bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Fibrillin‐3 and Transcription Factor‐7‐Like 2 Gene Variants With Metabolic Phenotypes in PCOS
Authors: Yalamanchi Sudha K. , Sam Susan , Cardenas Maria O. , Holaday Louisa W. , Urbanek Margrit , Dunaif Andrea
Published: February 2012

Polycystic ovary syndrome (PCOS) is a complex genetic disease characterized by heritable reproductive and metabolic abnormalities. Genetic variants associated with the reproductive phenotype have been mapped to the fibrillin‐3 (FBN3) gene and to a novel transcription factor‐7‐like 2 (TCF7L2) locus (rs11196236 G). The association of these genetic variants with metabolic phenotypes was investigated in 31 PCOS and 18 control women of European ancestry. The insulinogenic index during an oral glucose tolerance test (ΔI30/ΔG30) and insulin secretion rates at the maximal dose during a graded‐glucose infusion (ISRmax) were used as indexes of insulin secretion. Endogenous glucose production (EGP) and insulin sensitivity (M/I) were determined during a euglycemic clamp. The disposition index (DI) was calculated using M/I and ΔI30/ΔG30 or ISRmax. Compared with noncarriers (n = 10) and control (n = 10), M/I was decreased (P = 1.1 × 10−5) in heterozygous and homozygous PCOS carriers (n = 14) of rs11196236 G and this variant predicted M/I (partial r2 = 0.34, P = 0.005) in a regression analysis. Postabsorptive EGP tended to be higher (P = 0.040) in heterozygous and homozygous PCOS carriers of the FBN3‐associated allele (n = 12), allele 8 of D19S884 (FBN3+), compared to PCOS noncarriers (n = 19). PCOS carriers of the rs12255372 T (TCF7L2 Caucasian type 2 diabetes mellitus (T2D) locus) had no significant associated metabolic phenotypes. We conclude that rs11196236 G TCF7L2 variant is associated with peripheral insulin resistance in PCOS but this effect is not seen in control women. The FBN3 risk allele may be associated with changes in basal glucose homeostasis in PCOS. These findings require replication in additional PCOS cohorts.
Cytosolic Ca2+ regulates the energization of isolated brain mitochondria by formation of pyruvate through the malate–aspartate shuttle
Authors: Gellerich Frank Norbert , Gizatullina Zemfira , Trumbekaite Sonata , Korzeniewski Bernard , Gaynutdinov Timur , Seppet Enn , Vielhaber Stefan , Heinze Hans-Jochen , Striggow Frank
Published: February 2012

The glutamate-dependent respiration of isolated BM (brain mitochondria) is regulated by Ca2+cyt (cytosolic Ca2+) (S0.5=225±22 nM) through its effects on aralar. We now also demonstrate that the α-glycerophosphate-dependent respiration is controlled by Ca2+cyt (S0.5=60±10 nM). At higher Ca2+cyt (>600 nM), BM accumulate Ca2+ which enhances the rate of intramitochondrial dehydrogenases. The Ca2+-induced increments of state 3 respiration decrease with substrate in the order glutamate>α-oxoglutarate>isocitrate>α-glycerophosphate>pyruvate. Whereas the oxidation of pyruvate is only slightly influenced by Ca2+cyt, we show that the formation of pyruvate is tightly controlled by Ca2+cyt. Through its common substrate couple NADH/NAD+, the formation of pyruvate by LDH (lactate dehydrogenase) is linked to the MAS (malate–aspartate shuttle) with aralar as a central component. A rise in Ca2+cyt in a reconstituted system consisting of BM, cytosolic enzymes of MAS and LDH causes an up to 5-fold enhancement of OXPHOS (oxidative phosphorylation) rates that is due to an increased substrate supply, acting in a manner similar to a ‘gas pedal’. In contrast, Ca2+mit (intramitochondrial Ca2+) regulates the oxidation rates of substrates which are present within the mitochondrial matrix. We postulate that Ca2+cyt is a key factor in adjusting the mitochondrial energization to the requirements of intact neurons.
Perception of Surface Glossiness by Infants Aged 5 to 8 Months
Authors: Yang Jiale , Otsuka Yumiko , Kanazawa So , Yamaguchi Masami K , Motoyoshi Isamu
Published: February 2012

We examined glossiness perception in infants using a preferential looking paradigm. In experiment 1, the images of two doll-shaped objects with matte and glossy surfaces were presented to infants aged 5 to 6 and 7 to 8 months. The results showed that the 7 to 8 month olds, but not the 5 to 6 month olds, looked significantly longer at the glossy object than at the matte object. In experiment 2, we additionally employed an object that was matte and covered with textures of white paint splashes, whose luminance histogram was almost identical to that of the glossy object. The results showed that the 7 to 8 month old infants could discriminate between the glossy object and the textured object even though both had similar luminance histograms. Qualitatively similar results were obtained for simple spheres that did not contain facial features. Therefore, the results of experiments 1 and 2 were not due to differences in the visibility of the dolls' facial features. These findings suggest that 7 to 8 month old infants perceive difference between glossy objects and matte objects on the basis of surface representations.
Uterine distension differentially affects remodelling and distensibility of the uterine vasculature in non-pregnant rats
Authors: Osol George , Barron Carolyn , Mandalà Maurizio
Published: February 2012

During pregnancy the mammalian uterine circulation undergoes significant expansive remodelling necessary for normal pregnancy outcome. The underlying mechanisms are poorly defined. The goal of this study was to test the hypothesis that myometrial stretch actively stimulates uterine vascular remodelling by developing a new surgical approach to induce unilateral uterine distension in non-pregnant rats. Three weeks after surgery, which consisted of an infusion of medical-grade silicone into the uterine lumen, main and mesometrial uterine artery and vein length, diameter and distensibility were recorded. Radial artery diameter, distensibility and vascular smooth muscle mitotic rate (Ki67 staining) were also measured. Unilateral uterine distension resulted in significant increases in the length of main uterine artery and vein and mesometrial segments but had no effect on vessel diameter or distensibility. In contrast, there were significant increases in the diameter of the radial arteries associated with the distended uterus. These changes were accompanied by reduced arterial distensibility and increased vascular muscle hyperplasia. In summary, this is the first report to show that myometrial stretch is a sufficient stimulus to induce significant remodelling of uterine vessels in non-pregnant rats. Moreover, the results indicate differential regulation of these growth processes as a function of vessel size and type.
Mineralogical effects on the detectability of the postperovskite boundary
Authors: Grocholski Brent , Catalli Krystle , Shim Sang-Heon , Prakapenka Vitali
Published: February 2012

The discovery of a phase transition in Mg-silicate perovskite (Pv) to postperovskite (pPv) at lowermost mantle pressure-temperature (
P
 - 
T
) conditions may provide an explanation for the discontinuous increase in shear wave velocity found in some regions at a depth range of 200 to 400 km above the core-mantle boundary, hereafter the D
′′
discontinuity. However, recent studies on binary and ternary systems showed that reasonable contents of Fe
2+
and Al for pyrolite increase the thickness (width of the mixed phase region) of the Pv - pPv boundary (400–600 km) to much larger than the D
′′
discontinuity (≤ 70 km). These results challenge the assignment of the D
′′
discontinuity to the Pv - pPv boundary in pyrolite (homogenized mantle composition). Furthermore, the mineralogy and composition of rocks that can host a detectable Pv → pPv boundary are still unknown. Here we report in situ measurements of the depths and thicknesses of the Pv → pPv transition in multiphase systems (San Carlos olivine, pyrolitic, and midocean ridge basaltic compositions) at the
P
 - 
T
conditions of the lowermost mantle, searching for candidate rocks with a sharp Pv - pPv discontinuity. Whereas the pyrolitic mantle may not have a seismologically detectable Pv → pPv transition due to the effect of Al, harzburgitic compositions have detectable transitions due to low Al content. In contrast, Al-rich basaltic compositions may have a detectable Pv - pPv boundary due to their distinct mineralogy. Therefore, the observation of the D
′′
discontinuity may be related to the Pv → pPv transition in the differentiated oceanic lithosphere materials transported to the lowermost mantle by subducting slabs.
Entropic origin of Mg
2+
-facilitated RNA folding
Authors: Fiore Julie L. , Holmstrom Erik D. , Nesbitt David J.
Published: February 2012

Mg
2+
is essential for the proper folding and function of RNA, though the effect of Mg
2+
concentration on the free energy, enthalpy, and entropy landscapes of RNA folding is unknown. This work exploits temperature-controlled single-molecule FRET methods to address the thermodynamics of RNA folding pathways by probing the intramolecular docking/undocking kinetics of the ubiquitous GAAA tetraloop−receptor tertiary interaction as a function of [Mg
2+
]. These measurements yield the barrier and standard state enthalpies, entropies, and free energies for an RNA tertiary transition, in particular, revealing the thermodynamic origin of [Mg
2+
]-facilitated folding. Surprisingly, these studies reveal that increasing [Mg
2+
] promotes tetraloop–receptor interaction by reducing the entropic barrier (

) and the overall entropic penalty (

) for docking, with essentially negligible effects on both the activation enthalpy (

) and overall exothermicity (

). These observations contrast with the conventional notion that increasing [Mg
2+
] facilitates folding by minimizing electrostatic repulsion of opposing RNA helices, which would incorrectly predict a decrease in

and

with [Mg
2+
]. Instead we propose that higher [Mg
2+
] can aid RNA folding by decreasing the entropic penalty of counterion uptake and by reducing disorder of the unfolded conformational ensemble.
Stabilization and symbolism: language and regional politics in the Chuvash Republic
Authors: Marquardt Kyle L.
Published: February 2012

The government of the Chuvash Republic, an ethno-federal region of the Russian Federation, used a targeted and symbolic language policy in an attempt to stabilize the position of the republic's titular language while avoiding conflict with local Russophones and the Russian federal government. The resulting policy allowed the republic's government to frame the existence of an autonomous Chuvash republic – as well as the local elite's form of governance – as being essential to the preservation of the Chuvash language and thus the Chuvash people. In this way, it used language politics to strengthen its position vis-à-vis both local constituents and the Russian federal government. However, the limited nature of the government's program has made its gains tenuous in the face of continuing Russian political and cultural recentralization.
An inquiry into the linkage among nationalizing policies, democratization, and ethno-nationalist conflict: the Kurdish case in Turkey
Authors: Mousseau Demet Yalcin
Published: February 2012

This article analyzes the effects of nationalizing policies of the state, processes of democratization, and uneven socio-economic development on the rise of Kurdish ethno-mobilization led by the PKK terrorist organization since the 1980s in Turkey. Three features of the Turkish modernization context are identified as conducive for the rise and continuation of Kurdish ethno-mobilization: a) a nation-building autocratic state that resisted granting cultural rights and recognition for the Kurds; b) democratization with the exclusion of ethnic politics and rights; c) economic regional inequality that coincided with the regional distribution of the Kurdish population. It is argued that autocratic policies of the state during nation-building accompanied the development of an illiberal democracy and intolerance for cultural pluralism. These aspects of Turkish democracy seem to be incompatible with both the liberal and consociational models of democracy that accommodate ethnicity within multiculturalism.
Organelle segregation during mitosis: Lessons from asymmetrically dividing cells
Authors: Ouellet Jimmy , Barral Yves
Published: February 2012

Studies on cell division traditionally focus on the mechanisms of chromosome segregation and cytokinesis, yet we know comparatively little about how organelles segregate. Analysis of organelle partitioning in asymmetrically dividing cells has provided insights into the mechanisms through which cells control organelle distribution. Interestingly, these studies have revealed that segregation mechanisms frequently link organelle distribution to organelle growth and formation. Furthermore, in many cases, cells use organelles, such as the endoplasmic reticulum and P granules, as vectors for the segregation of information. Together, these emerging data suggest that the coordination between organelle growth, division, and segregation plays an important role in the control of cell fate inheritance, cellular aging, and rejuvenation, i.e., the resetting of age in immortal lineages.
Evolving to Divide the Fruits of Cooperation
Authors: Wagner Elliott O.
Published: February 2012

Cooperation and the allocation of common resources are core features of social behavior. Games idealizing both interactions have been studied separately. But here, rather than examining the dynamics of the individual games, the interactions are combined so that players first choose whether to cooperate, and then, if they jointly cooperate, they bargain over the fruits of their cooperation. It is shown that the dynamics of the combined game cannot simply be reduced to the dynamics of the individual games and that both cooperation and fair division are more likely in the combined game than in the constituent games taken separately.
Phosphorylation of Stim1 at serine 575 via netrin-2/Cdo–activated ERK1/2 is critical for the promyogenic function of Stim1
Authors: Lee Hye-Jin , Bae Gyu-Un , Leem Young-Eun , Choi Hyun-Kyung , Kang Tong Mook , Cho Hana , Kim Seong-Tae , Kang Jong-Sun
Published: February 2012

The promyogenic cell surface molecule Cdo is required for activation of extracellular signal-regulated kinase (ERK) and nuclear factor of activated T cells c3 (NFATc3) induced by netrin-2 in myogenic differentiation. However, the molecular mechanism leading to NFATc3 activation is unknown. Stromal interaction molecule 1 (Stim1), an internal calcium sensor of the endoplasmic reticulum store, promotes myogenesis via activation of NFATc3. In this study we investigated the functional interaction between Cdo and Stim1 in myogenic differentiation. Overexpression and depletion of Stim1 enhanced or decreased myotube formation, respectively. Of interest, Stim1 protein levels were decreased in Cdo-deficient perinatal hindlimb muscles or primary myoblasts; this correlates with defective NFATc3 activation in Cdo−/−myoblasts upon differentiation. Forced activation of NFATc3 by overexpression of calcineurin restored differentiation of Cdo-depleted C2C12 myoblasts. Furthermore, Cdo and Stim1 formed a complex in 293T cells or in differentiating C2C12 myoblasts. The netrin-2–mediated NFATc3 activation was coincident with robust interactions between Cdo and Stim1 in myoblasts and the ERK-mediated Stim1 phosphorylation at serine 575. The serine 575 phosphorylation was enhanced in C2C12 cells upon differentiation, and the alanine substitution of serine 575 failed to restore differentiation of Stim1-depleted myoblasts. Taken together, the results indicate that cell adhesion signaling triggered by netrin-2/Cdo induces Stim1 phosphorylation at serine 575 by ERK, which promotes myoblast differentiation.
Systematic survey of deubiquitinase localization identifies USP21 as a regulator of centrosome- and microtubule-associated functions
Authors: Urbé Sylvie , Liu Han , Hayes Sebastian D. , Heride Claire , Rigden Daniel J. , Clague Michael J.
Published: February 2012

Ubiquitination is a reversible modification that influences a broad range of physiological processes. There are approximately 90 deubiquitinases (DUBs) encoded in the human genome, of which 79 are predicted to have catalytic activity. We tagged 66 DUBs with green fluorescent protein and systematically surveyed their subcellular distribution, identifying enzymes specific to the nucleus, plasma membrane, and secretory and endocytic pathways. USP21 is unique in showing clear association with both centrosomes and microtubules. Using an in vitro assay, we show that microtubule binding is direct and identify a novel microtubule-binding motif encompassed within amino acids 59–75 of the N-terminus of USP21. Our functional studies indicate a key role for USP21 in the governance of microtubule- and centrosome-associated physiological processes: Depletion of USP21 in A549 cells compromises the reestablishment of a radial array of microtubules during recovery from cold-induced depolymerization and also reduces the probability of primary cilium formation, whereas USP21 knockdown in PC12 cells inhibits nerve growth factor–induced neurite outgrowth.
Colocalization of Mec1 and Mrc1 is sufficient for Rad53 phosphorylation in vivo
Authors: Berens Theresa J. , Toczyski David P.
Published: February 2012

When DNA is damaged or DNA replication goes awry, cells activate checkpoints to allow time for damage to be repaired and replication to complete. In Saccharomyces cerevisiae, the DNA damage checkpoint, which responds to lesions such as double-strand breaks, is activated when the lesion promotes the association of the sensor kinase Mec1 and its targeting subunit Ddc2 with its activators Ddc1 (a member of the 9-1-1 complex) and Dpb11. It has been more difficult to determine what role these Mec1 activators play in the replication checkpoint, which recognizes stalled replication forks, since Dpb11 has a separate role in DNA replication itself. Therefore we constructed an in vivo replication-checkpoint mimic that recapitulates Mec1-dependent phosphorylation of the effector kinase Rad53, a crucial step in checkpoint activation. In the endogenous replication checkpoint, Mec1 phosphorylation of Rad53 requires Mrc1, a replisome component. The replication-checkpoint mimic requires colocalization of Mrc1-LacI and Ddc2-LacI and is independent of both Ddc1 and Dpb11. We show that these activators are also dispensable for Mec1 activity and cell survival in the endogenous replication checkpoint but that Ddc1 is absolutely required in the absence of Mrc1. We propose that colocalization of Mrc1 and Mec1 is the minimal signal required to activate the replication checkpoint.
Urinary albumin excretion in heart failure with preserved ejection fraction: an interim analysis of the CHART 2 study
Authors: Miura Masanobu , Shiba Nobuyuki , Nochioka Kotaro , Takada Tsuyoshi , Takahashi Jun , Kohno Haruka , Shimokawa Hiroaki ,   on behalf of the CHART‐2 Investigators
Published: February 2012

Aims

Heart failure with preserved ejection fraction (HFpEF) is characterized by multiple co‐morbidities, including chronic kidney disease that is one of the prognostic risks for these patients. This study was performed to evaluate the value of determination of albuminuria using a urine dipstick test (UDT), combined with estimated glomerular filtration rate (eGFR), for predicition of mortality in HFpEF.

Methods and results

We enrolled 2465 consecutive patients with overt HF with EF ≥50% in our Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART‐2) study (NCT00418041). We defined trace or more UDT as positive. We divided the patients into the following four groups based on eGFR and UDT; group 1 (G1) (eGFR ≥60, negative UDT), G2 (eGFR ≥60, positive UDT), G3 (eGFR <60, negative UDT), and G4 (eGFR <60, positive UDT). In total, 29.5% of the HFpEF patients had a positive UDT. HFpEF patients with a positive UDT were characterized by higher brain natriuretic peptide levels and frequent histories of hypertension or diabetes. During a mean follow‐up of 2.5 years, HFpEF patients with a positive UDT showed higher mortality in each stratum of eGFR levels. A multivariable adjusted Cox model showed that when compared with G1 (reference), the hazard ratio of all‐cause death for G2, G3, and G4 was 2.44 (95% confidence interval 1.47–4.05, P=0.001), 1.43 (0.92–2.23, P=0.12), and 2.71 (1.72–4.27, P<0.001), respectively. Furthermore, the prognostic value of a positive UDT was robust for both cardiovascular and non‐cardiovascular deaths.

Conclusions

These results indicate that measurement of albuminuria in addition to eGFR is useful for appropriate risk stratification in HFpEF patients.
Clinical characteristics and outcomes of hospitalized heart failure patients with systolic dysfunction and chronic obstructive pulmonary disease: findings from OPTIMIZE‐HF
Authors: Mentz Robert J. , Fiuzat Mona , Wojdyla Daniel M. , Chiswell Karen , Gheorghiade Mihai , Fonarow Gregg C. , O'Connor Christopher M.
Published: February 2012

Aims

Chronic obstructive pulmonary disease (COPD) is common in heart failure (HF) patients, yet the population is poorly characterized and associated with conflicting outcomes data. We aimed to evaluate the clinical characteristics and outcomes of HF patients with systolic dysfunction and COPD in a large acute HF registry.

Methods and results

OPTIMIZE‐HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) was a performance‐improvement registry of patients hospitalized with HF (n =48 612), which included a pre‐specified subgroup of patients (n =5,701) with 60‐ to 90‐day follow‐up. We performed a retrospective analysis of the clinical characteristics and outcomes (length of stay, and in‐hospital and 60‐day mortality) of patients with systolic dysfunction according to baseline COPD status. COPD was present in 25% of the patients. These patients had more co‐morbidities compared with patients without COPD. They were less likely to receive a beta‐blocker or angiotensin‐converting enzyme inhibitor during hospitalization and at discharge (P < 0.001). COPD was associated with an increased median length of stay [5 days (interquartile range 3–8) vs. 4 days (interquartile range 3–7), P < 0.0001] and increased in‐hospital all‐cause and non‐cardiovascular (CV) mortality, with rates of 4.5% vs. 3.7% (P =0.01) and 1.0% vs. 0.6% (P =0.01), respectively, for the two endpoints, but similar 60‐day mortality (6.2% vs. 6.0%, P =0.28). After risk adjustment, the in‐hospital non‐CV mortality remained increased (odds ratio 1.65, 95% confidence interval 1.12–2.41; P =0.01).

Conclusion

The presence of COPD in HF patients with systolic dysfunction is associated with an increased burden of co‐morbidities, lower use of evidence‐based HF medications, longer hospitalizations, and increased in‐hospital non‐CV mortality, but similar post‐discharge mortality.
Radiology
Authors: Cascarini Luke , Schilling Clare , Gurney Ben , Brennan Peter
Published: February 2012

Guidelines for dental radiology 40

Dental radiography 42

Panoramic radiography 46

Facial and skull radiography 48

Ultrasonography 50

CT and cone beam CT 52

MRI and nuclear imaging 56

Sialography 57

• Although the radiation doses are generally quite low, the same rules apply as with other radiology and are controlled by IRMER (Ionizing Radiation (Medical Exposure) Regulations (2000))....
Commonly used drugs and dental materials
Authors: Cascarini Luke , Schilling Clare , Gurney Ben , Brennan Peter
Published: February 2012

Local anaesthetics 246

Analgesics and sedatives 248

Antimicrobials 250

Dental materials 252

Getting good anaesthesia is the key to stress-free procedures.

• The administration technique may be more important than product selection ( see p. 190), but you should be well informed about the drug you are using....
Out-of-Africa, the peopling of continents and islands: tracing uniparental gene trees across the map
Authors: Oppenheimer Stephen
Published: February 2012

Genetic relationships between human groups were first studied by comparisons of relative allele frequency at multiple loci. Geographical study of detailed, highly resolved trees of single, non-recombining uniparental loci (mitochondrial DNA: mtDNA and Y chromosome/non-recombining Y: NRY), following specific lineages rather than populations, then revolutionized knowledge of the peopling of the world, although, curiously, the use of geographically highly specific mutations that protect against malaria, found on individual autosomal globin genes, were first in single-locus phylogeography. mtDNA, with its high single nucleotide polymorphism (SNP) mutation rates and relative ease of dating, led the way and gave stronger proof of the recent near replacement of all human species by anatomically modern humans (AMH). AMH left Africa via a single southern exit about 70 000 years ago and rapidly spread around the Indian Ocean towards the Antipodes, long before a small branch left a South Asian colony, earlier on the trail, to populate Europe. The worldwide skeleton phylogeny of mtDNA is fully resolved, but a regional analysis will continue to illuminate subsequent migrations. NRY with a lower SNP mutation rate still has a dating problem relating to use the of single tandem repeats (STRs), but has validated mtDNA results and with more geographical specificity and genomic size, as with the autosomal human genome, has much more detail to offer for the future.
Distinct evolutionary strategies of human leucocyte antigen loci in pathogen-rich environments
Authors: Sanchez-Mazas Alicia , Lemaître Jean-François , Currat Mathias
Published: February 2012

Human leucocyte antigen (HLA) loci have a complex evolution where both stochastic (e.g. genetic drift) and deterministic (natural selection) forces are involved. Owing to their extraordinary level of polymorphism, HLA genes are useful markers for reconstructing human settlement history. However, HLA variation often deviates significantly from neutral expectations towards an excess of genetic diversity. Because HLA molecules play a crucial role in immunity, this observation is generally explained by pathogen-driven-balancing selection (PDBS). In this study, we investigate the PDBS model by analysing HLA allelic diversity on a large database of 535 populations in relation to pathogen richness. Our results confirm that geographical distances are excellent predictors of HLA genetic differentiation worldwide. We also find a significant positive correlation between genetic diversity and pathogen richness at two HLA class I loci (HLA-A and -B), as predicted by PDBS, and a significant negative correlation at one HLA class II locus (HLA-DQB1). Although these effects are weak, as shown by a loss of significance when populations submitted to rapid genetic drift are removed from the analysis, the inverse relationship between genetic diversity and pathogen richness at different loci indicates that HLA genes have adopted distinct evolutionary strategies to provide immune protection in pathogen-rich environments.
Oxidative Stress Level in the Testes of Mice and Rats during Nickel Intoxication
Authors: Murawska-Ciałowicz Eugenia , Bal Wojciech , Januszewska Lidia , Zawadzki Marcin , Rychel Joanna , Zuwała-Jagiełło Jolanta
Published: February 2012

The genotioxic and carcinogenic effect of nickel probably results from its capacity to produce reactive oxygen species (ROS) and disturb the redox balance. The aim of the study was to find out if rats lacking spermatic protamine 2 are less susceptible to Ni(II) than mice. Consequently, the levels of malondialdehyde + 4 hydroxynonenal (MDA+4HDA) − markers of lipid peroxidation, as well as the level of reduced glutathione (GSH) were measured within the rat and mouse testes. Our results showed that the levels of lipid peroxidation markers were elevated in testicular homogenates of intoxicated mice without any changes in rats. GSH level was lower in the group of intoxicated mice comparing to the control without statistically significant changes in rats’ homogenates. Moreover, the level of GSH in the testes of intoxicated mice was lower than in rats. On the basis of our results, it appears that Ni(II) can initiate oxidative stress in the testes of mice but not of rats and can reduce GSH level. Consequently, the antioxidative defense of the testes is reduced. Ni(II) that causes oxidative stress in the testes may also contribute to infertility.
The Presence of Visual Neglect after Thrombolytic Treatment in Patients with Right Hemisphere Stroke
Authors: Kettunen J. E. , Nurmi M. , Koivisto A.-M. , Dastidar P. , Jehkonen M.
Published: February 2012

Visual neglect (VN) is a common consequence of right hemisphere (RH) stroke. The aims of this study were to explore the presence of VN after RH stroke in the patients with (T+) or without (T−) thrombolytic treatment, and to determine whether thrombolysis is a predictor of VN. The study group consisted of 77 RH infarct patients. VN was evaluated with six conventional subtests of the Behavioural Inattention Test (BIT). Stroke severity was assessed using the National Institute of Health Stroke Scale (NIHSS). In the neuropsychological examination, 22% of all RH stroke patients had VN. VN was present in 15% of the patients in the T+ group and in 28% of the patients in the T− group, but the difference was not statistically significant. Despite that, patients in the T− group had a higher risk of VN than patients in the T+ group. Our results suggest that thrombolysis independently predicted absence of VN.
Age-associated DNA methylation in pediatric populations
Authors: Alisch Reid S. , Barwick Benjamin G. , Chopra Pankaj , Myrick Leila K. , Satten Glen A. , Conneely Karen N. , Warren Stephen T.
Published: February 2012

DNA methylation (DNAm) plays diverse roles in human biology, but this dynamic epigenetic mark remains far from fully characterized. Although earlier studies uncovered loci that undergo age-associated DNAm changes in adults, little is known about such changes during childhood. Despite profound DNAm plasticity during embryogenesis, monozygotic twins show indistinguishable childhood methylation, suggesting that DNAm is highly coordinated throughout early development. Here we examine the methylation of 27,578 CpG dinucleotides in peripheral blood DNA from a cross-sectional study of 398 boys, aged 3–17 yr, and find significant age-associated changes in DNAm at 2078 loci. These findings correspond well with pyrosequencing data and replicate in a second pediatric population (N = 78). Moreover, we report a deficit of age-related loci on the X chromosome, a preference for specific nucleotides immediately surrounding the interrogated CpG dinucleotide, and a primary association with developmental and immune ontological functions. Meta-analysis (N = 1158) with two adult populations reveals that despite a significant overlap of age-associated loci, most methylation changes do not follow a lifelong linear pattern due to a threefold to fourfold higher rate of change in children compared with adults; consequently, the vast majority of changes are more accurately modeled as a function of logarithmic age. We therefore conclude that age-related DNAm changes in peripheral blood occur more rapidly during childhood and are imperfectly accounted for by statistical corrections that are linear in age, further suggesting that future DNAm studies should be matched closely for age.
Constitutive Activation of Transcription Factor OsbZIP46 Improves Drought Tolerance in Rice
Authors: Tang Ning , Zhang Hua , Li Xianghua , Xiao Jinghua , Xiong Lizhong
Published: February 2012

OsbZIP46 is one member of the third subfamily of bZIP transcription factors in rice (Oryza sativa). It has high sequence similarity to ABA-responsive element binding factor (ABF/AREB) transcription factors ABI5 and OsbZIP23, two transcriptional activators positively regulating stress tolerance in Arabidopsis (Arabidopsis thaliana) and rice, respectively. Expression of OsbZIP46 was strongly induced by drought, heat, hydrogen peroxide, and abscisic acid (ABA) treatment; however, it was not induced by salt and cold stresses. Overexpression of the native OsbZIP46 gene increased ABA sensitivity but had no positive effect on drought resistance. The activation domain of OsbZIP46 was defined by a series of deletions, and a region (domain D) was identified as having a negative effect on the activation. We produced a constitutive active form of OsbZIP46 (OsbZIP46CA1) with a deletion of domain D. Overexpression of OsbZIP46CA1 in rice significantly increased tolerance to drought and osmotic stresses. Gene chip analysis of the two overexpressors (native OsbZIP46 and the constitutive active form OsbZIP46CA1) revealed that a large number of stress-related genes, many of them predicted to be downstream genes of ABF/AREBs, were activated in the OsbZIP46CA1 overexpressor but not (even down-regulated) in the OsbZIP46 overexpressor. OsbZIP46 can interact with homologs of SnRK2 protein kinases that phosphorylate ABFs in Arabidopsis. These results suggest that OsbZIP46 is a positive regulator of ABA signaling and drought stress tolerance of rice depending on its activation. The stress-related genes activated by OsbZIP46CA1 are largely different from those activated by the other rice ABF/AREB homologs (such as OsbZIP23), further implying the value of OsbZIP46CA1 in genetic engineering of drought tolerance.
Planarity of heteroaryldithiocarbazic acid derivatives showing tuberculostatic activity. IV. Diesters of benzoylcarbonohydrazonodithioic acid
Authors: Szczesio Małgorzata , Olczak Andrzej , Gobis Katarzyna , Foks Henryk , Główka Marek L.
Published: February 2012

Dimethyl (3,4-dichlorobenzoyl)carbonohydrazonodithioate, C10H10Cl2N2OS2, (D1), dibenzyl (3,4-dichlorobenzoyl)carbonohydrazonodithioate, C22H18Cl2N2OS2, (D2), dimethyl (3,4-dichlorobenzoyl)-1-methylcarbonohydrazonodithioate, C11H12Cl2N2OS2, (D3), 3,4-dichloro-N′-(1,3-dithiolan-2-ylidene)-N-methylbenzohydrazide, C11H10Cl2N2OS2, (D4), were synthesized as potential tuberculostatics. Compound (D1) (with two molecules in the asymmetric unit) was the only one showing tuberculostatic activity of the same range as the common drugs isoniazid and pyrazinamide. The molecular structures of the studied compounds depend on the substitution at the N atom adjacent to the carbonyl group. In the case of the unsubstituted derivatives (D1) and (D2), their central frames are generally planar with a twist of the 3,4-dichlorophenyl ring by 30–40°. Until now, coplanarity of the aromatic ring with the (methylene)carbonohydrazone fragment has been considered a prerequisite for tuberculostatic activity. TheN-methylated derivatives (D3) and (D4) show an additional twist along the N—C(=O) bond by 20–30° due to the spatial repulsion introduced by the methyl substituent.
Bis(methanol-κO)dioxido[3,3′-(1H-1,2,4-triazole-3,5-diyl)diphenolato-κ3O,N4,O′]uranium(VI) methanol monosolvate
Authors: Raspertova Ilona , Doroschuk Roman , Khomenko Dmytro , Lampeka Rostislav
Published: February 2012

The structure of the title compound, [U(C14H9N3O2)O2(CH3OH)2]·CH3OH, is the first to be reported for an actinide complex including triazole ligands. The UVIatom exhibits a pentagonal–bipyramidal NO6coordination environment, involving two axial oxide ligands [U=O = 1.766 (3) and 1.789 (3) Å], four equatorial O atoms [U—O = 2.269 (3)–2.448 (3) Å] from the ligand and the two coordinated methanol molecules, and one equatorial N atom [U—N = 2.513 (4) Å] from the ligand. In the crystal structure, the complex molecules are linkedviaintermolecular N—H...O and O—H...O hydrogen bonds to form a two-dimensional structure.
Thromboxane A2 receptor signaling facilitates tumor colonization through P‐selectin‐mediated interaction of tumor cells with platelets and endothelial cells
Authors: Matsui Yoshio , Amano Hideki , Ito Yoshiya , Eshima Koji , Suzuki Tastunori , Ogawa Fumihiro , Iyoda Akira , Satoh Yukitoshi , Kato Shintaro , Nakamura Masaki , Kitasato Hidero , Narumiya Shuh , Majima Masataka
Published: February 2012

Thromboxane A2 (TXA2) is a prostanoid formed by thromboxane synthase using the cyclooxygenase product, prostaglandin H(2), as the substrate. TXA2 was shown to enhance tumor metastasis, but the underlying mechanism remains unclear. B16F1 melanoma cells were intravenously injected into TXA2 receptor (TP) knockout mice (TP−/−) and wild‐type littermates (WT). TP−/− showed a reduction in B16F1 lung colonization and mortality rate, which were associated with a decreased number of platelets. Platelet activation as assessed by P‐selectin expression was suppressed in TP−/−. A selective P‐selectin neutralizing antibody decreased the lung colonization in WT mice, but not in TP−/−. The expression of P‐selectin glycoprotein ligand‐1 in B16F1 and HUVEC were enhanced by treatment with U46619, a thromboxane analog. The plasma levels of vascular endothelial growth factor (VEGF) and stromal‐derived factor (SDF)‐1 were lower in TP−/−. In TP−/−, the mobilization of progenitor cells expressing CXCR4+VEGFR1+ from bone marrow and the recruitment of those cells to lung tissues were suppressed. These results suggest that TP signaling plays a critical role in tumor colonization through P‐selectin‐mediated interactions between platelets‐tumor cells and tumor cells‐endothelial cells through the TP signaling‐dependent production of VEGF and SDF‐1, which might be involved in the mobilization of VEGFR1+CXCR4+ cells. Blockade of TP signaling might be useful in the treatment of tumor metastasis. (Cancer Sci 2012; 103: 700–707)
The co‐occurring use and misuse of cannabis and tobacco: a review
Authors: Agrawal Arpana , Budney Alan J. , Lynskey Michael T.
Published: February 2012

Aims  Cannabis and tobacco use and misuse frequently co‐occur. This review examines the epidemiological evidence supporting the life‐time co‐occurrence of cannabis and tobacco use and outlines the mechanisms that link these drugs to each other. Mechanisms include (i) shared genetic factors; (ii) shared environmental influences, including (iii) route of administration (via smoking), (iv) co‐administration and (v) models of co‐use. We also discuss respiratory harms associated with co‐use of cannabis and tobacco, overlapping withdrawal syndromes and outline treatment implications for co‐occurring use.

Methods  Selective review of published studies.

Results  Both cannabis and tobacco use and misuse are influenced by genetic factors, and a proportion of these genetic factors influence both cannabis and tobacco use and misuse. Environmental factors such as availability play an important role, with economic models suggesting a complementary relationship where increases in price of one drug decrease the use of the other. Route of administration and smoking cues may contribute to their sustained use. Similar withdrawal syndromes, with many symptoms in common, may have important treatment implications. Emerging evidence suggests that dual abstinence may predict better cessation outcomes, yet empirically researched treatments tailored for co‐occurring use are lacking.

Conclusions  There is accumulating evidence that some mechanisms linking cannabis and tobacco use are distinct from those contributing to co‐occurring use of drugs in general. There is an urgent need for research to identify the underlying mechanisms and harness their potential etiological implications to tailor treatment options for this serious public health challenge.
Does it matter where we measure blood pressure?
Authors: Tomlinson Laurie A. , Wilkinson Ian B.
Published: February 2012

Although blood pressure measured at the brachial artery plays a central role in our understanding and management of cardiovascular risk, in recent years great emphasis has been placed on the importance of central blood pressure. It seems straightforward that knowledge of the blood pressure directly affecting the major organs is important for understanding the pathophysiology and treatment of cardiovascular risk. However, the field has been troubled by controversies over measurement techniques and difficulty in designing therapies to modify central but not peripheral blood pressure. In this review, we consider the physiology underlying the change in blood pressure through the arterial tree and how central blood pressure can be measured. In addition, we review the evidence regarding the relationship of central BP to cardiovascular disease and the effects of treatment. New measurement techniques and evidence regarding the specific benefits of therapies in modulating central haemodynamics mean that this is a rapidly developing area, and understanding the concept of central blood pressure will be vital in the future.
Educating nonmedical prescribers
Authors: Stewart Derek , MacLure Katie , George Johnson
Published: February 2012

The last decade has seen developments in nonmedical prescribing, with the introduction of prescribing rights for healthcare professionals. In this article, we focus on the education, training and practice of nonmedical prescribers in the UK. There are around 20 000 nurse independent prescribers, 2400 pharmacist supplementary/independent prescribers, several hundred allied health professional supplementary prescribers and almost 100 optometrist supplementary/independent prescribers. Many are active prescribers, managing chronic conditions or acute episodes of infections and minor ailments. Key aims of nonmedical prescribing are as follows: to improve patient care; to increase patient choice in accessing medicines; and to make better use of the skills of health professionals. Education and training are provided by higher education institutions accredited by UK professional bodies/regulators,namely, the Nursing and Midwifery Council, General Pharmaceutical Council, Health Professions Council and General Optical Council. The programme comprises two main components: a university component equivalent to 26 days full‐time education and a period of learning in practice of 12 days minimum under the supervision of a designated medical practitioner. Course content focuses on the following factors: consultation, decision making, assessment and review; psychology of prescribing; prescribing in team context; applied therapeutics; evidence‐based practice and clinical governance; legal, policy, professional and ethical aspects; and prescribing in the public health context. Nonmedical prescribers must practise within their competence, demonstrating continuing professional development to maintain the quality engendered during training. Despite the substantial progress, there are several issues of strategy, capacity, sustainability and a research evidence base which require attention to fully integrate nonmedical prescribing within healthcare.
The pharmacokinetics of oxypurinol in people with gout
Authors: Stocker Sophie L. , McLachlan Andrew J. , Savic Radojka M. , Kirkpatrick Carl M. , Graham Garry G. , Williams Kenneth M. , Day Richard O.
Published: February 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Response to allopurinol in patients with gout is often suboptimal due to large variability in pharmacokinetics.

• The sources of the variability in oxypurinol pharmacokinetics have not been systematically identified and quantified.

• A therapeutic target 15–23 mg l−1 for oxypurinol concentrations has recently been established.

WHAT THIS STUDY ADDS

• Renal function and concomitant diuretic/probenecid use significantly influence oxypurinol pharmacokinetics.

• This model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degrees of renal impairment.

• Model predictions show a failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines.

AIMS Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations.

METHODS Non‐linear mixed effects modelling was applied to concentration–time data from 155 gouty patients with demographic, medical history and renal transporter genotype information.

RESULTS A one compartment pharmacokinetic model with first order absorption best described the oxypurinol concentration–time data. Renal function and concomitant medicines (diuretics and probenecid), but not transporter genotype, significantly influenced oxypurinol pharmacokinetics and reduced the between subject variability in the apparent clearance of oxypurinol (CL/Fm) from 65% to 29%. CL/Fm for patients with normal, mild, moderate and severe renal impairment was 1.8, 0.6, 0.3 and 0.18 l h−1, respectively. Model predictions showed a relationship between plasma oxypurinol and urate concentrations and failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines.

CONCLUSIONS In conclusion, this first established pharmacokinetic model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degrees of renal impairment.
Therapeutic strategies to deplete macrophages in atherosclerotic plaques
Authors: De Meyer Inge , Martinet Wim , De Meyer Guido R. Y.
Published: February 2012

Macrophages can be found in all stages of atherosclerosis and are major contributors of atherosclerotic plaque development, progression and destabilization. Continuous recruitment of monocytes drives this chronic inflammatory disease, which can be intervened by several strategies: reducing the inflammatory stimulus by lowering circulating lipids and promoting cholesterol efflux from plaque, direct and indirect targeting of adhesion molecules and chemokines involved in monocyte adhesion and transmigration and inducing macrophage death in atherosclerotic plaques in combination with anti‐inflammatory drugs. This review discusses the outlined strategies to deplete macrophages from atherosclerotic plaques to promote plaque stabilization.
Salivary levels of Bifidobacteria in caries‐free and caries‐active children
Authors: KAUR RAVINDER , GILBERT STEVEN C. , SHEEHY EVELYN C. , BEIGHTON DAVID
Published: February 2012

International Journal of Paediatric Dentistry 2013; 23: 32–38

Background  Salivary levels of Bifidobacteria have been shown to be significantly correlated with caries experience in adults but not as yet in children.

Hypothesis.  Salivary levels of Bifidobacteria are positively associated with caries experience in children.

Aim.  To compare the salivary concentrations of Bifidobacteria of caries‐free and caries‐active children.

Design.  Saliva was collected using the tongue‐loop method from 38 caries‐active children and from 22 clinically caries‐free children, and the numbers of Bifidobacteria, mutans streptococci, lactobacilli and yeasts were determined. Additionally, the age and gender of the children, a plaque index, sugar amount in diet, sugar frequency in diet, hygiene practice and fluoride toothpaste usage were recorded.

Results.  Bifidobacteria were isolated from 95% of the caries‐active children and from only 9% of the caries‐free children (P < 0.001). Salivary levels of Bifidobacteria were significantly correlated with amount of sugar in the diet, frequency of sugar consumption and oral hygiene practice. The significant variables that discriminated between the caries‐free and caries‐active subjects were salivary levels of Bifidobacteria, salivary levels of mutans streptococci and oral hygiene practice (χ2 = 72.57, P < 0.001) and overall 90.0% of cases were correctly classified.

Conclusions.  Salivary levels of Bifidobacteria are significantly associated with caries experience in children. The salivary levels of this genus may be a useful marker of caries risk.