bluuebunny/crossref_metadata_2025 huggingface dataset:
Poor Sleep Quality and Functional Decline in Older Women
Authors: Spira Adam P. , Covinsky Kenneth , Rebok George W. , Punjabi Naresh M. , Stone Katie L. , Hillier Teresa A. , Ensrud Kristine E. , Yaffe Kristine
Published: June 2012

Objectives

To determine whether objectively measured sleep quality predicts 5‐year incident instrumental activity of daily living (IADL) impairment and decline in grip strength and gait speed in older women.

Design

Prospective cohort.

Setting

Participants' homes, Study of Osteoporotic Fractures sites.

Participants

Eight hundred seventeen women with a mean age of 82.4 at baseline.

Measurements

Participants completed 4.1 ± 0.7 nights of wrist actigraphy at baseline and measures of IADL impairment, grip strength, and gait speed at baseline and 5‐year follow‐up.

Results

After 5 years of follow‐up, approximately 41% of participants had incident impairment in one or more IADLs. The quartile of women with the shortest total sleep time (TST) had 93% greater odds of incident IADL impairment than the longest sleepers (adjusted odds ratio (AOR) = 1.93, 95% confidence interval (CI) = 1.25–2.97). Similarly, the quartile of women with the lowest sleep efficiency (SE) had 65% greater odds of impairment than those with the highest (AOR = 1.65, 95% CI = 1.06–2.57). Women in the shortest TST quartile had twice the odds of declining grip strength as those with the longest TST (AOR = 1.97, 95% CI = 1.17–3.32). Finally, women in the quartiles with the most wake after sleep onset (WASO) and the lowest SE had approximately 90% greater odds of grip strength decline than those with the least WASO (AOR = 1.90, 95% CI = 1.11–3.24) and SE (AOR = 1.92, 95% CI = 1.12–3.29).

Conclusion

Findings indicate that shorter sleep duration, greater WASO, and lower SE are risk factors for functional or physical decline in older women.
Nurse Staffing and Postsurgical Outcomes in Black Adults
Authors: Brooks Carthon J. Margo , Kutney‐Lee Ann , Jarrín Olga , Sloane Douglas , Aiken Linda H.
Published: June 2012

Objectives

To determine the association between nurse staffing and postsurgical outcomes for older black adults, including 30‐day mortality and failure to rescue.

Design

A cross‐sectional study of University of Pennsylvania Multi‐State Nursing Care and Patient Safety Survey data, linked to 2006–2007 administrative patient discharge data from four states (CA, PA, NJ, FL), American Hospital Association Annual Survey data, and a U.S. Census‐derived measure of socioeconomic status (SES). Risk‐adjusted logistic regression models with correction for clustering were used for the analysis.

Setting

Five hundred ninety‐nine adult nonfederal acute care hospitals in California, Pennsylvania, New Jersey, and Florida

Participants

Five hundred forty‐eight thousand three hundred ninety‐seven individuals ages 65 and older undergoing general, orthopedic, or vascular surgery (94% white, 6% black).

Measurements

Thirty‐day mortality and failure to rescue (death after a complication).

Results

In models adjusting for sex and age, 30‐day mortality was significantly higher for black than white participants (odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.32–1.52). In fully adjusted models that accounted for SES, surgery type, and comorbidities, as well as hospital characteristics, including nurse staffing, the odds of 30‐day mortality were not significantly different for black and white participants. In the fully adjusted models, one additional patient in the average nurse's workload was associated with higher odds of 30‐day mortality for all patients (OR = 1.03, 95% CI = 1.01–1.05). A significant interaction was found between race and nurse staffing for 30‐day mortality, such that blacks experienced higher odds of death with each additional patient per nurse (OR = 1.10, 95% CI = 1.03–1.18) compared to whites (OR = 1.03, 95% CI = 1.01–1.06). Similar patterns were detected in failure‐to‐rescue models.

Conclusion

Older surgical patients experience poorer postsurgical outcomes, including mortality and failure to rescue, when cared for by nurses with higher workloads. The effect of nurse staffing inadequacies is more significant in older black individuals.
Antimicrobial and Antioxidative Strategies to Reduce Pathogens and Extend the Shelf Life of Fresh Red Meats
Authors: Sun Xiang Dong , Holley Richard A.
Published: June 2012

Abstract: The shelf life of packaged fresh red meats is most frequently determined by the activity of microorganisms, which results in the development of off‐odors, gas, and slime, but it is also influenced by biochemical factors such as lipid radical chain and pigment oxidation causing undesirable flavors and surface discoloration. The predominant bacteria associated with spoilage of refrigerated meats arePseudomonas, Acinetobacter/Moraxella (Psychrobacter), Shewanella putrefaciens,lactic acid bacteria,Enterobacteriaceae,andBrochothrix thermosphacta. The spoilage potential of these organisms and factors influencing their impact on meat quality are discussed. High O2‐modified atmosphere (80% O2+ 20% CO2) packaging (MAP) is commonly used for meat retail display but vacuum packaging remains the major MAP method used for meat distribution. Two‐step master packaging (outer anoxic‐20% CO2+ 80% N2/inner gas‐permeable film) is used for centralized MAP distribution, but CO use (0.4%) in low O2packaging systems is limited by consumer uncertainty that CO may mask spoilage. Active packaging where the film contributes more than a gas/physical barrier is an important technology and has been studied widely. Its application in combination with MAP is very promising but impediments remain to its widespread industrial use. The influence of processing technologies including modified atmospheres on lipid oxidation and discoloration of meats are analyzed. Because both organic acids and antioxidants have been evaluated for their effects on microorganism growth, in concert with the prevention of lipid oxidation, work in this area is examined.
Oat Beta‐Glucan: Its Role in Health Promotion and Prevention of Diseases
Authors: Daou Cheickna , Zhang Hui
Published: June 2012

Abstract:  This article presents an overview of the recent advances into the health promoting potentials of oat β‐glucan. Oat β‐glucan (OβG) consists mainly of the linear polysaccharide (1→3), (1→4)‐β‐D‐glucan and is often called β‐glucan. This soluble oat fiber is able to attenuate blood postprandial glycemic and insulinemic responses, to lower blood total cholesterol and low‐density lipoprotein (LDL) cholesterol, and to improve high‐density lipoprotein (HDL) cholesterol and blood lipid profiles as well as to maintain body weight. Thus, OβG intake is beneficial in the prevention, treatment, and control of diabetes and cardiovascular diseases. In addition, OβG can stimulate immune functions by activating monocytes/macrophages and increasing the amounts of immunoglobulin, NK cells, killer T‐cells, and so on, which will improve resistance to cancer and infectious and parasitic diseases, as well as increase biological therapies and their prevention. All these health benefits of OβG may be explained by its physicochemical properties (such as viscosity, molecular weight) which can be affected by extraction methods and its behavior in gastrointestinal tract. Articles documenting these health benefits and effects are reviewed.
Understanding Autism: How Family Therapists Can Support Parents of Children with Autism Spectrum Disorders
Authors: Solomon Alexandra H. , Chung Beth
Published: June 2012

The number of children diagnosed with an Autism Spectrum Disorder has increased dramatically in the last 20 years. Parents of children with autism experience a variety of chronic and acute stressors that can erode marital satisfaction and family functioning. Family therapists are well‐suited to help parents stay connected to each other as they create a “new normal.” However, family therapists need updated information about autism, and they need to understand how family therapy can help parents of children with autism. Because having a child with autism affects multiple domains of family life, this paper explores how family therapists can utilize an integrative approach with parents, enabling them to flexibly work with the domains of action, meaning, and emotion.
In the Name of the Nation: Blood Symbolism and the Political Habitus of Violence in Haiti
Authors: Marcelin Louis Herns
Published: June 2012

ABSTRACT  Analysis of cultural categories such as personhood, family, and community, and the class of relations they imply, highlights how blood symbolism is paradigmatic in the production of social and political boundaries among Haitians. The principle that endows an individual or an individual's family with a social identity also functions as an exclusionary principle, allowing one to ritually, morally, and physically destroy rivals in the name of family, community, or nation. Drawing from research conducted in rural and urban Haiti as well as in the Haitian diaspora, this article explores how blood constitutes an organizing principle of the Haitian sociocultural universe. [blood symbolism, ritual of violence, Haiti and political habitus, anthropology of power and politics, witchcraft]

RÉSUMÉ L’analyse des catégories culturelles comme le sang, la personne, la famille, la communauté, et les relations qu’elles impliquent, souligne à quel point le symbolisme du sang est paradigmatique dans la production de frontières sociales et politiques entre les Haïtiens. Le principe qui confère une identité sociale à un individu ou sa famille fonctionne également comme principe d’exclusion, permettant rituellement, moralement, et physiquement de détruire les rivaux, au nom de la famille, communauté ou nation. Puisant des recherches menées en Haïti et la diaspora haïtienne, cet article explore comment le sang constitue un principe organisateur de l’univers socioculturel haïtien.
Anatomies of Relatedness: Considering Personhood in Aboriginal Australia
Authors: Glaskin Katie
Published: June 2012

ABSTRACT Anthropologists have described Aboriginal Australian personhood in various ways. In 1986, Myers spoke about the tension between autonomy and relatedness that he identified as intrinsic aspects of Pintupi identity. More recently, Keen (2006) has identified the extension of Yolngu persons in time and space; others have described Aboriginal personhood as “dividual.” Based on ethnography from the northwest Kimberley region of Western Australia, I argue that one way of characterizing personhood is as an ontology of embodied relatedness. In this, I draw inspiration from Ashforth's (2011) approach to relational realism, in which he extends the field of relations under consideration to entities beyond the human. I also consider Viveiros de Castro's (2009) synthesis of kinship, exchange, and magic to argue that the relationship between these can be understood through the embodied relationality that is at the core of cultural conceptions of the person. [personhood, Aboriginal Australia, relatedness, embodiment]
The Past of Sex, Gender, and Health: Bioarchaeology of the Aging Skeleton
Authors: Agarwal Sabrina C.
Published: June 2012

ABSTRACT Empirical studies of bone maintenance in archaeological populations show that patterns of bone loss do not constitute predictable consequences of aging, either on age or sex. Our understanding of aging and gender identity in the past usually is structured by determining the category of biological sex, which is almost always the first step of bioarchaeological analysis. But this categorization can obscure our analyses and limit the questions that we investigate. The patterns of bone loss observed in archaeological populations illuminate the process of forming the body during the lifetime and the biocultural nature of human tissue. The results provide bioarchaeologists with a model for how to see variation in the morphology of the bone and how to reconstruct age and gender identity in the past. [bioarchaeology, gender, bone loss, aging, osteoporosis]

ABSTRACTO Estudios empíricos del mantenimiento de hueso en poblaciones arqueológicos demuestran que patrones de la perdida de hueso no constituyan consecuencias predichas del envejecimiento, ya sean en relación del edad o del sexo. Nuestro entendimiento del envejecimiento y la identidad de género en el pasado por lo general es estructurado por la determinación de categorías del sexo biológico, casi siempre el primer paso de análisis bioarqueológico. Pero esta categorización puede oscurar nuestra análisis, y limitar las preguntas que investigamos. Las patrones de perdida de hueso observados en poblaciones arqueológicos iluminan el proceso de formación del cuerpo durante el curso de la vida, y la naturaleza biocultural de tejidos humanos. Los resultados proveen un modelo para como los bioarqueólogos podemos observar variación en la morfología del hueso, y como reconstruimos la edad y identidad de genero en el pasado.

ABSTRAITE Les études empiriques sur l’entretien des os dans les populations archéologiques montrent que les tendances de la perte osseuse ne constituent pas des conséquences prévisibles du vieillissement, que ce soit sur​l’âge ou le sexe. Notre compréhension du vieillissement et de l’identité de genre dans le passé est habituellement structurés en déterminant la catégorie de sexe biologique, presque toujours la première étape de l’analyse bios archéologiques. Mais cette catégorisation peut obscurcir notre analyse, et limiter les questions que nous étudions. Les motifs de la perte osseuse observée dans les populations archéologiques éclairer le processus de formation du corps pendant la durée de vie et de la nature bioculturelle de tissus humains. Les résultats fournissent un modèle pour bio‐archéologues la façon dont nous pouvons voir la variation dans la morphologie de l’os, et comment reconstruire l’âge et l’identité de genre dans le passé.
Divergent diving behavior during short and long trips of a bimodal forager, the little auk Alle alle
Authors: Brown Zachary W. , Welcker Jorg , Harding Ann M. A. , Walkusz Wojciech , Karnovsky Nina J.
Published: June 2012

The purpose of this study was to characterize for the first time seabird diving behavior during bimodal foraging. Little auks Alle alle, small zooplanktivorous Alcids of the High Arctic, have recently been shown to make foraging trips of short and long duration. Because short (ST) and long trips (LT) are thought to occur in different locations and serve different purposes (chick‐ and self‐feeding, respectively) we hypothesized that foraging differences would be apparent, both in terms of water temperature and diving characteristics. Using Time Depth Recorders (TDRs), we tested this hypothesis at three colonies along the Greenland Sea with contrasting oceanographic conditions. We found that diving behavior generally differed between ST and LT. However, the magnitude of the disparity in diving characteristics depended on local foraging conditions. At the study site where conditions were favorable, diving behavior differed only to a small degree between LT and ST. Together with a lack of difference in diving depth and ocean temperature, this indicates that these birds did not increase their foraging effort during ST nor did they travel long distances to seek out more profitable prey. In contrast, where local foraging conditions were poor, birds increased their diving effort substantially to collect a chick meal during ST as indicated by longer, more U‐shaped dives with slower ascent rates and shorter resting times (post‐dive intervals and extended surface pauses). In addition, large differences in diving depth and ocean temperature indicate that birds forage on different prey species and utilize different foraging areas during LT, which may be up to 200 km away from the colony. Continued warming and deteriorating near‐colony foraging conditions may have energetic consequences for little auks breeding in the eastern Greenland Sea.
Testosterone treatment can increase circulating carotenoids but does not affect yellow carotenoid‐based plumage colour in blue tits Cyanistes caeruleus
Authors: Peters Anne , Roberts Mark L. , Kurvers Ralf H. J. M. , Delhey Kaspar
Published: June 2012

A number of mechanisms are responsible for producing the variation in natural colours, and these need not act in isolation. A recent hypothesis states that carotenoid‐based coloration, in addition to carotenoid availability, is also enhanced by elevated levels of circulating testosterone (T). This has only been tested for carotenoid‐coloured bare parts in birds. We performed an experimental manipulation of T levels and examined the effects on the yellow carotenoid‐based breast plumage in captive yearling blue tits Cyanistes caeruleus, of which half received a diet supplemented with carotenoids. T treatment resulted in elevated plasma T compared to controls and carotenoid supplementation strongly increased plasma carotenoid levels. T treatment resulted in an additional increase in plasma carotenoid levels but only in the carotenoid‐supplemented males. Carotenoid supplementation resulted in more intense breast colour (carotenoid chroma), as expected. However, there was no effect of testosterone on plumage coloration at either dietary carotenoid level. Our results suggest that T can cause an increase in plasma carotenoid concentration, but that this does not necessarily lead to improved carotenoid‐based plumage coloration.
Effects of self‐efficacy on oral health behaviours and gingival health in university students aged 18‐ or 19‐years‐old
Authors: Mizutani Shinsuke , Ekuni Daisuke , Furuta Michiko , Tomofuji Takaaki , Irie Koichiro , Azuma Tetsuji , Kojima Azusa , Nagase Jun , Iwasaki Yoshiaki , Morita Manabu
Published: June 2012

Aim

Although self‐efficacy is known to affect various health‐related practises, few studies have clearly examined how self‐efficacy correlates with oral health behaviors or the oral health condition. We examined the relationship between gingivitis, oral health behaviors and self‐efficacy in university students.

Material & Methods

A total of 2,111 students (1,197 males, 914 females) aged 18 and 19 years were examined. The degree of gingivitis was expressed as the percentage of bleeding on probing (%BOP). Additional information was collected via a questionnaire regarding oral health behaviors (daily frequency of tooth‐brushing, use of dental floss and regular check‐up). Self‐efficacy was assessed using the Self‐Efficacy Scale for Self‐care (SESS). Path analysis was used to test pathways from self‐efficacy to oral health behaviors and %BOP.

Results

In the final structural model, self‐efficacies were related to each other, and they affected oral health behaviors. Good oral health behaviors reduced dental plaque and calculus, and lower levels of dental plaque and calculus resulted in lower %BOP.

Conclusion

Higher self‐efficacy correlated with better oral health behaviours and gingival health in university students. Improving self‐efficacy may be beneficial for maintaining good gingival health in university students. To prevent gingivitis, the approach of enhancing self‐efficacy in university students would be useful.
People Smugglers, Statistics and Bone Age
Authors: Cole Tim
Published: June 2012

Desperate voyages, exploitation, naval interceptions and jailings … Who would guess that an obscure 50-year-old medical textbook about bone age in children would become the subject of statistical controversy in court cases about people smuggling across Australia?Tim Cole tells the story of how it happened.
A Thing of Beauty
Authors: O'Hagan Tony
Published: June 2012

Tony O'Hagan finds his favourite formula beautifully resolves an old statistical paradox.
Cloning, expression and biocharacterization of OfCht5, the chitinase from the insect Ostrinia furnacalis
Authors: Wu Qingyue , Liu Tian , Yang Qing
Published: June 2012

Abstract  Chitinase catalyzes β‐1,4‐glycosidic linkages in chitin and has attracted research interest due to it being a potential pesticide target and an enzymatic tool for preparation of N‐acetyl‐β‐D‐glucosamine. An individual insect contains multiple genes encoding chitinases, which vary in domain architectures, expression patterns, physiological roles and biochemical properties. Herein, OfCht5, the glycoside hydrolase family 18 chitinase from the widespread lepidopteran pest Ostrinia furnacalis, was cloned, expressed in the yeast Pichia pastoris and biochemically characterized in an attempt to facilitate both pest control and biomaterial preparation. Complementary DNA sequence analysis indicated that OfCHT5 consisted of an open reading frame of 1 665‐bp nucleotides. Phylogenic analysis suggested OfCht5 belongs to the Group I insect chitinases. Expression of OfCht5 in Pichia pastoris resulted in highest specific activity after 120 h of induction with methanol. Through two steps of purification, consisting of ammonium sulfate precipitation and metal chelating chromatography, about 7 mg of the recombinant OfCht5 was purified to homogeneity from 1 L culture supernatant. OfCht5 effectively converted colloidal chitin into chitobiose, but had relatively low activity toward α‐chitin. When chitooligosaccharides [(GlcNAc)n, n= 3–6] were used as substrates, OfCht5 was observed to possess the highest catalytic efficiency parameter toward (GlcNAc)4 and predominantely hydrolyzed the second glycosidic bond from the non‐reducing end. Together with β‐N‐acetyl‐D‐hexosaminidase OfHex1, OfCht5 achieved its highest efficiency in chitin degradation that yielded N‐acetyl‐β‐D‐glucosamine, a valuable pharmacological reagent and food supplement, within a molar concentration ratio of OfCht5 versus OfHex1 in the range of 9 : 1–15 : 1. This work provides an alternative to existing preparation of chitinase for pesticides and other applications.
Subclinical leishmaniasis associated with infertility and chronic prostatitis in a dog
Authors: Mir F. , Fontaine E. , Reyes‐Gomez E. , Carlus M. , Fontbonne A.
Published: June 2012

A stud dog was presented for acquired infertility. Haematospermia and teratozoospermia were found on two ejaculates 2 weeks apart. A presumptive diagnosis of prostatitis was made follo‐wing ultrasound examination. An ultrasound‐guided needle core biopsy was performed under general anaesthesia, revealing a mild chronic macrophagic and plasma cell prostatitis with intracytoplasmic amastigotes consistent withLeishmaniaspp. infection. Presence ofLeishmania infantum, Leishmania donovaniorLeishmania chagasiwas confirmed by polymerase chain reaction in seminal plasma. Serology and serum protein electrophoresis confirmed the diagnosis of a subclinical active systemic leishmaniasis. A meglumine antimoniate and allopurinol treatment was given which clearly improved within 3 months both general condition and the quality of sperm. To the authors’ knowledge, this is the first reported case of a prostatitis secondary to aLeishmaniaspp. infection. Subclinical systemic leishmaniasis should be considered in the differential diagnosis of infertility in dogs suffering from semen alterations.
Tight Junction in Blood‐Brain Barrier: An Overview of Structure, Regulation, and Regulator Substances
Authors: Liu Wei‐Ye , Wang Zhi‐Bin , Zhang Li‐Chao , Wei Xin , Li Ling
Published: June 2012

Blood‐brain barrier (BBB) is a dynamic interference that regulates the nutrition and toxic substance in and out of the central nervous system (CNS), and plays a crucial role in maintaining a stable circumstance of the CNS. Tight junctions among adjacent cells form the basic structure of BBB to limiting paracellular permeability. In the present review, the constituents of tight junction proteins are depicted in detail, together with the regulation of tight junction under stimulation and in pathological conditions. Tight junction modulators are also discussed.
Sympathetic activation during early pregnancy in humans
Authors: Jarvis Sara S. , Shibata Shigeki , Bivens Tiffany B. , Okada Yoshiyuki , Casey Brian M. , Levine Benjamin D. , Fu Qi
Published: June 2012

Key points

Sympathetic activity has been reported to increase in normotensive pregnant women, and to be even greater in women with gestational hypertension and preeclampsia at term.

Whether sympathetic overactivity develops early during pregnancy, remaining high throughout gestation, or whether it only occurs at term providing the substrate for hypertensive disorders is unknown.

We found that vasomotor sympathetic activity was markedly greater, diastolic pressure trended lower, total peripheral resistance decreased, sympathetic vascular transduction was blunted, and renin and aldosterone both were higher during early pregnancy (i.e. ≤8 weeks of gestation) than pre‐pregnancy.

It is suggested that sympathetic activation is a common characteristic of early pregnancy in normotensive women.

These results help us better understand blood pressure control mechanisms during normal pregnancy in humans.

Abstract  Sympathetic activity has been reported to increase in normotensive pregnant women, and to be even greater in women with gestational hypertension and preeclampsia at term. Whether sympathetic overactivity develops early during pregnancy, remaining high throughout gestation, or whether it only occurs at term providing the substrate for hypertensive disorders is unknown. We tested the hypothesis that sympathetic activation occurs early during pregnancy in humans. Eleven healthy women (29 ± 3 (SD) years) without prior hypertensive pregnancies were tested during the mid‐luteal phase (PRE) and early pregnancy (EARLY; 6.2 ± 1.2 weeks of gestation). Muscle sympathetic nerve activity (MSNA) and haemodynamics were measured supine, at 30 deg and 60 deg upright tilt for 5 min each. Blood samples were drawn for catecholamines, direct renin, and aldosterone. MSNA was significantly greater during EARLY than PRE (supine: 25 ± 8 vs. 14 ± 8 bursts min−1, 60 deg tilt: 49 ± 14 vs. 40 ± 10 bursts min−1; main effect, P < 0.05). Resting diastolic pressure trended lower (P= 0.09), heart rate was similar, total peripheral resistance decreased (2172 ± 364 vs. 2543 ± 352 dyne s cm−5; P < 0.05), sympathetic vascular transduction was blunted (0.10 ± 0.05 vs. 0.36 ± 0.47 units a.u.−1 min−1; P < 0.01), and both renin (supine: 27.9 ± 6.2 vs. 14.2 ± 8.7 pg ml−1, P < 0.01) and aldosterone (supine: 16.7 ± 14.1 vs. 7.7 ± 6.8 ng ml−1, P= 0.05) were higher during EARLY than PRE. These results suggest that sympathetic activation is a common characteristic of early pregnancy in humans despite reduced diastolic pressure and total peripheral resistance. These observations challenge conventional thinking about blood pressure regulation during pregnancy, showing marked sympathetic activation occurring within the first few weeks of conception, and may provide the substrate for pregnancy induced cardiovascular complications.
Nitric oxide formation versus scavenging: the red blood cell balancing act
Authors: Owusu Benjamin Y. , Stapley Ryan , Patel Rakesh P.
Published: June 2012

Abstract  Nitric oxide (NO) is a key modulator of vascular homeostasis controlling critical functions related to blood flow, respiration, cell death and proliferation, and protecting the vasculature from pro‐inflammatory and coagulative stresses. Inhibition of NO formation, and/or diversion of NO away from its physiological signalling targets lead to dysregulated NO bioavailability, a hallmark of numerous vascular and pulmonary diseases. Current concepts suggest that the balance between NO formation and NO scavenging is critical in disease development, with the corollary being that redressing the balance offers a target for therapeutic intervention. Evidence presented over the last two decades has seen red blood cells (RBCs) and haemoglobin specifically emerge as prominent effectors in this paradigm. In this symposium review article, we discuss recent insights into the mechanisms by which RBCs may modulate the balance between NO‐formation and inhibition. We discuss how these mechanisms may become dysfunctional to cause disease, highlight key questions that remain, and discuss the potential impact of these insights on therapeutic opportunities.
Hypertension is critically dependent on the carotid body input in the spontaneously hypertensive rat
Authors: Abdala Ana P. , McBryde Fiona D. , Marina Nephtali , Hendy Emma B. , Engelman Zoar J. , Fudim Marat , Sobotka Paul A. , Gourine Alexander V. , Paton Julian F. R.
Published: June 2012

Key points

Peripheral chemoreflex sensitivity is enhanced in hypertension yet the role of these receptors in the development and maintenance of high blood pressure remains unknown.

Carotid chemoreceptors were denervated in both young and adult spontaneously hypertensive rats (SHRs) by sectioning the carotid sinus nerves bilaterally while recording arterial blood pressure chronically using radio telemetry.

Carotid sinus denervation (CSD) in the young animals prevented arterial pressure from reaching the hypertensive levels observed in sham‐operated animals whereas in adult SHRs arterial pressure fell by ∼20 mmHg.

After CSD there was a decrease in sympathetic activity, measured indirectly using power spectral analysis and hexamethonium, and an improvement in baroreceptor reflex gain.

Carotid bodies are active in the SHR and contribute to both the development and maintenance of hypertension; whether carotid body ablation is a useful anti‐hypertensive intervention in drug‐resistant hypertensive patients remains to be resolved.

Abstract  The peripheral chemoreflex is known to be enhanced in individuals with hypertension. In pre‐hypertensive (PH) and adult spontaneously hypertensive rats (SHRs) carotid body type I (glomus) cells exhibit hypersensitivity to chemosensory stimuli and elevated sympathoexcitatory responses to peripheral chemoreceptor stimulation. Herein, we eliminated carotid body inputs in both PH‐SHRs and SHRs to test the hypothesis that heightened peripheral chemoreceptor activity contributes to both the development and maintenance of hypertension. The carotid sinus nerves were surgically denervated under general anaesthesia in 4‐ and 12‐week‐old SHRs. Control groups comprised sham‐operated SHRs and aged‐matched sham‐operated and carotid sinus nerve denervated Wistar rats. Arterial blood pressure was recorded chronically in conscious, freely moving animals. Successful carotid sinus nerve denervation (CSD) was confirmed by testing respiratory responses to hypoxia (10% O2) or cardiovascular responses to i.v. injection of sodium cyanide. In the SHR, CSD reduced both the development of hypertension and its maintenance (P < 0.05) and was associated with a reduction in sympathetic vasomotor tone (as revealed by frequency domain analysis and reduced arterial pressure responses to administration of hexamethonium; P < 0.05 vs. sham‐operated SHR) and an improvement in baroreflex sensitivity. No effect on blood pressure was observed in sham‐operated SHRs or Wistar rats. In conclusion, carotid sinus nerve inputs from the carotid body are, in part, responsible for elevated sympathetic tone and critical for the genesis of hypertension in the developing SHR and its maintenance in later life.
Microstructure, phase transition, and interfacial chemistry of Gd2O3/Si(111) grown by electron-beam physical vapor deposition
Authors: Weng Xiaojun , Grave Daniel A. , Hughes Zachary R. , Wolfe Douglas E. , Robinson Joshua A.
Published: June 2012

The effects of growth temperature, film thickness, and oxygen flux on the microstructure, phase transition, and interfacial chemistry of gadolinium oxide (Gd2O3) films grown on Si(111) substrates by electron-beam physical vapor deposition were investigated using a combination of transmission electron microscopy (TEM), electron diffraction, scanning TEM, x-ray energy dispersive spectrometry, and electron energy loss spectrometry. The authors find that a low growth temperature (250 °C) and a high oxygen flux (200 sccm) led to a small grain size and a high porosity of the Gd2O3 film. Lowering the oxygen flux to 50 sccm led to reduced film porosity, presumably due to the increased diffusion length of the Gd atoms on the surface. Increasing the growth temperature to 650 °C resulted in a film with large columnar grains and elongated pores at the grain boundaries. Thin films grown at 250 °C consisted of cubic Gd2O3, but thermodynamically less stable monoclinic phase formed as the film thickness increased. Lowering the oxygen flux apparently further promoted the formation of the monoclinic phase. Furthermore, monoclinic phase dominated in the films grown at 650 °C. Such phase transitions may be related to the stress evolution of the films at different temperatures, thicknesses, and oxygen fluxes. Enhanced Gd2O3/Si interfacial reaction was observed as the growth temperature, film thickness, and oxygen flux increased. Moreover, oxygen was found to play a crucial role in the Gd2O3/Si interfacial reaction and the formation of Gd-Si-O interface layers, which proceeded by the reaction of excess oxygen with Si followed by the intermixing of SiOx and Gd2O3.
Characterization of Polymyxin B-Induced Nephrotoxicity: Implications for Dosing Regimen Design
Authors: Abdelraouf Kamilia , Braggs Kirk H. , Yin Taijun , Truong Luan D. , Hu Ming , Tam Vincent H.
Published: June 2012

The increasing prevalence of multidrug-resistant Gram-negative infections has led to renewed interest in the use of systemic polymyxin B. However, the nephrotoxic properties of polymyxin B are still poorly understood. The objective of this study was to characterize nephrotoxicity associated with polymyxin B, with an emphasis on examining the impact of dosing frequencies on the onset of nephrotoxicity. Sprague-Dawley rats were divided into two groups and administered the same total daily dose of polymyxin B subcutaneously but with different dosing frequencies (either 20 mg/kg of body weight every 24 h [q24h] or 5 mg/kg q6h). Drug concentrations in renal tissue were compared between the two groups at 24 h. Kidney tissues were harvested at 48 h and compared histologically. Serum creatinine was measured daily for up to 10 days, and nephrotoxicity was defined as a significant elevation in serum creatinine (≥2× baseline). Kaplan-Meier analysis was used to compare the onset of nephrotoxicity. Polymyxin B-induced nephrotoxicity manifested as elevation in serum creatinine and acute tubular necrosis. Extensive injury of the proximal tubules was observed. The lesions were more severe and higher drug concentrations were achieved in the kidneys of the q6h dosing group. The q24h dosing group experienced a more gradual onset of nephrotoxicity, which could be attributed to the lower kidney tissue drug concentrations (48.5 ± 17.4 μg/g versus 92.1 ± 18.1 μg/g of polymyxin B1,P= 0.04). Preferential accumulation of polymyxin B in the kidneys suggests that uptake to renal cells is a nonpassive process and q24h dosing was less nephrotoxic than q6h dosing.
Anti-Helicobacter pylori Potential of Artemisinin and Its Derivatives
Authors: Goswami Suchandra , Bhakuni Rajendra S. , Chinniah Annalakshmi , Pal Anirban , Kar Sudip K. , Das Pratap K.
Published: June 2012

The antimalarial drug artemisinin fromArtemisia annuademonstrated remarkably strong activity againstHelicobacter pylori, the pathogen responsible for peptic ulcer diseases. In an effort to develop a novel antimicrobial chemotherapeutic agent containing such a sesquiterpene lactone endoperoxide, a series of analogues (2 natural and 15 semisynthetic molecules), including eight newly synthesized compounds, were investigated against clinical and standard strains ofH. pylori. The antimicrobial spectrum against 10H. pyloristrains and a few other bacterial and fungal strains indicated specificity against the ulcer causing organism. Of five promising molecules, a newly synthesized ether derivative β-artecyclopropylmether was found to be the most potent compound, which exhibited MIC range, MIC90, and minimum bactericidal concentration range values of 0.25 to 1.0 μg/ml, 1.0 μg/ml, and 1 to 16 μg/ml, respectively, against both resistant and sensitive strains ofH. pylori. The molecule demonstrated strong bactericidal kinetics with extensive morphological degeneration, retained functional efficacy at stomach acidic pH unlike clarithromycin, did not elicit drug resistance unlike metronidazole, and imparted sensitivity to resistant strains. It is not cytotoxic and exhibitsin vivopotentiality to reduce theH. pyloriburden in a chronic infection model. Thus, β-artecyclopropylmether could be a lead candidate for anti-H. pyloritherapeutics. Since the recurrence of gastroduodenal ulcers is believed to be mainly due to antibiotic resistance of the commensal organismH. pylori, development of a candidate drug from this finding is warranted.
Infection Dynamics and Response to Chemotherapy in a Rabbit Model of Tuberculosis using [
18
F]2-Fluoro-Deoxy-
d
-Glucose Positron Emission Tomography and Computed Tomography
Authors: Via Laura E. , Schimel Dan , Weiner Danielle M. , Dartois Veronique , Dayao Emmanuel , Cai Ying , Yoon Young-Soon , Dreher Matthew R. , Kastenmayer Robin J. , Laymon Charles M. , Carny J. Eoin , Flynn JoAnne L. , Herscovitch Peter , Barry Clifton E.
Published: June 2012

With a host of new antitubercular chemotherapeutics in development, methods to assess the activity of these agents beyond mouse efficacy are needed to prioritize combinations for clinical trials. Lesions in
Mycobacterium tuberculosis
-infected rabbits are hypoxic, with histopathologic features that closely resemble those of human tuberculous lesions. Using [
18
F]2-fluoro-deoxy-
d
-glucose ([
18
F]FDG) positron emission tomography–computed tomography (PET-CT) imaging, we studied the dynamics of tuberculosis infection in rabbits, revealing an initial inflammatory response followed by a consolidative chronic disease. Five weeks after infection, as much as 23% of total lung volume was abnormal, but this was contained and to some extent reversed naturally by 9 weeks. During development of this chronic state, individual lesions in the same animal had very different fates, ranging from complete resolution to significant progression. Lesions that remained through the initial stage showed an increase in volume and tissue density over time by CT. Initiation of chemotherapy using either isoniazid (INH) or rifampin (RIF) during chronic infection reduced bacterial load with quantitative changes in [
18
F]FDG uptake, lesion density and total lesion volume measured by CT. The [
18
F]FDG PET uptake in lesions was significantly reduced with as little as 1 week of treatment, while the volume and density of lesions changed more slowly. The results from this study suggest that rabbits may be a useful surrogate species for evaluating novel chemotherapies and understanding changes in both PET and CT scans in human clinical trials.
Bifunctional CD4–DC-SIGN Fusion Proteins Demonstrate Enhanced Avidity to gp120 and Inhibit HIV-1 Infection and Dissemination
Authors: Du Tao , Hu Kai , Yang Jun , Jin Jing , Li Chang , Stieh Daniel , Griffin George E. , Shattock Robin J. , Hu Qinxue
Published: June 2012

Early stages of mucosal infection are potential targets for HIV-1 prevention. CD4 is the primary receptor in HIV-1 infection whereas DC-SIGN likely plays an important role in HIV-1 dissemination, particularly during sexual transmission. To test the hypothesis that an inhibitor simultaneously targeting both CD4 and DC-SIGN binding sites on gp120 may provide a potent anti-HIV strategy, we designed constructs by fusing the extracellular CD4 and DC-SIGN domains together with varied arrangements of the lengths of CD4, DC-SIGN and the linker. We expressed, purified and characterized a series of soluble CD4-linker–DC-SIGN (CLD) fusion proteins. Several CLDs, composed of a longer linker and an extra neck domain of DC-SIGN, had enhanced affinity for gp120 as evidenced by molecular-interaction analysis. Furthermore, such CLDs exhibited significantly enhanced neutralization activity against both laboratory-adapted and primary HIV-1 isolates. Moreover, CLDs efficiently inhibited HIV-1 infection in
trans
via a DC-SIGN-expressing cell line and primary human dendritic cells. This was further strengthened by the results from the human cervical explant model, showing that CLDs potently prevented both localized and disseminated infections. This is the first time that soluble DC-SIGN-based bifunctional proteins have demonstrated anti-HIV potency. Our study provides proof of the concept that targeting both CD4 and DC-SIGN binding sites on gp120 represents a novel antiviral strategy. Given that DC-SIGN binding to gp120 increases exposure of the CD4 binding site and that the soluble forms of CD4 and DC-SIGN occur
in vivo
, further improvement of CLDs may render them potentially useful in prophylaxis or therapeutics.
Understanding the Molecular Determinants of Substrate and Inhibitor Specificities in the Carbapenemase KPC-2: Exploring the Roles of Arg220 and Glu276
Authors: Papp-Wallace Krisztina M. , Taracila Magdalena A. , Smith Kerri M. , Xu Yan , Bonomo Robert A.
Published: June 2012

β-Lactamases are important antibiotic resistance determinants expressed by bacteria. By studying the mechanistic properties of β-lactamases, we can identify opportunities to circumvent resistance through the design of novel inhibitors. Comparative amino acid sequence analysis of class A β-lactamases reveals that many enzymes possess a localized positively charged residue (e.g., R220, R244, or R276) that is critical for interactions with β-lactams and β-lactamase inhibitors. To better understand the contribution of these residues to the catalytic process, we explored the roles of R220 and E276 in KPC-2, a class A β-lactamase that inactivates carbapenems and β-lactamase inhibitors. Our study reveals that substitutions at R220 of KPC-2 selectively impact catalytic activity toward substrates (50% or greater reduction in
k
cat
/

K
m

). In addition, we find that residue 220 is central to the mechanism of β-lactamase inhibition/inactivation. Among the variants tested at Ambler position 220, the R220K enzyme is relatively “inhibitor susceptible” (

K
i

of 14 ± 1 μM for clavulanic acid versus

K
i

of 25 ± 2 μM for KPC-2). Specifically, the R220K enzyme is impaired in its ability to hydrolyze clavulanic acid compared to KPC-2. In contrast, the R220M substitution enzyme demonstrates increased

K
m

values for β-lactamase inhibitors (>100 μM for clavulanic acid versus 25 ± 3 μM for the wild type [WT]), which results in inhibitor resistance. Unlike other class A β-lactamases (i.e., SHV-1 and TEM-1), the amino acid present at residue 276 plays a structural rather than kinetic role with substrates or inhibitors. To rationalize these findings, we constructed molecular models of clavulanic acid docked into the active sites of KPC-2 and the “relatively” clavulanic acid-susceptible R220K variant. These models suggest that a major 3.5-Å shift occurs of residue E276 in the R220K variant toward the active S70 site. We anticipate that this shift alters the shape of the active site and the positions of two key water molecules. Modeling also suggests that residue 276 may assist with the positioning of the substrate and inhibitor in the active site. These biochemical and molecular modeling insights bring us one step closer to understanding important structure-activity relationships that define the catalytic and inhibitor-resistant profile of KPC-2 and can assist the design of novel compounds.
Identification of Signaling Pathways Mediating Cell Cycle Arrest and Apoptosis Induced by Porphyromonas gingivalis in Human Trophoblasts
Authors: Inaba Hiroaki , Kuboniwa Masae , Sugita Hideyuki , Lamont Richard J. , Amano Atsuo
Published: June 2012

Epidemiological and interventional studies of humans have revealed a close association between periodontal diseases and preterm delivery of low-birth-weight infants.
Porphyromonas gingivalis
, a periodontal pathogen, can translocate to gestational tissues following oral-hematogenous spread. We previously reported that
P. gingivalis
invades extravillous trophoblast cells (HTR-8) derived from the human placenta and inhibits proliferation through induction of arrest in the G
1
phase of the cell cycle. The purpose of the present study was to identify signaling pathways mediating cellular impairment caused by
P. gingivalis
. Following
P. gingivalis
infection, the expression of Fas was induced and p53 accumulated, responses consistent with response to DNA damage. Ataxia telangiectasia- and Rad3-related kinase (ATR), an essential regulator of DNA damage checkpoints, was shown to be activated together with its downstream signaling molecule Chk2, while the p53 degradation-related protein MDM2 was not induced. The inhibition of ATR prevented both G
1
arrest and apoptosis caused by
P. gingivalis
in HTR-8 cells. In addition, small interfering RNA (siRNA) knockdown of p53 abrogated both G
1
arrest and apoptosis. The regulation of apoptosis was associated with Ets1 activation. HTR-8 cells infected with
P. gingivalis
exhibited activation of Ets1, and knockdown of Ets1 with siRNA diminished both G
1
arrest and apoptosis. These results suggest that
P. gingivalis
activates cellular DNA damage signaling pathways that lead to G
1
arrest and apoptosis in trophoblasts.
Role of Lipid Rafts and Flagellin in Invasion of Colonic Epithelial Cells by Shiga-Toxigenic Escherichia coli O113:H21
Authors: Rogers Trisha J. , Thorpe Cheleste M. , Paton Adrienne W. , Paton James C.
Published: June 2012

Shiga-toxigenic
Escherichia coli
(STEC) O113:H21 strains that lack the locus of enterocyte effacement (LEE) efficiently invade eukaryotic cells
in vitro
, unlike LEE-positive O157:H7 strains. We used a
fliC
deletion mutant of the O113:H21 STEC strain 98NK2 (98NK2Δ
fliC
) to show that invasion of colonic epithelial (HCT-8) cells is heavily dependent on production of flagellin, even though adherence to the cells was actually enhanced in the mutant. Flagellin binds and signals through Toll-like receptor 5 (TLR5), but there was no evidence that either TLR5, the adaptor protein myeloid differentiation primary response gene 88 (MyD88), or the serine kinase interleukin-1 receptor-associated kinase (IRAK) were required for invasion of HCT-8 cells by strain 98NK2, as judged by transfection, RNA knockdown, or inhibitor studies. However, pretreatment of cells with anti-asialo-GM1 significantly decreased 98NK2 invasion (by 40.8%), while neuraminidase treatment (which cleaves terminal sialic acid residues, thus converting GM1 into asialo-GM1) significantly increased invasion (by 70.7%). Pretreatment of HCT-8 cells with either the cholesterol-depleting agent methyl-β-cyclodextrin (MβCD) or the tyrosine kinase inhibitor genistein significantly decreased invasion by 98NK2, indicating a potential role for lipid rafts in the invasion mechanism. Confocal microscopy also showed invading 98NK2 colocalized with lipid raft markers caveolin-1 and GM1. Interestingly, anti-asialo-GM1, neuraminidase, MβCD, and genistein have similar effects on the vestigial level of STEC invasion seen for STEC strain 98NK2Δ
fliC
, indicating that lipid rafts mediate a common step in flagellin-dependent and flagellin-independent cellular invasion.