidence of MetS than CNTL (29.2% of PARA, 15.4% of TETRA, and 3.6% of CNTL.) MetS was not significantly correlated with vitamin E or TBARS. Location of spinal cord lesion correlated with SBP (r=0.522; p<0.0001) and DBP (r=0.319; p=0.026.) TBARS was 20.3% higher in PARA with lesions at L3‐L4 than in TETRA with C2‐C5 lesions (p=0.044.)Conclusion: People with SCI are at greater risk for MetS than CNTL and location of spinal cord lesion may contribute to this risk.Supported by Spinal Cord Injury Research Foundation Grant #1803, Paralyzed Veterans of America
Risk of severe depressive mood decreases with improving hemoglobin levels, but only when daytime salivary cortisol concentration is low
Authors: Rahn Maike , Haas Jere D , Hernández‐Cordero Sonia L , Campirano Fabricio A , Villapando Salvador , Rivera Juan 
Published: June 2021

Previous research indicates that stressor exposure increases risk of severe depressive mood in iron deficient Hispanic women (Rahn 2007). Iron status, severity of depressive mood (Beck depression inventory, BDI), and salivary cortisol concentration were assessed in 48 female Mexican factory workers from the state of Morelos. Iron status measures were hemoglobin, ferritin, protoporphyrin, MCV and transferrin saturation. Salivary cortisol was sampled as a biological marker of stress for 2 successive days. The area under the cortisol concentration curve (AUC) over 7 daytime hours was estimated. Fatigue was assessed with the Fatigue Severity Scale. Mean age was 29 years; mean hemoglobin was 131 g/L (SD=18) and ranged from 8.8 to 16.1 g/L. Anemia with iron depletion occurred in 25% of subjects, while severe depressive mood (BDI score≥29) was found in 31%. The outcome of the logistic regression analysis was risk of severe depressive mood (BDI ≥29) compared to the reference group (BDI<29). Hemoglobin (continuous) and AUC (<median, ≥median) were combined in an interaction term; additional covariates were fatigue, and household crowding and SES. Women with AUC<median had a 6% decrease (p‐value of subgroup=0.04) in odds of severe depressive mood with every one g/L increase of hemoglobin (p‐value of interaction=0.08); no significant slope was found with AUC≥median.This research was supported by the NIH predoctoral nutrition training grant 3 T32 DK007158‐29, the Einaudi Center for International Studies and the N.S. Meinig Professorship, Cornell University.
Overweight duration interacts with added salt intake in increasing odds of hypertension among adult women in Cebu, Philippines
Authors: Lee Nanette , Adair Linda 
Published: June 2021

Being overweight (OW) and high salt intake are known to increase hypertension (HTN) risk. Less is known about the effect of OW duration on HTN risk and whether it interacts with salt intake. Using a sample of 2,003 Filipino women (ages 35–69 yrs) followed for 22 years (1983–2005), this study examined the independent and joint effects of duration of OW (BMI>=25 kg/m2) and high added salt intake on HTN risk. We used data from the Cebu Longitudinal Health and Nutrition Survey and identified 5 patterns of OW history and duration: OW >15 yrs (19%), OW 7–15 yrs (12%), OW <7 yrs (11%), history of OW but not currently OW (10%) and never OW (48%). Added salt intake was deemed high if above mean values. Adjusting for current BMI, age and other confounders, the odds of being hypertensive increases with longer duration of OW. Odds (95% CI) of HTN were highest among women with longest OW duration: 2.0 (1.2, 3.4) for OW >15 yrs, 1.5 (0.9, 2.4) for OW 7–15 yrs, and 1.1 (0.7, 1.7) for OW <7 yrs compared to never OW women. HTN odds among women with high added salt intake were 1.5 (1.1, 2.1) times that of women with low added salt intake. There is significant interaction between OW duration and added salt intake. The odds of HTN among women OW >15 yrs with high added salt intake were 4.4 (2.4, 8.1) times compared to never OW women with low added salt intake. To reduce HTN prevalence, efforts to prevent earlier weight gain and decrease added salt intake should be strengthened.Funding: NIH 5 R01 TW05596‐04 and 5 D43 TW00633‐06‐09
Eating patterns and risk for overweight in children with Attention Deficit Hyperactive Disorder (ADHD)
Authors: Barak Anat , McCrory Megan A , Lovejoy Jennifer C , Weber Wendy 
Published: June 2021

Children with ADHD may be at increased risk for overweight. Although meal skipping, frequent snacking, and excessive consumption of foods high in fat and sugar have been associated with both a tendency toward obesity and poor behavioral symptoms, the link between ADHD and excess weight is poorly understood. We examined BMI distribution and eating patterns in children with different types of ADHD: combined Inattentive/Hyperactivity (IH; n=13) vs. Inattentive (I; n=8). A retrospective chart review of children with ADHD treated at theBastyr Center for Natural Health from 2001–2006 and who completed a 3‐day diet diary was conducted. We found a non‐significant difference between the ADHD subtypes in BMI distribution (27% of IH vs 50% of I children were at risk for overweight). There were no significant differences between ADHD subtypes in dietary intake. However, a low variety of energy weak foods relative to energy dense foods was associated with a higher BMI percentile (r=−0.45 in all children and r=−0.76 in the I group; P=0.05). ADHD symptom severity was not associated with either BMI percentile or dietary intake. This study suggests there may be a relationship between BMI and ADHD subtype, which may be partially explained by dietary variety. Further research is needed to understand the obesity‐ADHD connection.Grant Funding Source: none