bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of rapid fluid loading on airway structure and function in healthy humans
Authors: Ceridon Maile L , Snyder Eric M , Strom Nicholas A , Tschirren Juerg , Johnson Bruce D
Published: June 2021

The causes of reduced pulmonary function (PF) in heart failure (HF) patients remain unclear, but may be due to increased pulmonary congestion. Rapid fluid loading (RFL) in healthy adults has been used to simulate intra‐thoracic fluid overload common in HF. This study examined PF using plethysmography, and airway lumen cross sectional area (Alumen), airway wall thickness (taw), and vascular volume using non‐contrast CT imaging before and after RFL in 22 healthy adults. Average infusion volume was 2190 ± 412 ml over 20 ± 3 min. Vascular volume, heart rate, and cardiac output increased (p<0.001). O2 saturation and mean arterial pressure were unchanged. Forced vital capacity (FVC) and expiratory flow measures decreased post RFL (ΔFVC=−13±9%, ΔFEV1=−15±10%, ΔFEF25‐75=−17±19%, p<0.001). Alumen was unchanged from the trachea through airway generation 3; taw decreased in the trachea (p<0.05) but remained unchanged in airway generations 1–3. Both measures increased at airway generation 4 (p<0.01). Changes in taw and Alumen were unrelated and were also independent of any changes in vascular volume or PF. This data suggests that RFL in healthy adults results in decreases in PF, however these decreases are not due to changes in Alumen, taw, or pulmonary blood volume of the larger airways and vessels that can be easily imaged without contrast. Further studies will be needed to assess bronchial changes in the mid to smaller airways.
Ca2+ signaling in glutamate‐stimulated CO production by newborn pig astrocytes
Authors: Tcheranova Dilyara , Parfenova Helena , Leffler Charles W.
Published: June 2021

CO, a product of heme degradation by heme oxygenase (HO), is a vasodilator and a mediator of glutamate‐induced dilation of newborn pig cerebral arterioles. Glutamate rapidly increases CO production by piglet astrocytes via posttranslational activation of constitutive HO‐2. We tested the hypothesis that glutamate‐induced CO production by astrocytes is mediated by intracellular Ca2+ signaling. CO production by freshly isolated and cultured astrocytes from newborn pig brain cortex was detected by gas chromatography/mass spectrometry. Alteration of extracellular Ca2+ did not change astrocyte CO production. Depletion of intracellular Ca2+ with ionomycin in a Ca2+‐free buffer greatly reduced HO activity. Increasing intracellular Ca2+ from 0 to 1 μM in the presence of ionomycin dose‐dependently elevated CO production up to 4‐fold. Glutamate (10−4M) stimulated HO activity in control, but not in Ca2+‐depleted astrocytes. Furthermore, when intracellular Ca2+ was clamped constant (ionomycin and 0–1μM Ca2+), glutamate failed to increase CO production at any level of intracellular Ca2+. Thapsigargin reduced basal CO production and blocked glutamate‐induced CO production, suggesting importance of intracellular Ca2+ stores. These data suggest glutamate‐induced CO production by astrocytes is mediated by Ca2+ signaling involving intracellular Ca2+ stores. Research support by NHLBI/NIH.
Inhibitory modulation of the defense response in the dorsal periaqueductal gray
Authors: Dean C , Kumaraswamy M
Published: June 2021

The defense response, which includes an increase in sympathetic nerve activity (SNA) and blood pressure (BP), is used as a model for imposed stress, and the dorsal periaqueductal gray (dPAG) is a key integrative site for this response. Background data suggests that 5‐HT and GABA have an inhibitory influence on the defense response at the level of the midbrain. The role of these neurotransmitters in the modulation of SNA was examined with the aim of understanding the dPAG neurocircuitry involved in the mediation of the autonomic responses to stress.

The synaptic excitant d,l‐homocysteic acid (DLH) was microinjected into the dPAG of anesthetized rats to identify a site from which sympathoexcitatory and pressor components characteristic of a defense response could be evoked. The effects of 5‐HT1A and GABAA receptor antagonists at the identified site on baseline and DLH‐evoked responses in renal SNA and BP were determined. The GABA antagonist gabazine and the 5‐HT1A receptor antagonist WAY‐100635 evoked a slight increase in baseline SNA, enhanced the DLH‐induced renal sympathoexcitation and induced twitching of the whiskers and movements indicative of a defense response. These data suggest that neurons mediating the autonomic components of the defense response in the dPAG are under tonic GABAergic and serotonergic inhibition. Supported by the AHA‐Greater Midwest Affiliate.
Does L‐Arginine Really Augment Synthesis of Nitric Oxide in Pharmacological Studies?
Authors: Talman William T. , Dragon Deidre Nitschke , Langasek Julie
Published: June 2021

L‐arginine (L‐Arg), the critical substrate in synthesis of nitric oxide (NO·), is often used in pharmacological studies to assess effects of synthesis and release of NO·. The inactive stereoisomer D‐Arg is used as an inactive control. Because we found that cardiovascular responses to injection into the nucleus tractus solitarii (NTS) of the free amino acid L‐Arg differed from those after L‐Arg HCl we sought to test the hypothesis that effects of D‐Arg would likewise vary with the chemical preparation. In anesthetized rats instrumented for recording arterial blood pressure (AP) and heart rate (HR) we assessed AP and HR changes after unilateral microinjection (50 nl) of L‐Arg, D‐Arg, L‐Arg HCl or D‐Arg HCl at doses of 1, 10, and 50 nmoles. Similar dose‐related depressor and bradycardiac responses followed injection of either free L‐Arg or free D‐Arg unilaterally into the NTS. D‐Arg HCl elicited minimal pressor responses in contrast to depressor responses after L‐Arg HCl. Bilateral microinjection of free L‐Arg led to mild but significant elevations of MAP with no significant change in HR. By comparison, bilateral injection of L‐Arg HCl did not change MAP or HR, but bilateral injection of D‐Arg HCl increased MAP with little change in HR. Caution must be used in concluding that NO· causes responses to L‐Arg. The preparation (free or HCl) of the amino acid should always be specified. Support: NIH R01 HL59593 and VA Merit Review.
Hypoxia upregulates GLUT‐1 expression in rat pulmonary endothelial cells even in hyperglycemia
Authors: Viator Ryan Joseph , Solodushko Victor G , Benny Margaret E , Fouty Brian W
Published: June 2021

Hyperglycemia is common in critical illness and is associated with worse outcome. Why this occurs is not clear. Glucose entry into endothelial cells occurs mainly through the sodium‐independent, non‐insulin regulated, glucose transporter 1 (GLUT‐1). The level of GLUT‐1 expression is a key determinant of how much glucose enters endothelial cells. Hyperglycemia decreases GLUT‐1 expression, whereas hypoxia and inflammation increase expression. In critical illness, where hyperglycemia, hypoxia and inflammation are all present, the net effect on GLUT‐1 expression in pulmonary artery endothelial cells is unknown. Cultured Rat Pulmonary Artery Endothelial Cells (RPAECs) were exposed to hypoxia (5% O2) and either high (20 mmol) or low (5 mmol) glucose, and GLUT‐1 protein expression was determined. Hypoxia (5% oxygen) increased GLUT‐1 protein expression in RPAECs in both high (20 mmol) and low (5 mmol) glucose based on Western blot analysis and immunocytochemistry. Additionally, the hypoxia‐induced upregulation of GLUT‐1 correlated with increased glucose uptake. In conclusion, hypoxia upregulates GLUT‐1 even in hyperglycemia and increases glucose uptake in RPAECs. This may be important in understanding the detrimental effects of hyperglycemia in critical illness. [This work is supported by funding from the NIH/NHLBI grant HL073244 and the NIH training grant HL076125.]
The characteristics of mitochondrial Ca2+ dynamics in single permeabilized ventricular myocytes of rat
Authors: Leem Chae Hun , Ha Jeong Mi , Seol Chang Ahn , Jung Jin Hee , Koh Eun A , Youm Jae Boum , Choe Han , Jang Yeon Jin
Published: June 2021

We would like to study the characteristics of the mitochondrial Ca2+ dynamics in permeabilized rat ventricular myocytes. We monitored NADH, Ca2+ with Fura‐2‐FF and the mitochondrial membrane potential (ψm) with TMRE, simultaneously. We also developed a new correction method for correcting signal interference between NADH and Fura‐2‐FF. The application of 1 μM Ca2+ without cytosolic Na+ could increase intramitochondial Ca2+ upto 8 μM, which is far less than electrochemical equilibrium. The increase and loading kinetics of Ca2+ were strongly affected by the cytosolic Ca2+ concentration itself and completely blocked by RuR. The Ca2+ efflux from the mitochondria was strongly affected by the cytosolic Na+ concentration, suggested the major role of mitochondrial Na+‐Ca2+ exchange (mito‐NCX) in the Ca2+ efflux from the mitocondria. We found the cytosolic K+ was an obligatory ion to activate Ca2+ efflux through mito‐NCX. Cytosolic Cl− did not affect the mitochondrial Ca2+ dynamics. Cytosolic phosphate in addition to Ca2+ strongly inhibited Ca2+ loading and depolarized ψm. This depolarization was not blocked by CsA or 5‐HD. The increase phosphate with the increase of the cytocolic Ca2+ probably plays an important role in the degradation of mitochondrial function. This mechanism must be closely related to the post‐ischemic reperfusion injury of the heart. Supported by the grant (No. R01‐2004‐000‐10374‐0) from KOSEF
Estrogen increases the expression of intracellular calcium uptake mechanisms in coronary arteries
Authors: Muldrew Edwin , J.F Brent
Published: June 2021

The sarcoplasmic reticulum (SR) membrane protein Ca2+‐ATPase (SERCA) helps to regulate intracellular Ca2+ levels, and thus, control arterial tone. We hypothesize that estrogen's (E2) protective effect against vascular disease is partly attributed to the ability of the SR to regulate intracellular Ca2+levels. The aim of this study was to investigate the effect of physiological E2 concentrations on SERCA expression. Right coronary arteries were dissected from female pig hearts. The distal portion of the arteries were sectioned into longitudinal strips and incubated for 24 hours in E2 (1 × 10−9M and 1 × 10−12M). Antibodies reactive to SERCA2, PKG, and PKA were used to determine immunoreactivity in homogenized tissue after the 24 hours of treatment. The results indicate that 1 × 10−9M E2 elicits a 51±8% increase in SERCA2 expression, as well as a corresponding increase in PKG and PKA expression. This suggests that E2 upregulates SERCA2 expression and its regulatory kinases, which may be a protective benefit for pre‐menopausal women. Support: NCRR of the NIH, Grant #P20 RR‐16460
Opioid Compounds Inhibit Hepatic Stellate Cell Activation and Collagen Expression: A Possible Mechanism for Attenuation of Liver Fibrosis
Authors: Day Stephani A , Clemens Mark G , Wu Edwin , Schrum Laura W
Published: June 2021

Hepatic fibrosis is characterized by activated hepatic stellate cells (HSCs) and increased type I collagen deposition. JKB‐122, an opioid compound, protects against liver fibrosis. JKB‐121, an analog of JKB‐122, is predicted to have a similar efficacy. Both JKB‐122 and JKB‐121 are known to bind to opiate receptors and to modulate inflammatory cytokine activities. JKB‐119, an opioid‐like compound, has anti‐inflammatory activity without any significant binding affinity to opiate receptors. To delineate which activity is attributed to the anti‐fibrotic activity, we determined the effects JKB‐119 and JKB‐121 had on HSC activation and collagen expression. HSCs were culture‐activated and treated with each drug, and RT‐PCR and Western blots were performed to determine collagen and smooth muscle α–actin (SMA) expression. HSCs treated with JKB‐119 or JKB‐121 showed a decrease in collagen and SMA mRNA expression. Similarly, SMA protein concentrations were reduced. These data suggest that the anti‐inflammatory properties of these drugs may act directly on HSC activation and collagen production abrogating liver fibrosis without modulation of opiate receptors. Understanding how HSCs respond to each of these drugs and what role opiate receptor signaling plays in these cells can lead to the development of novel therapeutics for liver fibrosis. Supported by SRL of North Carolina Biotechnology Center.
Role of voltage‐gated potassium channels in the response to oxygen in chicken embryo ductus arteriosus
Authors: Cobeño Laura , Villamor Eduardo , Cogolludo Angel , Frazziano Giovanna , Moral Javier , Zoer Bea , Moreno Laura , Perez‐Vizcaino Francisco
Published: June 2021

Inhibition of voltage‐gated potassium (Kv) channels by O2 has been reported as a central mechanism involved in ductus arteriosus (DA) closure in mammals. Herein, we have investigated the role of Kv channels in the developmental and regional responses to O2 in chicken embryo DA. Experiments were performed in the pulmonary or aortic sides of the DA isolated from chicken embryos incubated for 15 or 20 days and in myocytes isolated from these tissues. Under control conditions, the amplitude of the potassium currents were similar in myocytes from the pulmonary or aortic sides of the 20‐day DA and around two fold higher than in 15‐day DA myocytes. The increase in O2 tension from 0 to 21% induced a partial (30±4%) and a total (96±4%) reduction of the current (measured at 0mV) in myocytes isolated from the pulmonary side of 15‐day and 20‐day DA, respectively. No effects were observed in myocytes isolated from the aortic side of the 20‐day DA. Addition of DPO‐1, a selective inhibitor of the Kv1 channels subfamily, markedly reduced the contraction induced by O2. Our results indicate that, like in mammals, inhibition of Kv channels (especially of the Kv1 subfamily) is involved in the contraction of chicken DA by oxygen. This inhibitory effect augments with maturation and is restricted to the pulmonary side of the DA.

Supported by SAF2005‐03770 and Fundacion Mutua Madrileña
Expression of VEGF and correlation of MVD and TIDC in periampullary adencocarcinoma tissues
Authors: Wang Shu‐Qing , Liu Cheng‐Wei , Kang* Yu‐Ming , Lv Da‐Ming , Wang* Shu‐Qiu
Published: June 2021

The present study was undertaken to investigate the relationship between VEGF, MVD, S‐100+, CD83+, TIDC and the metastasis and the degree of malignancy in periampullary adencocarcinoma.

Method: The expression of VEGF, MVD, S‐100+, CD83+ and TIDC were detected in oncologic tissues by streptavidin peroxidase immunohistochemistry from 25 patients who caught with periampullary adencocarcinoma.

Results: The expression of VEGF in periampullary adencocarcinoma tissues was higher than normal control (p<0.05). A positive correlation was observed between the expression of VEGF and MVD. S‐100+, TIDC was correlated with pathological type of tumor and lymphatic metastasis, but it was unrelated with sex and age. Compared with control, more S‐100+, TIDC and fewer CD83+, TIDC were in periampullary adencocarcinoma. The expression of VEGF was negatively correlated with S‐100+ TIDC, and it inhibited the maturation of TIDC.

Conclusions: Upregulation of VEGF expression in periampullary adencocarcinoma might play an important role in tumor angiogenesis.TIDC was found in periampullary adencocarcinoma and maturation of TIDC was inhibited by VEGF.
Zfra is an inhibitor of Bcl‐2 expression and cytochrome c release from the mitochondria
Authors: Chang Nan‐Shan , Hsu Li‐Jin
Published: June 2021

Zfra is a small size 31‐amino‐acid C2H2 zinc finger‐like protein, which is known to interact with c‐Jun N‐terminal kinase 1 (JNK1), WW domain‐containing oxidoreductase (WWOX, FOR or WOX1), TNF receptor‐associated death domain protein (TRADD) and nuclear factor kappaB (NF‐kappaB) during stress response. Here, we show that Zfra became phosphorylated at Ser8 (as determined by specific antibody) and translocated to the mitochondria in response to inducers of mitochondrial permeability transition (MPT) (e.g. staurosporine and betulinic acid). Overexpressed Zfra induced cell death. This event is associated, in part, with increased dissipation of mitochondrial membrane potential (MMP) and increased chromosomal DNA fragmentation. Intriguingly, Zfra significantly downregulated Bcl‐2 and yet blocked cytochrome c release from the mitochondria. Overexpression of an S8G‐Zfra mutant (Ser8 to Gly8 alteration) could not result in cell death, due to its failure of translocating to the mitochondria and causing MMP dissipation. Proapoptotic WOX1 physically interacted with Zfra and induced cytochrome c release from the mitochondria. Zfra blocked the effect of WOX1. Taken together, Ser8 is essential for overexpressed Zfra to exert cell death via the mitochondrial pathway. Zfra downregulates Bcl‐2 and induces MMP dissipation but causes no cytochrome c release, indicating a novel death pathway from the mitochondria.
Comparative analysis of selenocysteine machinery and selenoproteome gene expression in mouse brain identifies neurons as key functional sites of selenium in mammals
Authors: Zhang Yan , Zhou You , Schweizer Ulrich , Savaskan Nicolai E. , Hua Deame , Kipnis Jonathan , Hatfield Dolph L. , Gladyshev Vadim N.
Published: June 2021

Although dietary selenium (Se) deficiency results in phenotypes associated with selenoprotein depletion in various organs, the brain is protected from Se loss. To address the role of Se in brain function, we carried out comparative gene expression analyses for the complete selenoproteome and associated biosynthetic factors. Using the Allen Brain Atlas, we evaluated 159 regions of adult mouse brain and provided experimental analyses of selected selenoproteins. All 24 selenoprotein mRNAs were expressed in the mouse brain. Most strikingly, neurons in olfactory bulb, hippocampus, cerebral cortex and cerebellar cortex were exceptionally rich in selenoprotein gene expression, in particular in GPx4, SelK, SelM, SelW and Sep15. A contrasting pattern was observed for another highly expressed selenoprotein gene, SelP, which we suggest to provide neurons with Se. Cluster analysis of the expression data linked certain selenoproteins and selenocysteine machinery genes and suggested functional linkages among selenoproteins, such as that between SelM and Sep15. Overall, this study suggests that the key functions of selenium in mammals are confined to certain neurons in the brain.
Expression of the Human UGT1 Locus in Transgenic Mice by WY‐14643 and Implications on Drug Metabolism Through Peroxisome Proliferator‐Activated Receptor (PPAR) α Activation
Authors: Senekeo‐Effenberger Kathy , Chen S. , Brace‐Sinnokrak E. , Bonzo J. A. , Yueh M‐F. , Argikar U. , Kaeding J. , Trottier J. , Remmel R. P. , Ritter J. K. , Barbier O. , Tukey R. H.
Published: June 2021

Transgenic mice carrying the human UDP‐glucuronosyltransferase‐1 locus (Tg‐UGT1) was recently created and shown to express the nine UGT1A genes in a pattern that resembles their expression in human tissues. In the present study, UGT1A1, 1A3, 1A4, and 1A6 have been identified as targets of PPARα in human hepatocytes and Tg‐UGT1 mice. Oral administration of WY‐14643 to Tg‐UGT1 mice led to inductionof these proteins in either the liver, gastrointestinal tract, or kidney. With UGT1A3 previously identified as the major human enzyme involved in human C24‐glucuronidation of lithocholic acid (LCA), the dramatic induction of liver UGT1A3 RNA in Tg‐UGT1 mice was consistent with the formation of LCA‐24G in plasma. Furthermore, PPAR‐responsive elements were identified flanking the UGT1A1, UGT1A3, and UGT1A6 genes by a combination of site‐directed mutagenesis, specific binding to the PPARα receptor, and functional response in HepG2 cells overexpressing PPARα. In conclusion, these results suggest that oral fibrate treatment in humans will induce the UGT1A family of proteins in the gastrointestinal tract and liver, influencing first‐pass metabolism of other drugs that are taken concurrently with hypolipidemic therapy. (Supported by USPHS grants ES10337 and GM49135).
Fe and Zn bioavailability from red (merlot) and white (great northern) bean‐based (Phaseolus vulgaris) diets fed to anemic young pigs
Authors: Tako Elad , Glahn R. P. , Welch R. M. , Lei X. , Laparra J. M. , Rutzke M. , Miller D. D.
Published: June 2021

Beans contribute significant amounts of Fe in the diets of many populations. A major cause of Fe deficiency is poor Fe bioavailability from plant ‐ based diets containing Fe absorption inhibitors such as polyphenols. Our objective was to compare Fe and Zn bioavailability between red and white beans which differ in their polyphenol content.

Anemic piglets at age 4 wks were allocated into 2 treatment groups (n=10) and fed corn/bean rations containing either 37% white or 37% red beans. Diets had no supplemental Fe. Pigs were given a meal containing intrinsically labeled (58Fe, 70Zn) beans followed by an intravenous (i.v.) injection of 54Fe and 67Zn on day 7 and again on day 21 of the experiment to assess Fe and Zn absorption. Blood samples were taken periodically. On day 35, animals were killed and duodenal sections were collected for DMT1 gene expression analysis. Fe absorption was calculated from 58Fe concentrations incorporated in hemoglobin. Zn absorption was calculated from the ratios of 70Zn to 67Zn in plasma. Fe absorption was 14% and 16% from the 1st meal and 9% and 10.5% from the 2nd meal for the white and red beans, respectively (P>.05). Zn absorption was 34% and 30% from the 1st meal (P>.05) and 28% and 37% from the 2nd meal (P<.05) for the white and red beans, respectively. DMT1 gene expression did not differ between treatments. These results show that Fe and Zn bioavailability from red/white bean‐based meals is similar.
Dynamic coordination of macronutrient balance during infant growth: Insights from a mathematical model
Authors: Hall Kevin D , Jordan Peter N
Published: June 2021

We developed a mathematical model that quantitatively integrates longitudinal data on body composition changes and CO2 production rates from the doubly‐labeled water method to calculate both the energy intake requirements and, for the first time, the macronutrient oxidation rates during normal infant growth. The figure shows that the calculated net fat oxidation rate was initially less than 20 kcal/kg/day despite consuming more than 60 kcal/kg/day of dietary fat. Fat oxidation increased over the first several months but slowly decreased from 6 months onward, while carbohydrate and protein oxidation rates dropped immediately after birth before continuously increasing from 3 months onward. The calculated energy intake requirements were slightly lower than previous estimates and were robust to realistic variations in body weight, body composition, and diet composition, but depended sensitively on variations in CO2 production data. The model presents a dynamic picture of how macronutrient oxidation adapts in concert with changes of diet and energy expenditure to give rise to normal tissue deposition and growth.
Boron intakes in selected populations in Turkey and the US.
Authors: Meacham Susan , Sayli Ugur , Korkmaz Mehmet , Carper Stephen , Bakirdere Sezgin , Ataman O. Yavuz
Published: June 2021

Average intakes determined using different methods have estimated 1.0–1.2 mg boron (B)/d for adults in the United States (US). Similar intakes have been reported in Turkey where limited control subjects were compared with subjects living in B‐rich areas. In Turkey an initial study observed a decrease in incidence of cervical cancer‐related histopathological findings when B intakes were 8.41 mg/d in naturally B‐rich regions. A US study reported an inverse relationship between natural B concentrations in the water and prostate cancer. In the US differing B intakes have been observed in US college females with a 20% increase observed when diets considered adequate on the basis of 7 of 8 key nutrients (1.28 ± 1.00 mg/d; n=13) were compared to all diets (1.02 ± 0.83 mg/d, n=28). Elderly women (85% of 39; 71.2 ± 10.2 yr) reported consuming 1–29 dietary supplements daily. In the US B is listed on 107 commercial product labels, some providing 3 mg B/tablet. B was identified by high resolution ICP‐MS analysis in commercial products without listing B on the label (i.e., 152 μg B/g and 137 μg B/g in two products). Confirming B intakes in subpopulations consuming higher than average daily intakes from both natural and supplement sources should be confirmed. Further studies are needed in these subpopulations to support the observed healthful benefits with regard to cancer and to elucidate the mechanism of action of B in humans.
Capture of malaria antigens by microvascular endothelial cells: implication in pathology
Authors: Jambou Ronan , Combes Valerie , Sanchez‐Perez Angeles , Grau Georges
Published: June 2021

Cerebral malaria, a major cause of death during malaria, is associated with sequestration of parasitised red blood cells (PRBC) in brain vessels. Raised plasma levels of both malaria‐specific and self‐reacting antibodies are common during malaria. The role of self‐reacting antibodies in pathogenesis is still debated, but implication of malaria specific antibodies in vessel lesions has not been investigated. To address this question we first explored the transfer of malaria antigens to human brain endothelial cells (HBEC), by incubating them with calcein‐AM‐ and PKH 26‐labelled P. falciparum‐infected RBC, for cytoplasmic and membrane identification, respectively. Immunofluorescent detection of malaria antigens was performed on HBEC after incubation of PRBC using a pool of hyperimmune plasmas from patients from malaria endemic area. Second, the antigens transferred to HBEC by this process were characterised by Western blot using mAbs raised against MSP antigens. This study demonstrates the transfer of parasite antigens to the HBEC through a mechanism dependent on their binding of the PRBC and on their engulfment. These results can be related to previous studies which showed deposition of IgE, IgG, malaria antigens and fibrin on brain vessels from patients who died of cerebral malaria. This capture of malaria antigen can transform microvascular endothelium in a target for the immune response of the patient
Human Beta Defensin 3 (HBD3) induces migration and activation of antigen presenting cells and acts as an immune enhancer
Authors: Tewary Poonam , Li Zhenhua , de la Rosa Gonzalo , Chen Qian , Oppenheim Joost , Yang De
Published: June 2021

Beta Defensins (BDs) are small, cationic peptides, classified by their pattern of conserved cysteines, that are primarily known for their antimicrobial properties. They also act as chemoattractantagents for monocytes and dendritic cells in mammals The best characterized human BDs are HBD1, HBD2, and mouse BD1∼3 (MBD1∼3). HBD1∼2 and MBD2∼3 are chemotactic for immature dendritic cells (iDCs), memory T cells, and mast cells. HBD2 and MBD2 are capable of activating mast cells and DCs. Human β‐defensin 3 (hBD3) is a highly basic 45‐amino‐acid protein that acts both as an antimicrobial agent and as a chemoattractant molecule. The effects of HBD3 and its mouse ortholog, MBD14, on leukocytes are largely uncharacterized to date. Here we report that HBD3 simultaneously acts as a chemoattractant and activator of antigen presenting cells. Using synthetic and recombinant HBD3, we observed that HBD 3 induced migration of CD34 progenitor derived iDCs and CCR6 transfected HEK 293 cells in a dose dependent manner. HBD3 was also chemotactic for human monocytes and was able to induce calcium flux in or by monocytes. HBD3 also induced activation of monocytes by upregulating surface expression of costimulatory molecules like CD40, CD64, CD80, CD86, MHC class II and adhesion molucles like LFA3 and ICAM1. Furthermore HBD3 induced production of IL‐6, IL‐8, IL‐1beta and TNF alpha by monocytes. When injected into mouse peritoneal cavity, HBD3 also caused a marked recruitment of neutrophils and macrophages. Thus, HBD3 appears to be an important mobilizer and activator of innate inflammatory and adaptive immune responses.
Efficacy of iron folic acid tablets vs. a powdered mixture of mineral and vitamins to control anemia during pregnancy
Authors: Hyder Ziauddin , Choudhury Nuzhat , Zlotkin Stanley
Published: June 2021

Introduction: A powdered mixture of mineral and vitamins (PMV) in a small sachet, Sprinkles™, is effective in controlling anemia in young children. A similar mixture targeted to pregnant women might be appropriate.

Objective: To determine the efficacy of a PMV packaged in single serving sachets compared to IFA in pregnant women.

Method: A cluster randomized trial was carried out in 42 antenatal care centers operated by BRAC in Bangladesh. Anemic women aged 15–45 years, gestational age 14–20 weeks and Hb 70–110 g/L were allocated to either tablets (n=92) or PMV (n=121). Each tablet and PMV sachet contained 60mg elemental iron and 400μg folic acid. Data collection was done at baseline and at gestational weeks 24, 28 and 34. Hb was measured using HemoCue®. Adherence was assessed by counting the number of sachets or tablets consumed.

Results: Hb did not differ significantly between the tablet and PMV groups at 24 and 28 weeks. However, at week 32, mean Hb was higher in tablet (110.2 g/L, SD 11.1) compared to PMV group (105.6 g/L, SD 11.1) (P<0.05). At week 32, mean percent adherence was 76% in tablet and 58% in PMV group (P<0.05). After controlling for adherence, however, the Hb response did not differ between the groups.

Conclusion: Efficacy of iron and folic acid delivered by tablet or PMV in a sachet was comparable when adherence was controlled for.
Cost estimations of different types of micronutrient supplements for children and pregnant women
Authors: Colchero Arantxa , Neufeld Lynnette
Published: June 2021

Few studies have attempted to compare the cost of different types of micronutrient supplements that are commonly used in public health programs. The objective of this study was to assess the costs of three types of nutritional supplements with identical micronutrient content: fortified food (FF) currently provided to children and pregnant and lactating women in Mexico's Oportunidades program; syrup (SY) for children or tablets for women and; Sprinkles for children and women (SK). We estimated the cost per recommended dose of acquiring (with delivery in Mexico City) and distributing the supplements, assuming distribution by the public sector. Indirect costs to beneficiaries or families were not assessed. Sensitivity analysis was conducted on uncertain parameters. The average cost per dose of FF for children was US$0.13 and US$0.19 for women. The average cost for SY was US$0.17 and the tablets US$0.07 and average cost per dose of SK was US$0.03 (for children or women). The information obtained in this analysis is a necessary complement to impact and acceptability data to assist decision makers regarding the most appropriate and feasible micronutrient supplement for public programs.

The Oportunidades program funded this research and holds the rites to the data obtained.
Health‐Related Quality of Life by Socioeconomic Factors and Health‐Related Behaviors of the Elderly in Rural Area
Authors: CHOE JEONG‐SOOK , KWON Sung‐ok
Published: June 2021

Objectives:

This study was to identify socioeconomic factors and health‐related behaviors influencing on HRQOL (health‐related quality of life) for the older adults in rural area.

Methods:

483 subjects aged over 65 years responded a direct interview, which covered HRQOL, BMI(Body Mass Index), socioeconomic characteristics, and health‐related behaviors including smoking, drinking, and exercise.

Results:

The mean healthy days were 15.1 days/month and not significantly different by sex. Men didn't show a significant difference in HRQOL by age group. But women reported lower levels of healthy days and higher levels of activity limitation and physical unhealthy days with increasing age. Results from ANCOVA showed HRQOL to be significantly associated with education, job, and family type. Men presented no significant difference in HRQOL by health‐related behaviors, but women who have been drinking, or have less number of chronic diseases reported higher mean healthy days and lower activity limitation days, physical unhealthy days, and mental unhealthy days. Older adults who reported good to excellent self‐rated health were higher healthy days and lower activity limitation, physical unhealthy days, and mental unhealthy days than those who reported fair to poor health status.

Conclusions:

The HRQOL for the older adults in rural area was related to socioeconomic characteristics, health‐related behaviors and self‐rated health status. A better understanding of factors related to HRQOL would help to improve the older adults' quality of life.
Marginal copper deficiency impairs endothelium‐dependent relaxation responses across two generations
Authors: Anderson Cindy M , Johnson W Thomas
Published: June 2021

The generational effects of marginal copper (Cu) deficiency on vascular function have not been characterized. In this study, the vascular consequences of marginal Cu deficiency were determined by relaxation responses in mesenteric arteries of dams and two generations of offspring. Pups from dams (first generation, F1) fed AIN93G diet containing 1mgCu/kg (CuD) were cross fostered to dams fed diet with 6 mg Cu/kg (CuA) [3 weeks preconception through end of lactation] and vice versa on postnatal day (PND) 1. Control pups remained with their birth dams. After weaning, all F1 offspring were transitioned to CuA rat chow. F1 offspring were mated within groups to determine perpetuation of vascular effects from marginal Cu deficiency, resulting in second‐generation offspring (F2). A small wire myograph was used to determine mesenteric arterial responses in dams on PND 21 and in F1 and F2 offspring groups at 9 weeks of age. There were no significant differences in relaxation responses in dams. In F1 offspring, CuD during lactation led to impaired endothelium‐dependent relaxation. In F2 offspring, impaired endothelium‐dependent relaxation occurred in male offspring born to dams with CuD in‐utero. These findings indicate that future impairment of endothelium‐dependent relaxation results from exposure to CuD during the critical developmental windows of lactation, propagated by CuD exposure in fetal development.
The green tea polyphenol, (−)‐epigallocatechin‐3‐gallate, inhibits obesity and metabolic syndrome in high‐fat fed mice
Authors: Bose Mousumi , Lambert Joshua D , Ju Jihyeung , Reuhl Kenneth R , Shapses Sue A , Yang Chung S
Published: June 2021

We investigated the effects of the green tea polyphenol, (−)‐epigallocatechin‐3‐gallate (EGCG), on high‐fat induced obesity, metabolic syndrome and fatty liver in mice. EGCG treatment (3.2 g/kg diet) for 16 weeks significantly reduced body weight gain, percent body fat, and visceral fat weight (37% decrease) in high‐fat fed mice. The body weight and fat decreases were associated with increased fecal lipid content (2‐fold increase). EGCG significantly attenuated insulin resistance (76% decrease) and monocyte chemoattractant protein (MCP‐1) levels in high‐fat fed mice. EGCG also significantly decreased liver weight, triglyceride content (69% decrease), and plasma alanine aminotransferase levels. Histological analyses of liver samples showed decreased lipid accumulation in hepatocytes in EGCG‐treated mice compared to high‐fat fed controls. In another experiment, short‐term EGCG treatment (3.2 g/kg diet, 4 weeks) significantly decreased mesenteric fat weight (35% decrease) and fasting blood glucose (22% decrease) in high‐fat fed obese mice. Our results indicate that 16‐week EGCG treatment attenuated the development of obesity and fatty liver. Short‐term EGCG treatment reversed pre‐existing high‐fat induced metabolic pathologies in obese mice. These effects may be mediated by decreased lipid absorption, decreased inflammation and other mechanisms (Supported by NIH grant CA8896 and CA 125780).
Toxic effects of consumption of ‘hijiki’ seaweed in rats
Authors: Yokoi Katsuhiko , Shizuka Hitomi , Konomi Aki
Published: June 2021

‘Hijiki’ (Hijikia fusiforme) is a sort of seaweed consumed in Japan, although it contains high amount of inorganic arsenic (As). The average portion of inorganic As in total As of ‘hijiki’ is circa 70% (Food Standards Agency, UK). Authoritative agents of Australia, New Zealand, Canada and UK are prohibiting import, sale and consumption of ‘hijiki’. We tested detrimental effects of ‘hijiki’ using rats. Twenty 3‐week‐old male Fisher rats were equally divided to two groups: control group (CON) given AIN‐93G diet and ‘hijiki’ group (HIJ) given ‘hijiki’ diet that contained 30 g ‘hijiki’ powder/kg in place of α‐cornstarch. Rats were ad libitum fed diets and deionized water for 7 weeks. The ‘hijiki’ powder contained 102±2 (mean ± SD) mg total As/kg. Food intake and body weight gain were not affected by consumption of ‘hijiki’. ‘Hijiki’ significantly increased rectal temperature by 0.5°C. Total As concentration measured by ICP‐MS was markedly and significantly increased by ‘hijiki’. Total As (ng/g) in CON vs HIJ was respectively 12±12 vs 3168±571 in liver; 177±11 vs 67600±2700 in blood. ‘Hijiki’ consumption significantly decreased plasma free fatty acids and increased plasma total and LDL‐cholesterol and phospholipids. It decreased TIBC and increased plasma ALP, choline esterase, inorganic phosphorus and Mg. These results suggest that subacute oral exposure of ‘hijiki’ is detrimental mainly due to inorganic As.
Tumor to tumor metastasis causing rapid meningioma enlargement: a case report
Authors: Tolocica Ioana , Narendra Sonia , Fuller Christine
Published: June 2021

Metastasis of systemic malignancies to primary intracranial tumors is uncommon. Occasional reports have seen meningiomas as hosts for metastatic carcinomas, especially from lung and breast. We report a case of a 46 year‐old woman who presented with headache and a rapidly enlarging right frontal dural‐based lesion. She had been diagnosed at birth with bilateral retinoblastoma, treated with left enucleation and Co‐60 radiation to the right eye. She was subsequently diagnosed with papillary thyroid carcinoma in 2000 and invasive ductal carcinoma with solitary sentinel lymph node metastasis in 2004. In 1997, she underwent the first of three resections for a meningioma of the right sphenoid wing and orbit; gamma knife radiosurgery was utilized for control of residual tumor. Serial imaging studies revealed growth of two additional presumptive meningiomas in parasellar and right frontal locations, the later showing recent rapid enlargement in 2007 necessitating surgical intervention. Microscopic and immunohistochemical assessment of this lesion revealed a WHO grade I meningioma harboring metastatic invasive ductal carcinoma. Further work‐up revealed extensive metastasis to axial skeleton, liver and spleen. This case emphasizes the need for surgical evaluation of rapidly enlarging dural‐based lesions in patients with systemic malignancies as these lesions may represent meningiomas, metastases, or both.
Lipomatous supratentorial primitive neuroectodermal tumor with glioblastomatous differentiation
Authors: Chamberlain Wendy A. , Prayson Richard A
Published: June 2021

Cases of cerebral neuroblastoma or supratentorial primitive neuroectodermal tumor with malignant glioblastomatous components are relatively uncommon. Less frequent is the combination of these two elements with a mesenchymal component. We report a case of lipomatous supratentorial primitive neuroectodermal tumor with glioblastomatous differentiation occurring in a 48‐year‐old woman. She presented with headaches and confusion. A right parietal lobe mass was excised and subsequently recurred, requiring additional surgery ten months later. The patient died 13 months after initial surgery. Histology showed a proliferation of small, rounded, synaptophysin‐positive‐staining neural cells consistent with neuroblastoma. These cells were arranged against a benign lipomatous background. The second resection consisted primarily of glioblastomatous‐like tissue with an intermixed lipomatous component. The glioblastoma component was marked by prominent cellularity, moderate nuclear pleomorphism, readily identifiable mitotic activity, vascular proliferative changes, and necrosis. The glioblastomatous component of the tumor demonstrated GFAP immunoreactivity. A Ki‐67 labeling index of 18.9% was noted in the initial resection. The case serves as a focus for discussion on the relationship of the various components (embryonal, mesenchymal and glial) of this tumor.
Cooperation between IgG receptors (FcγRIIa) and TLR4 in human neutrophils
Authors: Fudala Rafal , Stankowska Dorota , Krupa Agnieszka , Kurdowska Anna
Published: June 2021

Previous studies from our laboratory revealed that the presence of anti‐IL‐8 autoantibody:IL‐8 complexes in lung fluids from patients with ALI/ARDS is an important prognostic indicator for the development and outcome of ALI/ARDS. Further, we showed that purified anti‐IL‐8 autoantibody:IL‐8 complexes trigger chemotaxis of neutrophils, induce activation of these cells, and prolong the lifespan of neutrophils via IgG receptors, FcγRIIa. Sepsis is considered the major risk factor for development of ALI/ARDS, and LPS has been recognized as a causative factor for progression to ALI/ARDS. In the current study we demonstrated that the expression of FcγRIIa is increased in human neutrophils after LPS treatment. TLR4 and FcγRIIa co‐localize in LPS stimulated neutrophils but not in unstimulated cells. The interaction between TLR4 and FcγRIIa was confirmed by FRET (Fluorescence Resonance Energy Transfer). Treatment with LPS also enhances the pro‐inflammatory activity of anti‐IL‐8:IL‐8 complexes in neutrophils. We observed a substantial increase in the amount of myeloperoxidase in neutrophils pre‐treated with LPS and simulated with the complexes, elevated activation of NFκB and ERK. Our findings indicate that LPS affects activity of anti‐IL‐8:IL‐8 complexes by increasing expression of FcγRIIa, and evoking structural changes that lead to TLR4 and FcγRIIa clustering.

Supported by the NIH grant HL073245.
Morphine‐induced tolerance and dependence develops in the mouse isolated ileum but not colon
Authors: Ross Gracious R , Gabra Bichoy H , Dewey William L , Akbarali Hamid I
Published: June 2021

Morphine tolerance and dependence have been demonstrated historically in ileum but not in the colon, the major organ associated with constipation. Here we evaluated the development of tolerance and dependence to morphine in the isolated tissue segments from the mouse ileum and colon. Isometric force was measured from longitudinal and circular muscle preparations of ileum and colon from placebo‐ (PP) and morphine‐pelleted (MP) mice. Morphine inhibition of field stimulated contractions of the longitudinal muscle was dose dependent with comparable pD2 values from the ileum (7.1) and colon (7.8) (n=6) of PP mice. However, the dose‐response was shifted to the right for the ileum (pD2= 5.1) but not the colon (pD2= 6.9) of MP mice. Morphine produced contractions of circular muscle preparations in ileum and colon. Repeated administration of morphine in the organ bath produced tolerance in the ileum by the 4th application but not the colon from PP mice. Whereas in tissues from MP mice, where tolerance has already developed, further tolerance to the contractile response to morphine did not develop in the ileum. Naloxone precipitated a withdrawal contracture in the longitudinal muscle after long‐term morphine incubation in the ileum but not the colon. These findings demonstrate that tolerance does not develop in the colon and may explain the lack of tolerance to morphine‐induced constipation. Supported by DK46367, DA01647
Chronic d‐amphetamine alters food‐reinforced responding and cocaine self‐administration under a progressive‐ratio schedule in rhesus monkeys
Authors: Czoty Paul W , Martelle Jennifer L , Garrett Nicholas R , Nader Michael A
Published: June 2021

d‐Amphetamine (AMPH) decreases cocaine self‐administration (SA) in laboratory animals, and reduces cocaine use in humans. In these studies, effects of chronic AMPH were examined in four rhesus monkeys responding under a progressive‐ratio (PR) schedule of cocaine injection. Each day, 1‐g food pellets were available under a fixed‐ratio 50 schedule starting at 8am for 23 h or until the day's food ration was earned. On another lever, cocaine (0.003–0.56 mg/kg/inj) was available under a PR schedule from 3pm until 2 h passed without an injection. Cocaine access was suspended and AMPH (0.01–0.1 mg/kg/hr, i.v.) was administered by continuous infusion for 5 days. Dose‐related reductions in food‐reinforced responding were observed during AMPH treatment that dissipated when AMPH administration was discontinued. Dose‐related reductions in the reinforcing strength of 0.03 mg/kg/inj cocaine were observed when cocaine was made available starting the day after AMPH treatment, but not when a 6‐day washout period intervened; effects were similar when treatment with a low dose of AMPH was extended to 12 days. Importantly, AMPH‐induced reductions in food‐maintained responding recovered faster than AMPH‐induced decreases in cocaine SA. Ongoing experiments are assessing whether longer durations of AMPH treatment lead to more persistent reductions in cocaine SA. Support: DA 06634.
SN79, A Novel Sigma (σ) ‐ 2 Receptor Antagonist, Attenuates Cocaine‐Induced Behaviors In Mice
Authors: Kaushal Nidhi , Croom Caroline , Shaikh Jamaluddin , Narayanan Sanju , Mesangeau Christophe , Poupaert Jacques H , McCurdy Christopher R , Matsumoto Rae R
Published: June 2021

Cocaine is highly addictive and its abuse is involved in more emergency room visits than any other illicit drug. Unfortunately, there is no effective pharmacotherapy to treat it. Cocaine interacts with both sigma (σ)‐1 & 2 receptors. The role of σ‐1 receptors in attenuating cocaine‐induced behaviors has been established using pharmacological antagonists and antisense oligonucleotides. In contrast, the role of σ‐2 receptors in the treatment of cocaine abuse is unclear due to the lack of σ‐2 selective compounds. In the present study, radioligand and behavioral studies were conducted to characterize SN79, a putative σ‐2 selective compound. Radioligand binding studies showed that SN79 has nanomolar affinity for σ‐2 receptors and negligible affinity for σ‐1 receptors. In behavioral studies, pretreatment of male, Swiss Webster mice with SN79 (0.1–10 mg/kg) significantly attenuated the effects produced by a convulsive (70 mg/kg) or locomotor stimulant (20 mg/kg) dose of cocaine. SN79 also significantly blocked the development and expression of the sensitized response to subchronic treatment with cocaine. Alone, SN79 had sedative effects at acute higher doses, which disappeared upon repeated exposure. These results point towards the importance of targeting σ‐2 receptors in the development of an effective anti‐cocaine therapy, and also establish SN79 as the most σ‐2 selective compound to date.

(Support: DA013978, DA023205)