Frontal Variant of Alzheimer Disease Differentiated From Frontotemporal Dementia Using in Vivo Amyloid and Tau Imaging.
The frontal variant of Alzheimer disease (fvAD) is characterized by behavioral and/or dysexecutive impairments that can resemble those of behavioral-variant frontotemporal dementia (bvFTD). This overlap, in addition to the lack of consensus clinical criteria for fvAD, complicates its identification. We provide the first case report of fvAD differentiated in vivo from bvFTD using amyloid-beta and tau PET imaging. The patient, a right-handed woman, presented with forgetfulness at age 60. Cognitive testing at that time revealed mild impairments in memory, attention, and executive functions. Three years later, her family reported that she was displaying socially inappropriate behaviors, inertia, diminished social interest, and altered food preferences-the sum of which met the criteria for possible bvFTD. PET using an amyloid-beta tracer (F-AZD4694) identified diffuse amyloid plaques across the cerebral cortex. PET using a tau tracer specific for neurofibrillary tangles (F-MK6240) identified substantial tau pathology in the brain's frontal lobes. Together with the clinical findings, these images supported the diagnosis of fvAD rather than bvFTD. Considering past and emerging evidence that tau topography in Alzheimer disease (AD) matches the clinical features of AD, we discuss the potential utility of in vivo tau imaging using F-MK6240 for identifying fvAD.


GQDs-MSNs nanocomposite nanoparticles for simultaneous intracellular drug delivery and fluorescent imaging.
Although number of stimuli-responsive drug delivery systems based on mesoporous silica nanoparticles (MSNs) have been developed, the simultaneous real-time monitoring of carrier in order to guarantee proper drug targeting still remains as a challenge. GQDs-MSNs nanocomposite nanoparticles composed of graphene quantum dots (GQDs) and MSNs are proposed as efficient doxorubicin delivery and fluorescent imaging agent, allowing to monitor intracellular localization of a carrier and drug diffusion route from the carrier. Graphene quantum dots (average diameter 3.65 ± 0.81 nm) as a fluorescent agent were chemically immobilized onto mesoporous silica nanoparticles (average diameter 44.08 ± 7.18 nm) and loaded with doxorubicin. The structure, morphology, chemical composition, and optical properties as well as drug release behavior of doxorubicin (DOX)-loaded GQDs-MSNs were investigated. Then, the in vitro cytotoxicity, cellular uptake, and intracellular localization studies were carried out. Prepared GQDs-MSNs form stable suspensions exhibiting excitation-dependent photoluminescence (PL) behavior. These nanocomposite nanoparticles can be easily DOX-loaded and show pH- and temperature-dependent release behavior. Cytotoxicity studies proved that GQDs-MSNs nanocomposite nanoparticles are nontoxic; however, when loaded with drug, they enable the therapeutic activity of DOX via its active delivery and release. GQDs-MSNs owing to their fluorescent properties and efficient in vitro cellular internalization via caveolae/lipid raft-dependent endocytosis show a high potential for the optical imaging, including the simultaneous real-time optical tracking of the loaded drug during its delivery and release. Graphical abstract.


Unexpected severe calcification after transplantation of bone marrow cells in acute myocardial infarction.
There has been a rapid increase in the number of clinical trials using unselected bone marrow (BM) cells or the mononuclear fraction of BM cells for treating ischemic heart diseases. Thus far, no significant deleterious effects or complications have been reported in any studies using BM-derived cells for treatment of various cardiac diseases. Seven-week-old female Fisher-344 rats underwent surgery to induce acute myocardial infarction and were randomized into 3 groups of 16 rats, each receiving intramyocardial injection of either 7x10(5) DiI-labeled total BM cells (TBMCs), the same number of DiI-labeled, clonally expanded BM multipotent stem cells, or the same volume of phosphate-buffered saline in the peri-infarct area. Echocardiography 2 weeks after cell transplantation indicated intramyocardial calcification in 4 of 14 surviving rats (28.5%) in the TBMC group. Histological examination with hematoxylin and eosin staining and von Kossa staining confirmed the presence of extensive intramyocardial calcification. Alkaline phosphatase staining revealed strong positivity surrounding the calcified area suggestive of ongoing osteogenic activity. Fluorescent microscopic examination revealed that acellular calcific areas were surrounded by DiI-labeled TBMCs, suggesting the direct involvement of transplanted TBMCs in myocardial calcification. In contrast, in hearts receiving equal volumes of saline or BM multipotent stem cells delivered in the same manner, there was no evidence of calcification. These results demonstrate that direct transplantation of unselected BM cells into the acutely infarcted myocardium may induce significant intramyocardial calcification.


Immunocytochemical localization of a neuronal nicotinic receptor: the beta 2-subunit.
We have characterized in adult rat the tissue-specific expression of the nicotinic ACh receptor (AChR) beta 2-subunit using antisera raised against fusion protein constructs. Immunohistochemical localization revealed immunoreactivity distributed throughout the neuraxis. Overall, beta 2-like immunoreactivity (beta 2-LI) correlated well with in situ localization of beta 2 transcript in neuronal cell bodies. Particularly strong labeling was detected in the thalamus, and scattered other regions, whereas relatively weak staining was observed in the hypothalamus and amygdala. At the cellular level, beta 2-LI appeared to be exclusively neuronal and concentrated predominantly in perikarya, although strongly positive dendrites (cerebral cortical pyramidal neurons, cerebellar Purkinje cells) and axon terminals (e.g., striatum) were detected. At the ultrastructural level, beta 2-LI was membrane associated, with strong staining observed in endoplasmic reticulum and cytoplasmic transport vesicles. beta 2-LI was rarely detected at synapses. The widespread distribution of beta 2 suggests it may serve as a common subunit in different AChR combinations in various brain regions. Regulation of the expression of beta 2-subunit appears to be relatively unrestrained, with an apparent excess of protein synthesized in the cytoplasm relative to that which ultimately arrives at functional targets in the plasma membrane.


Why do we study animal toxins?
Venom (toxins) is an important trait evolved along the evolutionary tree of animals. Our knowledges on venoms, such as their origins and loss, the biological relevance and the coevolutionary patterns with other organisms are greatly helpful in understanding many fundamental biological questions, i.e., the environmental adaptation and survival competition, the evolution shaped development and balance of venoms, and the sophisticated correlations among venom, immunity, body power, intelligence, their genetic basis, inherent association, as well as the cost-benefit and trade-offs of biological economy. Lethal animal envenomation can be found worldwide. However, from foe to friend, toxin studies have led lots of important discoveries and exciting avenues in deciphering and fighting human diseases, including the works awarded the Nobel Prize and lots of key clinic therapeutics. According to our survey, so far, only less than 0.1% of the toxins of the venomous animals in China have been explored. We emphasize on the similarities shared by venom and immune systems, as well as the studies of toxin knowledge-based physiological toxin-like proteins/peptides (TLPs). We propose the natural pairing hypothesis. Evolution links toxins with humans. Our mission is to find out the right natural pairings and interactions of our body elements with toxins, and with endogenous toxin-like molecules. Although, in nature, toxins may endanger human lives, but from a philosophical point of view, knowing them well is an effective way to better understand ourselves. So, this is why we study toxins.


Proteinmorphosis: a mechanical model for protein conformational changes.
Proteinmorphosis is a physically-based interactive modeling system for simulating large or small conformational changes of proteins and protein complexes. It takes advantage of the cross-linked one-dimensional nature of protein chains. The user can, based on her chemical knowledge, pull pairs of points (lying either on a single protein or on different molecules) together by specifying geometric distance constraints. The resulting conformation(s) of the molecule(s) of interest is computed by an efficient finite element formalism taking into account elasticity of the protein backbone, van der Waals repulsions, hydrogen bonds, salt bridges and the imposed distance constraints. The conformational change is computed incrementally and the result can be visualized as an animation; complete interactivity is provided to position and view the proteins as desired by the user. Physical properties of regions on the protein can also be chosen interactively. The conformational change of calmodulin upon peptide binding is examined as a first experiment. It is found that the result is satisfactory in reproducing the conformational change that follows on peptide binding. We use Proteinmorphosis to study the cooperative hemoglobin oxygen binding mechanism in a second, more sophisticated, experiment. Different modeling strategies are designed to understand the allosteric (cooperative) binding process in this system and the results are found to be consistent with existing hypotheses.


Silicon dual-ring modulator driven by differential signal.
A silicon dual-ring modulator consisting of two serially cascaded rings with embedded PN junctions is driven by a differential signal pair. We show by simulation and experiment that the device has advantages over the single-ring modulator in terms of optical bandwidth, 3-dB modulation bandwidth and bit rate, at the expense of a 1.7-dB increase in the transmission penalty and a twofold increase of the RF power consumption. Driven by differential pseudo random binary sequence (PRBS) signals of 0.5-V peak-to-peak voltage (Vpp), the dual-ring modulator exhibits optical bandwidths of 66 pm and 40 pm at 12.5 Gb/s and 20 Gb/s, respectively. In contrast, the single-ring modulator has an optical bandwidth of 26 pm under a single-end PRBS signal of 0.5 Vpp at 12.5 Gb/s, and its eye diagram closes if the bit rate rises to 20 Gb/s.


Diagnosis of osteoporosis in statin-treated patients is dose-dependent.
Whether HMG-CoA-reductase inhibition, the main mechanism of statins, plays a role in the pathogenesis of osteoporosis, is not entirely known so far. Consequently, this study was set out to investigate the relationship of different kinds and dosages of statins with osteoporosis, hypothesising that the inhibition of the synthesis of cholesterol could influence sex-hormones and therefore the diagnosis of osteoporosis. Medical claims data of all Austrians from 2006 to 2007 was used to identify all patients treated with statins to compute their daily defined dose averages of six different types of statins. We applied multiple logistic regression to analyse the dose-dependent risks of being diagnosed with osteoporosis for each statin individually. In the general study population, statin treatment was associated with an overrepresentation of diagnosed osteoporosis compared with controls (OR: 3.62, 95% CI 3.55 to 3.69, p<0.01). There was a highly non-trivial dependence of statin dosage with the ORs of osteoporosis. Osteoporosis was underrepresented in low-dose statin treatment (0-10 mg per day), including lovastatin (OR: 0.39, CI 0.18 to 0.84, p<0.05), pravastatin (OR: 0.68, 95% CI 0.52 to 0.89, p<0.01), simvastatin (OR: 0.70, 95% CI 0.56 to 0.86, p<0.01) and rosuvastatin (OR: 0.69, 95% CI 0.55 to 0.87, p<0.01). However, the exceeding of the 40 mg threshold for simvastatin (OR: 1.64, 95% CI 1.31 to 2.07, p<0.01), and the exceeding of a 20 mg threshold for atorvastatin (OR: 1.78, 95% CI 1.41 to 2.23, p<0.01) and for rosuvastatin (OR: 2.04, 95% CI 1.31 to 3.18, p<0.01) was related to an overrepresentation of osteoporosis. Our results show that the diagnosis of osteoporosis in statin-treated patients is dose-dependent. Thus, osteoporosis is underrepresented in low-dose and overrepresented in high-dose statin treatment, demonstrating the importance of future studies' taking dose-dependency into account when investigating the relationship between statins and osteoporosis.


Pulse oximetry adoption and oxygen orders at paediatric admission over 7 years in Kenya: a multihospital retrospective cohort study.
To characterise adoption and explore specific clinical and patient factors that might influence pulse oximetry and oxygen use in low-income and middle-income countries (LMICs) over time; to highlight useful considerations for entities working on programmes to improve access to pulse oximetry and oxygen. A multihospital retrospective cohort study. All admissions (n=132 737) to paediatric wards of 18 purposely selected public hospitals in Kenya that joined a Clinical Information Network (CIN) between March 2014 and December 2020. Pulse oximetry use and oxygen prescription on admission; we performed growth-curve modelling to investigate the association of patient factors with study outcomes over time while adjusting for hospital factors. Overall, pulse oximetry was used in 48.8% (64 722/132 737) of all admission cases. Use rose on average with each month of participation in the CIN (OR: 1.11, 95% CI 1.05 to 1.18) but patterns of adoption were highly variable across hospitals suggesting important factors at hospital level influence use of pulse oximetry. Of those with pulse oximetry measurement, 7% (4510/64 722) had hypoxaemia (SpO2 <90%). Across the same period, 8.6% (11 428/132 737) had oxygen prescribed but in 87%, pulse oximetry was either not done or the hypoxaemia threshold (SpO2 <90%) was not met. Lower chest-wall indrawing and other respiratory symptoms were associated with pulse oximetry use at admission and were also associated with oxygen prescription in the absence of pulse oximetry or hypoxaemia. The adoption of pulse oximetry recommended in international guidelines for assessing children with severe illness has been slow and erratic, reflecting system and organisational weaknesses. Most oxygen orders at admission seem driven by clinical and situational factors other than the presence of hypoxaemia. Programmes aiming to implement pulse oximetry and oxygen systems will likely need a long-term vision to promote adoption, guideline development and adherence and continuously examine impact.


Megakaryocytes, malignancy and bone marrow vascular niches.
Dynamic interactions between hematopoietic cells and their specialized bone marrow microenvironments, namely the vascular and osteoblastic 'niches', regulate hematopoiesis. The vascular niche is conducive for thrombopoiesis and megakaryocytes may, in turn, regulate the vascular niche, especially in supporting vascular and hematopoietic regeneration following irradiation or chemotherapy. A role for platelets in tumor growth and metastasis is well established and, more recently, the vascular niche has also been implicated as an area for preferential homing and engraftment of malignant cells. This article aims to provide an overview of the dynamic interactions between cellular and molecular components of the bone marrow vascular niche and the potential role of megakaryocytes in bone marrow malignancy.


Phase diagrams of the LiBH4-NaBH4-KBH4 system.
A combination of experimental and computational techniques has been used to fully describe the thermodynamic properties and phase diagrams of the LiBH4-NaBH4-KBH4 system. The Calphad method was used to assess the thermodynamic properties of LiBH4-NaBH4, LiBH4-KBH4, and NaBH4-KBH4 binary systems and to extend the investigation to the LiBH4-NaBH4-KBH4 ternary system. Samples with various compositions in the ternary system were synthesised, both by ball milling and manual mixing of the parent borohydrides, and their thermal stability has been studied using in situ synchrotron radiation X-ray diffraction as a function of temperature and using differential scanning calorimetry. From collected experimental and literature data, a thermodynamic assessment of the ternary system led to the determination of the phase diagrams. In all cases, the solid solutions can be described in the frame of the regular solution model, with interaction parameters positive or equal to zero (i.e. ideal solution). In contrast, the liquid phase was described using negative interaction parameters. A new ternary eutectic composition was estimated and it was confirmed experimentally to be equal to a molar fraction of 0.66LiBH4-0.11NaBH4-0.23KBH4 with a melting temperature of 102 °C.


Antiretroviral therapy in HIV-1-infected individuals with CD4 count below 100 cells/mm3 results in differential recovery of monocyte activation.
Reversal of monocyte and macrophage activation and the relationship to viral suppression and T cell activation are unknown in patients with advanced HIV-1 infection, initiating antiretroviral therapy. This study aimed to determine whether reduction in biomarkers of monocyte and macrophage activation would be reduced in conjunction with viral suppression and resolution of T cell activation. Furthermore, we hypothesized that the addition of CCR5 antagonism (by maraviroc) would mediate greater reduction of monocyte/macrophage activation markers than suppressive antiretroviral therapy alone. In the CCR5 antagonism to decrease the incidence of immune reconstitution inflammatory syndrome study, antiretroviral therapy-naïve patients received maraviroc or placebo in addition to standard antiretroviral therapy. PBMCs and plasma from 65 patients were assessed during 24 wk of antiretroviral therapy for biomarkers of monocyte and macrophage activation. Markers of monocyte and macrophage activation were reduced significantly by 24 wk, including CD14(++)CD16(+) intermediate monocytes (P < 0.0001), surface CD163 (P = 0.0004), CD169 (P < 0.0001), tetherin (P = 0.0153), and soluble CD163 (P < 0.0001). A change in CD38(+), HLA-DR(+) CD8 T cells was associated with changes in CD169 and tetherin expression. Maraviroc did not affect biomarkers of monocyte/macrophage activation but resulted in greater percentages of CCR5-positive monocytes in PBMC. HIV-1 suppression after 24 wk of antiretroviral therapy, with or without maraviroc, demonstrates robust recovery in monocyte subset activation markers, whereas soluble markers of activation demonstrate minimal decrease, qualitatively differentiating markers of monocyte/macrophage activation in advanced disease.


Predicting the effects of coastal hypoxia on vital rates of the planktonic copepod Acartia tonsa Dana.
We describe a model predicting the effects of low environmental oxygen on vital rates (egg production, somatic growth, and mortality) of the coastal planktonic copepod Acartia tonsa. Hypoxic conditions can result in respiration rate being directly limited by oxygen availability. We hypothesized that A. tonsa egg production, somatic growth, and ingestion rates would all respond in a similar manner to low oxygen conditions, as a result of oxygen dependent changes in respiration rate. Rate data for A. tonsa egg production, somatic growth, and ingestion under low environmental oxygen were compiled from the literature and from supplementary experiments. The response of these rates to oxygen was compared by converting all to the analogous units in terms of oxygen utilization, which we termed analogous respiration rate. These analogous respiration rates, along with published measurements of respiration rates, were used to parameterize and evaluate the relationship between A. tonsa respiration rate and environmental oxygen. At 18 °C, our results suggest that A. tonsa experiences sub-lethal effects of hypoxia below an oxygen partial pressure of 8.1 kPa (~3.1 mg L(-1) = 2.3 mL L(-1)). The results of this study can be used to predict the effects of hypoxia on A. tonsa growth and mortality as related to environmental temperature and oxygen partial pressure. Such predictions will be useful as a way to incorporate the effects of coastal hypoxia into population, community, or ecosystem level models that include A. tonsa. This approach can also be used to characterize the effects of hypoxia on other aquatic organisms.


Beyond altruistic and commercial contract motherhood: the professional model.
It has become common to distinguish between altruistic and commercial contract motherhood (or 'surrogacy'). Altruistic arrangements are based on the 'gift relationship': a woman is motivated by altruism to have a baby for an infertile couple, who are free to reciprocate as they see fit. By contrast, in commercial arrangements both parties are motivated by personal gain to enter a legally enforceable agreement, which stipulates that the contract mother or 'surrogate' is to bear a child for the intending parents in exchange for a fee. She is required to undergo medical examinations and to refrain from behaviour that could harm the foetus. The intending parents are the child's legal parents from the outset. The parties to the contract can, but are not expected to, maintain contact after the transaction is completed. We argue that contract motherhood should not be organized according to the norms of the gift relationship, and that contract mothers should be compensated for their labour. However, we accept that there are good reasons for rejecting the commercial model as a suitable framework for contract pregnancy, and argue, instead, in favour of viewing it as a profession.


Detection of Trichomonas vaginalis DNA by use of self-obtained vaginal swabs with the BD ProbeTec Qx assay on the BD Viper system.
Trichomonas vaginalis is the most prevalent nonviral sexually transmitted infection worldwide, and improved diagnostic methods are critical for controlling this pathogen. Diagnostic assays that can be used in conjunction with routine chlamydia/gonorrhea nucleic acid-based screening are likely to have the most impact on disease control. Here we describe the performance of the new BD T. vaginalis Qx (TVQ) amplified DNA assay, which can be performed on the automated BD Viper system. We focus on data from vaginal swab samples, since this is the specimen type routinely used for traditional trichomonas testing and the recommended specimen type for chlamydia/gonorrhea screening. Vaginal swabs were obtained from women attending sexually transmitted disease or family planning clinics at 7 sites. Patient-collected vaginal swabs were tested by the TVQ assay, and the Aptima T. vaginalis (ATV) assay was performed using clinician-collected vaginal swabs. Additional clinician-collected vaginal swabs were used for the wet mount and culture methods. Analyses included comparisons versus the patient infection status (PIS) defined by positive results with the wet mount method or culture, direct comparisons assessed with κ scores, and latent class analysis (LCA) as an unbiased estimator of test accuracy. Data from 838 women, 116 of whom were infected with T. vaginalis, were analyzed. The TVQ assay sensitivity and specificity estimates based on the PIS were 98.3% and 99.0%, respectively. The TVQ assay was similar to the ATV assay (κ=0.938) in direct analysis. LCA estimated the TVQ sensitivity and specificity as 98.3 and 99.6%, respectively. The TVQ assay performed well using self-collected vaginal swabs, the optimal sample type, as recommended by the CDC for chlamydia/gonorrhea screening among women.


No booster dose for yellow fever vaccination: what are the consequences for the activity of vaccination in travel clinics?
In April 2013, the Strategic Advisory Group of Experts (SAGE) on immunization stated that a single dose of yellow fever (YF) vaccine is sufficient in the general population to confer a lifelong protection against YF. When the period of validity of the International Certificate of Vaccination (ICV) will be extended to a lifetime in June 2016, no booster dose will be needed. The objective of this prospective study was to determine the potential impact of the SAGE recommendations on the vaccination activity of our travel clinics. We showed that among 1,037 subjects seen in our three travel clinics for a YF vaccination in 2013, about 32.3% went for a booster dose that is no longer useful according to the SAGE. A drop in vaccination activity has to be expected by travel clinics in the next years, and changes in daily exercise have to be anticipated, as YF vaccination is a large part of the regular work of many healthcare providers specialized in travel medicine.


Decreased maternal serum acetate and impaired fetal thymic and regulatory T cell development in preeclampsia.
Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4+ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.


Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial.
To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase trial in adult and pediatric myositis patients. Adults with refractory polymyositis (PM) and adults and children with refractory dermatomyositis (DM) were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal values on core set measures (CSMs) for adults. Juvenile DM patients required ≥3 abnormal CSMs, with or without muscle weakness. Patients were randomized to receive either rituximab early or rituximab late, and glucocorticoid or immunosuppressive therapy was allowed at study entry. The primary end point compared the time to achieve the International Myositis Assessment and Clinical Studies Group preliminary definition of improvement (DOI) between the 2 groups. The secondary end points were the time to achieve ≥20% improvement in muscle strength and the proportions of patients in the early and late rituximab groups achieving the DOI at week 8. Among 200 randomized patients (76 with PM, 76 with DM, and 48 with juvenile DM), 195 showed no difference in the time to achieving the DOI between the rituximab late (n = 102) and rituximab early (n = 93) groups (P = 0.74 by log rank test), with a median time to achieving a DOI of 20.2 weeks and 20.0 weeks, respectively. The secondary end points also did not significantly differ between the 2 treatment groups. However, 161 (83%) of the randomized patients met the DOI, and individual CSMs improved in both groups throughout the 44-week trial. Although there were no significant differences in the 2 treatment arms for the primary and secondary end points, 83% of adult and juvenile myositis patients with refractory disease met the DOI. The role of B cell-depleting therapies in myositis warrants further study, with consideration for a different trial design.


Children's medical fears, coping behaviors, and pain perceptions during a lumbar puncture.
This study explored the relationships among medical fears, coping behaviors, and acute pain perceptions in 17 children with cancer who were encountering a painful medical procedure. The children completed the Child Medical Fear Scale (CMFS) before undergoing a lumbar puncture (LP), which was videotaped. The children's coping behaviors during the procedure were rated independently and classified as active or passive behaviors. Immediately following the LP, the children, using a pictorial scale, reported their pain perceptions. Most of the children's scores on the CMFS indicated a moderately low level of fear of medical experiences. A majority of the children perceived a great deal of pain during the LP. During the five phases of the painful medical procedure, more than half of the children exhibited a combination of active and passive behaviors. No significant differences were found between exhibited active or passive coping behaviors and reported medical fear levels; however, children who exhibited passive coping behaviors reported more pain than those who demonstrated active coping behaviors. Implications for practice relate to the need for continual preparation and support of children during a painful procedure.


Helicobacter pylori-induced histone modification, associated gene expression in gastric epithelial cells, and its implication in pathogenesis.
Histone modifications are critical in regulating gene expression, cell cycle, cell proliferation, and development. Relatively few studies have investigated whether Helicobacter pylori, the major cause of human gastric diseases, affects histone modification. We therefore investigated the effects of H. pylori infection on histone modifications in a global and promoter-specific manner in gastric epithelial cells. Infection of gastric epithelial cells by wild-type H. pylori induced time- and dose-dependent dephosphorylation of histone H3 at serine 10 (H3 Ser10) and decreased acetylation of H3 lysine 23, but had no effects on seven other specific modifications. Different cag pathogenicity island (PAI)-containing-clinical isolates showed similar abilities to induce H3 Ser10 dephosphorylation. Mutation of cagA, vacA, nonphosphorylateable CagA mutant cagA(EPISA), or disruption of the flagella showed no effects, while deletion of the entire cagPAI restored the H3 Ser10 phosphorylation to control levels. Analysis of 27 cagPAI mutants indicated that the genes that caused H3 Ser10 dephosphorylation were similar to those that were previously found to induce interleukin-8, irrespective of CagA translocation. This effect was independent of ERK or p38 pathways and type I interferon signaling. Additionally, c-Jun and hsp70 gene expression was associated with this histone modification. These results demonstrate that H. pylori alters histone modification and host response via a cagA-, vacA-independent, but cagPAI-dependent mechanisms, which contribute to its persistent infection and pathogenesis.


Immune cells in cardiac repair and regeneration.
The immune system is fundamental to tissue homeostasis and is the first line of defense following infection, injury or disease. In the damaged heart, large numbers of immune cells are recruited to the site of injury. These cells play an integral part in both repair by scar formation and the initiation of tissue regeneration. They initially assume inflammatory phenotypes, releasing pro-inflammatory cytokines and removing dead and dying tissue, before entering a reparative stage, replacing dead muscle tissue with a non-contractile scar. In this Review, we present an overview of the innate and adaptive immune response to heart injury. We explore the kinetics of immune cell mobilization following cardiac injury and how the different innate and adaptive immune cells interact with one another and with the damaged tissue. We draw on key findings from regenerative models, providing insight into how to support a robust immune response permissible for cardiac regeneration. Finally, we consider how the latest technological developments can offer opportunities for a deeper and unbiased functional understanding of the immune response to heart disease, highlighting the importance of such knowledge as the basis for promoting regeneration following cardiac injury in human patients.


The Gilles de la Tourette syndrome: the current status.
Gilles de la Tourette syndrome (GTS) is characterised by multiple motor and one or more vocal/phonic tics. GTS was once thought to be rare, but many relatively recent studies suggest that the prevalence is about 1% of the worldwide community, apart from in Sub-Saharan Black Africa. Comorbidity and coexistent psychopathology are common, occurring in about 90% of clinical cohorts and individuals in the community. The most common comorbidities are attention deficit hyperactivity disorder, obsessive-compulsive behaviours, and disorder, and autistic spectrum disorders, while the most common coexisting psychopathologies are depression, anxiety and behavioural disorders such as oppositional defiant and conduct disorder. There has been an increasing amount of evidence to show that the quality of life in young people is reduced when compared with normative data or healthy control populations. It is widely accepted that most cases of GTS are inherited, but the genetic mechanisms appear much more complex than previously understood, as evidenced by many recent studies; indeed, there have been suggestions of 'general neurodevelopmental genes' which affect the brain development after which the 'specific GTS gene(s)' may further affect the phenotype. Other aetiopathogenetic suggestions have included environmental factors such as neuro-immunological factors, infections, prenatal and peri-natal difficulties and androgen influences. Few studies have addressed aetiology and phenotype, but initial results are exciting. The search for endophenotypes has followed subsequently. Intriguing neuroanatomical and brain circuitry abnormalities have now been suggested in GTS; the most evidence is for cortical thinning and a reduction in the size of the caudate nucleus. Thorough assessment is imperative and multidisciplinary management is the ideal. Treatment should be 'symptom targeted', and in mild cases, psycho-education and reassurance for the patient and the family may be sufficient. Behavioural treatments such as Comprehensive Behavioural Intervention for Tics including Habit Reversal Training have been shown to be significantly better than other behavioural/psychological treatments and 'placebo'. Medication is often necessary for moderately affected individuals. In more severe cases, medical treatment is not simple and referral to an expert may be advisable. In general, neuroleptics and clonidine or guanfacine are the medications of choice for the tics. Other treatments which may be needed for loud and severe phonic tics include botulinum toxin. In severe adult GTS patients who are refractory to medication and other therapies, deep brain stimulation looks promising.


HIV-1 Tat-Induced Astrocytic Extracellular Vesicle miR-7 Impairs Synaptic Architecture.
Although combination antiretroviral therapy (cART) has improved the health of millions of those living with HIV-1 (Human Immunodeficiency Virus, Type 1), the penetration into the central nervous system (CNS) of many such therapies is limited, thereby resulting in residual neurocognitive impairment commonly referred to as NeuroHIV. Additionally, while cART has successfully suppressed peripheral viremia, cytotoxicity associated with the presence of viral Transactivator of transcription (Tat) protein in tissues such as the brain, remains a significant concern. Our previous study has demonstrated that both HIV-1 Tat as well as opiates such as morphine, can directly induce synaptic alterations via independent pathways. Herein, we demonstrate that exposure of astrocytes to HIV-1 protein Tat mediates the induction and release of extracellular vesicle (EV) microRNA-7 (miR-7) that is taken up by neurons, leading in turn, to downregulation of neuronal neuroligin 2 (NLGN2) and ultimately to synaptic alterations. More importantly, we report that these impairments could be reversed by pretreatment of neurons with a neurotrophic factor platelet-derived growth factor-CC (PDGF-CC). Graphical Abstract.


Point-of-sale alcohol promotions in the Perth and Sydney metropolitan areas.
Point-of-sale (POS) is increasingly being used as a marketing tool for alcohol products, and there is a growing body of evidence suggesting that these materials are positively associated with drinking and contribute to creating a pro-alcohol environment. The purpose of the present study was to document the nature and extent of POS alcohol promotions in bottle shops in two Australian capital cities. A purposive sample of 24 hotel bottle shops and liquor stores was selected across Sydney (New South Wales) and Perth (Western Australia) and audited for the presence and nature of POS marketing. Point-of-sale promotions were found to be ubiquitous, with an average of 33 promotions per outlet. Just over half were classified as 'non-price' promotions (e.g. giveaways and competitions). Spirits were the most commonly promoted type of alcohol. The average number of standard drinks required to participate in the promotions ranged from 12 for ready to drinks to 22 for beer. Alcohol outlets that were part of supermarket chains had a higher number of promotions, more price-based promotions, and required a greater quantity of alcohol to be purchased to participate in the promotion. The data collected in this study provides a starting point for our understanding of POS promotions in Australia, and poses important questions for future research in this area.


Convection-enhanced delivery of M13 bacteriophage to the brain.
Recent studies indicate that M13 bacteriophage, a very large nanoparticle, binds to β-amyloid and α-synuclein proteins, leading to plaque disaggregation in models of Alzheimer and Parkinson disease. To determine the feasibility, safety, and characteristics of convection-enhanced delivery (CED) of M13 bacteriophage to the brain, the authors perfused primate brains with bacteriophage. Four nonhuman primates underwent CED of M13 bacteriophage (900 nm) to thalamic gray matter (4 infusions) and frontal white matter (3 infusions). Bacteriophage was coinfused with Gd-DTPA (1 mM), and serial MRI studies were performed during infusion. Animals were monitored for neurological deficits and were killed 3 days after infusion. Tissues were analyzed for bacteriophage distribution. Real-time T1-weighted MRI studies of coinfused Gd-DTPA during infusion demonstrated a discrete region of perfusion in both thalamic gray and frontal white matter. An MRI-volumetric analysis revealed that the mean volume of distribution (Vd) to volume of infusion (Vi) ratio of M13 bacteriophage was 2.3 ± 0.2 in gray matter and 1.9 ± 0.3 in white matter. The mean values are expressed ± SD. Immunohistochemical analysis demonstrated mean Vd:Vi ratios of 2.9 ± 0.2 in gray matter and 2.1 ± 0.3 in white matter. The Gd-DTPA accurately tracked M13 bacteriophage distribution (the mean difference between imaging and actual bacteriophage Vd was insignificant [p > 0.05], and was -2.2% ± 9.9% in thalamic gray matter and 9.1% ± 9.5% in frontal white matter). Immunohistochemical analysis revealed evidence of additional spread from the initial delivery site in white matter (mean Vd:Vi, 16.1 ± 9.1). All animals remained neurologically intact after infusion during the observation period, and histological studies revealed no evidence of toxicity. The CED method can be used successfully and safely to distribute M13 bacteriophage in the brain. Furthermore, additional white matter spread after infusion cessation enhances distribution of this large nanoparticle. Real-time MRI studies of coinfused Gd-DTPA (1 mM) can be used for accurate tracking of distribution during infusion of M13 bacteriophage.


Presymptomatic diagnosis of von Hippel-Lindau disease with flanking DNA markers.
Von Hippel-Lindau (VHL) disease is a dominantly inherited cancer syndrome characterised by the development of retinal, cerebellar, and spinal haemangioblastomas, renal cell carcinoma, and phaeochromocytoma. The gene for VHL disease has been mapped to chromosome 3p25-p26 and flanking markers identified. We have investigated the usefulness of currently available DNA markers for the presymptomatic diagnosis of VHL disease. In the first part of this investigation, genetic linkage data from two previously published studies were updated and reanalysed to provide accurate estimates of sex specific recombination fractions and to confirm that there is no evidence of locus heterogeneity. In the second part of this study, 14 families containing 23 asymptomatic subjects at 50% prior risk of VHL disease were investigated with closely linked DNA markers (RAF1, D3S18, D3S732). Seventeen subjects were informative with one or more markers, six of whom were informative at markers flanking the VHL disease gene. By combining age related and DNA based risk information the carrier risk for 11 subjects was reduced to < 2%.


ADHD in the Arab world: a review of epidemiologic studies.
Epidemiological studies on psychiatric disorders are quite rare in the Arab World. This article reviews epidemiological studies on ADHD in all the Arab countries. All epidemiological studies on ADHD conducted from 1966 through th present were reviewed. Samples were drawn from the general community, primary care clinical settings, and populations of traumatized children. Data on prevalence, gender differences, risk factors, comorbidity, and burden of ADHD were reviewed. ADHD rates in Arab populations were similar to those in other cultures. Comparisons within Arab studies were difficult given the variability of methodology and instruments used. There is an important need for research on ADHD in the Arab World, not only to assess the national prevalence in children and adolescents, but also to look at the differential burden and treatment of this disorder, which has high levels of mental comorbidities and high impact across the life span.


Ciprofloxacin-resistant Haemophilus influenzae strains possess mutations in analogous positions of GyrA and ParC.
The nucleotide sequences of the quinolone resistance-determining regions of the gyrA and parC genes from five ciprofloxacin-resistant strains of Haemophilus influenzae (MICs, 2 to 32 micrograms/ml) isolated from patients with cystic fibrosis and three ciprofloxacin-susceptible strains of H. influenzae (MICs, < or = 0.1 micrograms/ml) were determined. Four of the five resistant strains possessed at least one amino acid substitution in each of the GyrA and ParC fragments studied. The mutations identified in GyrA were a serine at residue 84 (Ser-84) to Leu or Tyr and Asp-88 to Asn or Tyr. ParC mutations were in positions exactly analogous to those identified in GyrA, namely, Ser-84 to Ile and Glu-88 to Lys. The Glu-88 to Lys ParC substitution was identified only in high-level ciprofloxacin-resistant strains. These mutations have been shown to be the origin of the observed resistance after transformation into ciprofloxacin-susceptible H. influenzae isolates. These results suggest that H. influenzae isolates require at least one amino acid substitution in both GyrA and ParC in order to attain significant levels of resistance to quinolones.


A comparative study of most suitable miniplate fixation for mandibular symphysis fracture using a finite element model.
The purpose of this study is to determine the most stable fixation method for mandibular symphysis fractures by comparing the mechanical characteristics of models fixed at different positions with different numbers of plates. Fractures were generated in 3-dimensional finite element models, and were fixed with a single miniplate, parallel double miniplates, or perpendicular double miniplates. A 300 N perpendicular load was then applied on the left molar region, and a finite element analysis was performed. We compared vertical gaps between the fractured surfaces, maximum stress within the screw/plating system, and maximum stress around screw holes in the bone. Compared to the single miniplate, both the parallel and perpendicular double miniplates demonstrated significantly less stress in the screw/plating system and screw holes in the bone. In addition, the perpendicular double miniplateshad significantly smaller vertical gaps between fracture surfaces when compared to the single miniplate. Comparing parallel and perpendicular double miniplate fixations, less stress was found around the screw holes of the perpendicular miniplate models than those of the parallel miniplatemodels. There were no differences in vertical gaps or maximum stress within the screw/plating systems between the 2 double miniplate fixations. These results suggest that perpendicular double miniplate fixation is more suitable for fixing mandibular symphysis fractures.


Alzheimer's disease and insulin resistance: translating basic science into clinical applications.
Alzheimer's disease (AD) and diabetes are currently considered among the top threats to human health worldwide. Intriguingly, a connection between these diseases has been established during the past decade, since insulin resistance, a hallmark of type 2 diabetes, also develops in Alzheimer brains. In this article, the molecular and cellular mechanisms underlying defective brain insulin signaling in AD are discussed, with emphasis on evidence that Alzheimer's and diabetes share common inflammatory signaling pathways. I put forward here a hypothesis on how a cross-talk between peripheral tissues and the brain might influence the development of AD, and highlight important unanswered questions in the field. Furthermore, I discuss a rational basis for the use of antidiabetic agents as novel and potentially effective therapeutics in AD.


Crosslinked gelatin matrices: release of a random coil macromolecular solute.
The purpose of this investigation was to evaluate the effect of matrix crosslinking and solute size on release of a random coil macromolecular solute from crosslinked gelatin matrices. Gelatin hydrogel matrices crosslinked with different molar ratios of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC):epsilon-amino groups on gelatin (1:1, 4:1, and 10:1) were prepared containing dextran of molecular weights 12, 20, and 77 kDa, and hydrodynamic diameters 54, 74, and 133 A, respectively. The extent of matrix crosslinking was determined quantitatively and used to calculate the molecular weight between crosslinks (Mc). The Mc parameter and equilibrium swelling ratio (Qm) were used to calculate an estimated matrix mesh size (xi). The in vitro release of incorporated dextran was evaluated at 37 degrees C in PBS at pH 7.4 for approximately 80 h. The one-, four- and 10-fold molar ratios of crosslinking agent EDC yielded 24, 41, and 78% of gelatin matrix crosslinking, respectively. The calculated average matrix mesh size ranged from 338 to 90 A. The effect of matrix crosslinking varied with solute size, from retarding diffusional release of the dextran to completely entrapping it inside the crosslinked matrices. These results support the threshold concept of solute size relative to matrix mesh size for release of a flexible, random coil macromolecular solute from a hydrogel.


Methodological developments in searching for studies for systematic reviews: past, present and future?
The Cochrane Collaboration was established in 1993, following the opening of the UK Cochrane Centre in 1992, at a time when searching for studies for inclusion in systematic reviews was not well-developed. Review authors largely conducted their own searches or depended on medical librarians, who often possessed limited awareness and experience of systematic reviews. Guidance on the conduct and reporting of searches was limited. When work began to identify reports of randomized controlled trials (RCTs) for inclusion in Cochrane Reviews in 1992, there were only approximately 20,000 reports indexed as RCTs in MEDLINE and none indexed as RCTs in Embase. No search filters had been developed with the aim of identifying all RCTs in MEDLINE or other major databases. This presented The Cochrane Collaboration with a considerable challenge in identifying relevant studies.Over time, the number of studies indexed as RCTs in the major databases has grown considerably and the Cochrane Central Register of Controlled Trials (CENTRAL) has become the best single source of published controlled trials, with approximately 700,000 records, including records identified by the Collaboration from Embase and MEDLINE. Search filters for various study types, including systematic reviews and the Cochrane Highly Sensitive Search Strategies for RCTs, have been developed. There have been considerable advances in the evidence base for methodological aspects of information retrieval. The Cochrane Handbook for Systematic Reviews of Interventions now provides detailed guidance on the conduct and reporting of searches. Initiatives across The Cochrane Collaboration to improve the quality inter alia of information retrieval include: the recently introduced Methodological Expectations for Cochrane Intervention Reviews (MECIR) programme, which stipulates 'mandatory' and 'highly desirable' standards for various aspects of review conduct and reporting including searching, the development of Standard Training Materials for Cochrane Reviews and work on peer review of electronic search strategies. Almost all Cochrane Review Groups and some Cochrane Centres and Fields now have a Trials Search Co-ordinator responsible for study identification and medical librarians and other information specialists are increasingly experienced in searching for studies for systematic reviews.Prospective registration of clinical trials is increasing and searching trials registers is now mandatory for Cochrane Reviews, where relevant. Portals such as the WHO International Clinical Trials Registry Platform (ICTRP) are likely to become increasingly attractive, given concerns about the number of trials which may not be registered and/or published. The importance of access to information from regulatory and reimbursement agencies is likely to increase. Cross-database searching, gateways or portals and improved access to full-text databases will impact on how searches are conducted and reported, as will services such as Google Scholar, Scopus and Web of Science. Technologies such as textual analysis, semantic analysis, text mining and data linkage will have a major impact on the search process but efficient and effective updating of reviews may remain a challenge.In twenty years' time, we envisage that the impact of universal social networking, as well as national and international legislation, will mean that all trials involving humans will be registered at inception and detailed trial results will be routinely available to all. Challenges will remain, however, to ensure the discoverability of relevant information in diverse and often complex sources and the availability of metadata to provide the most efficient access to information. We envisage an ongoing role for information professionals as experts in identifying new resources, researching efficient ways to link or mine them for relevant data and managing their content for the efficient production of systematic reviews.


Pathways from education to fertility decline: a multi-site comparative study.
Women's education has emerged as a central predictor of fertility decline, but the many ways that education affects fertility have not been subject to detailed comparative investigation. Taking an evolutionary biosocial approach, we use structural equation modelling to examine potential pathways between education and fertility including: infant/child mortality, women's participation in the labour market, husband's education, social network influences, and contraceptive use or knowledge across three very different contexts: Matlab, Bangladesh; San Borja, Bolivia; and rural Poland. Using a comparable set of variables, we show that the pathways by which education affects fertility differ in important ways, yet also show key similarities. For example, we find that across all three contexts, education is associated with delayed age at first birth via increasing women's labour-force participation, but this pathway only influences fertility in rural Poland. In Matlab and San Borja, education is associated with lower local childhood mortality, which influences fertility, but this pathway is not important in rural Poland. Similarities across sites suggest that there are common elements in how education drives demographic transitions cross-culturally, but the differences suggest that local socioecologies also play an important role in the relationship between education and fertility decline.


Sex differences in the HPA axis.
The hypothalamic-pituitary-adrenal (HPA) axis is a major component of the systems that respond to stress, by coordinating the neuroendocrine and autonomic responses. Tightly controlled regulation of HPA responses is critical for maintaining mental and physical health, as hyper- and hypo-activity have been linked to disease states. A long history of research has revealed sex differences in numerous components of the HPA stress system and its responses, which may partially form the basis for sex disparities in disease development. Despite this, many studies use male subjects exclusively, while fewer reports involve females or provide direct sex comparisons. The purpose of this article is to present sex comparisons in the functional and molecular aspects of the HPA axis, through various phases of activity, including basal, acute stress, and chronic stress conditions. The HPA axis in females initiates more rapidly and produces a greater output of stress hormones. This review focuses on the interactions between the gonadal hormone system and the HPA axis as the key mediators of these sex differences, whereby androgens increase and estrogens decrease HPA activity in adulthood. In addition to the effects of gonadal hormones on the adult response, morphological impacts of hormone exposure during development are also involved in mediating sex differences. Additional systems impinging on the HPA axis that contribute to sex differences include the monoamine neurotransmitters norepinephrine and serotonin. Diverse signals originating from the brain and periphery are integrated to determine the level of HPA axis activity, and these signals are, in many cases, sex-specific.


European Union implementation of Article 5.3 of the Framework Convention on Tobacco Control.
Article 5.3 of the World Health Organization's Framework Convention on Tobacco Control (FCTC) requires Parties to the agreement to take proactive measures to protect health policy from the vested interests of the tobacco industry. Parties to the FCTC are required to submit periodic reports to the Convention Secretariat on the efforts undertaken to implement it. Previous analyses of national compliance with the FCTC suggest that Article 5.3 implementation is piecemeal and insufficient in many contexts, with governments relying on general transparency and other existing policies for the purpose of Article 5.3 implementation. No in-depth study of Article 5.3 compliance within the European Union (EU) - a signatory to the Convention - has been undertaken. This study seeks to assess the extent of Article 5.3 compliance in European Union institutions, through an analysis of the mechanisms in place in the European Commission and European Parliament. It analyses EU documents relevant to Article 5.3 compliance, as well as semi-structured interviews with policy actors in the EU institutions and the field of tobacco control. As with many national governments, Article 5.3 compliance within EU institutions is partial and incomplete. Much of the compliance activity cited in EU reports is derived from general codes of conduct for EU staff and the Juncker Commission's transparency agenda. Interview respondents reveal widespread lack of knowledge about the existence of the FCTC and Article 5.3 amongst key policy actors across the institutions. Within the Commission policies vary greatly between Directorates General, and issues surrounding the conceptualisation of the role of Members of the European Parliament affect implementation in that context. While there is growing awareness of the issue in both the Commission and the Parliament, in large part as a result of the experience of lobbying over the Tobacco Products Directive, there remains considerable resistance in both institutions to further substantive action to implement Article 5.3. We recommend that a binding and comprehensive policy and code of conduct, specifically designed for the implementation of Article 5.3 and based on the World Health Organization's guidelines, be created to cover the activities of all employees of all EU institutions. Crucially, such guidelines would need to deal explicitly with third parties acting for the tobacco industry.


Standing Up Slowly Antagonises Initial Blood Pressure Decrease in Older Adults with Orthostatic Hypotension.
Orthostatic hypotension (OH) is common in older adults and associated with increased morbidity and mortality, loss of independence and high health-care costs. Standing up slowly is a recommended non-pharmacological intervention. However, the effectiveness of this advice has not been well studied. The aim of this study was to investigate whether standing up slowly antagonises posture-related blood pressure (BP) decrease in a clinically relevant population of geriatric outpatients. In this cross-sectional study, 24 community-dwelling older adults referred to a geriatric outpatient clinic and diagnosed with OH were included. BP was measured continuously during 3 consecutive transitions from supine to standing position during normal, slow and fast transition. The relative BP decrease at 0-15 s after slow transition was significantly lower than after normal transition (p = 0.003 for both systolic BP and diastolic BP) and fast transition (p = 0.045 for systolic BP; diastolic BP: non-significant). The relative diastolic BP decrease at 60-180 s after normal transition was significantly lower than after fast transition (p = 0.029). Standing up slowly antagonises BP decrease predominantly during the first 15 s of standing up in a clinically relevant population of geriatric outpatients diagnosed with OH. Results support the non-pharmacological intervention in clinical practice to counteract OH.


Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials.
To determine whether parachutes are effective in preventing major trauma related to gravitational challenge. Systematic review of randomised controlled trials. Medline, Web of Science, Embase, and the Cochrane Library databases; appropriate internet sites and citation lists. Studies showing the effects of using a parachute during free fall. Death or major trauma, defined as an injury severity score > 15. We were unable to identify any randomised controlled trials of parachute intervention. As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute.


Association of Sleep Quality With Greater Left Ventricular Mass in Children Aged 9 to 11 Years.
Research has consistently found associations between sleep characteristics and cardiovascular disease risk in children, adolescents, and adults. Although primarily investigated in clinical samples (e.g., in those with sleep disorders), greater left ventricular mass is associated with poor sleep quality in nonclinical adult populations as well; however, this has not been evaluated in children or adolescents. Our study aim was to consider the relationship between objectively measured sleep characteristics and left ventricular mass in children. We assessed sleep and cardiac structure in a biracial sample of 9- to 11-year-old children (n = 176; 41% White, 59% Black; 50% female). Sleep was assessed with actigraphy for five nights. Cardiac dimensions were assessed using echocardiography. After adjusting for covariates, we found that poor sleep quality was associated with significantly greater left ventricular mass (β = 0.13, t(167) = 2.14, p = .034, Cohen d = 0.16, for activity during sleep; β = 0.15, t(167) = 2.43, p = .016, Cohen d = 0.18, for sleep fragmentation). Other cardiac dimensions (namely, relative wall thickness and right ventricular dimension) were also significantly associated with sleep characteristics. Notably, associations did not differ as a function of sex or race. The present findings are novel and unique because no prior reports have systematically documented the association between poor sleep quality with potentially detrimental cardiac remodeling in a nonclinical sample of children. However, the novelty and importance of these findings require additional research for confirmation.


The primary prevention of epilepsy: A report of the Prevention Task Force of the International League Against Epilepsy.
Among the causes of epilepsy are several that are currently preventable. In this review, we summarize the public health burden of epilepsy arising from such causes and suggest priorities for primary epilepsy prevention. We conducted a systematic review of published epidemiologic studies of epilepsy of 4 preventable etiologic categories-perinatal insults, traumatic brain injury (TBI), central nervous system (CNS) infection, and stroke. Applying consistent criteria, we assessed the quality of each study and extracted data on measures of risk from those with adequate quality ratings, summarizing findings across studies as medians and interquartile ranges. Among higher-quality population-based studies, the median prevalence of active epilepsy across all ages was 11.1 per 1000 population in lower- and middle-income countries (LMIC) and 7.0 per 1000 in high-income countries (HIC). Perinatal brain insults were the largest attributable fraction of preventable etiologies in children, with median estimated fractions of 17% in LMIC and 15% in HIC. Stroke was the most common preventable etiology among older adults with epilepsy, both in LMIC and in HIC, accounting for half or more of all new onset cases. TBI was the attributed cause in nearly 5% of epilepsy cases in HIC and LMIC. CNS infections were a more common attributed cause in LMIC, accounting for about 5% of all epilepsy cases. Among some rural LMIC communities, the median proportion of epilepsy cases attributable to endemic neurocysticercosis was 34%. A large proportion of the overall public health burden of epilepsy is attributable to preventable causes. The attributable fraction for perinatal causes, infections, TBI, and stroke in sum reaches nearly 25% in both LMIC and HIC. Public health interventions addressing maternal and child health care, immunizations, public sanitation, brain injury prevention, and stroke prevention have the potential to significantly reduce the burden of epilepsy.


Transitions of tethered chain molecules under tension.
An applied tension force changes the equilibrium conformations of a polymer chain tethered to a planar substrate and thus affects the adsorption transition as well as the coil-globule and crystallization transitions. Conversely, solvent quality and surface attraction are reflected in equilibrium force-extension curves that can be measured in experiments. To investigate these effects theoretically, we study tethered chains under tension with Wang-Landau simulations of a bond-fluctuation lattice model. Applying our model to pulling experiments on biological molecules we obtain a good description of experimental data in the intermediate force range, where universal features dominate and finite size effects are small. For tethered chains in poor solvent, we observe the predicted two-phase coexistence at transitions from the globule to stretched conformations and also discover direct transitions from crystalline to stretched conformations. A phase portrait for finite chains constructed by evaluating the density of states for a broad range of solvent conditions and tensions shows how increasing tension leads to a disappearance of the globular phase. For chains in good solvents tethered to hard and attractive surfaces we find the predicted scaling with the chain length in the low-force regime and show that our results are well described by an analytical, independent-bond approximation for the bond-fluctuation model for the highest tensions. Finally, for a hard or slightly attractive surface the stretching of a tethered chain is a conformational change that does not correspond to a phase transition. However, when the surface attraction is sufficient to adsorb a chain it will undergo a desorption transition at a critical value of the applied force. Our results for force-induced desorption show the transition to be discontinuous with partially desorbed conformations in the coexistence region.


Presence of potential bacterial pathogens in a municipal drinking water supply system.
The quality of drinking water is a major public concern, but the detection of most potential pathogens is not always included in drinking water hygienic monitoring or is only assessed with highly biased cultivation-based methods. In this study, the occurrence of Pseudomonas aeruginosa and Legionella spp. was examined with taxon-specific PCRs in samples taken at ten points of a municipal drinking water supply system in three months. Sequence analysis confirmed the positivity of samples and revealed a diverse community of legionellae. The results showed that chlorination was an important and effective disinfection method against pathogenic bacteria in drinking water, but pathogenic bacteria could reoccur in the system farther away from the chlorination point. No strong correlation was found between the presence of the investigated potentially pathogenic bacteria and the measured abiotic and biotic parameters within the investigated range. It is hypothesized that instead of physicochemical parameters, the main factors influencing the presence of pathogens in the drinking water were rather the composition of the microbial community, the biotic interactions between individual non-pathogenic and pathogenic microorganisms (competition or promotion of growth) and the structure of biofilm grown on the inner surface of the supply system.


Control of Precision Grip Force in Lifting and Holding of Low-Mass Objects.
Few studies have investigated the control of grip force when manipulating an object with an extremely small mass using a precision grip, although some related information has been provided by studies conducted in an unusual microgravity environment. Grip-load force coordination was examined while healthy adults (N = 17) held a moveable instrumented apparatus with its mass changed between 6 g and 200 g in 14 steps, with its grip surface set as either sandpaper or rayon. Additional measurements of grip-force-dependent finger-surface contact area and finger skin indentation, as well as a test of weight discrimination, were also performed. For each surface condition, the static grip force was modulated in parallel with load force while holding the object of a mass above 30 g. For objects with mass smaller than 30 g, on the other hand, the parallel relationship was changed, resulting in a progressive increase in grip-to-load force (GF/LF) ratio. The rayon had a higher GF/LF force ratio across all mass levels. The proportion of safety margin in the static grip force and normalized moment-to-moment variability of the static grip force were also elevated towards the lower end of the object mass for both surfaces. These findings indicate that the strategy of grip force control for holding objects with an extremely small mass differs from that with a mass above 30 g. The data for the contact area, skin indentation, and weight discrimination suggest that a decreased level of cutaneous feedback signals from the finger pads could have played some role in a cost function in efficient grip force control with low-mass objects. The elevated grip force variability associated with signal-dependent and internal noises, and anticipated inertial force on the held object due to acceleration of the arm and hand, could also have contributed to the cost function.


Incomplete stent apposition in Enterprise stent-mediated coiling of aneurysms: persistence over time and risk of delayed ischemic events.
Incomplete stent apposition of the closed cell-design Enterprise stent following stent-mediated coil embolization of intracranial aneurysms has been associated with increased risk of periprocedural thromboembolic events. In this study, the authors seek to determine the natural history of incomplete stent apposition and evaluate the clinical implications of the phenomenon. Since January 2009, all patients receiving Enterprise stents in the treatment of intracranial aneurysms at the authors' institution have undergone serial 3-T MRI with incomplete stent apposition identified by the crescent sign on multiplanar reconstructions of MR angiograms. Magnetic resonance images and MR angiograms obtained at 3, 9, and 18 months after stent-assisted coil embolization were analyzed along with admission and follow-up clinical medical records. These records were evaluated for any radiographic and clinical, transient or permanent ischemic neurological events. Fifty patients receiving Enterprise stents were eligible for inclusion and analysis in the study. Incomplete stent apposition was identified in postoperative imaging studies in 22 (44%) of 50 patients, with 19 (86%) of 22 crescent signs persisting and 3 (14%) of 22 crescent signs resolving on subsequent serial imaging. Delayed ischemic events occurred in 8 (16%) of 50 cases, and all cases involved patients with incomplete stent apposition. The events were transient ischemic attacks (TIAs) in 5 cases, asymptomatic radiographic strokes in 2 cases, and symptomatic strokes and TIAs in the final case. There were no delayed ischemic events in patients who did not have incomplete stent apposition. Only 1 of the delayed ischemic events (2%) was permanent and symptomatic. The postoperative presence of a crescent sign and persistence of the crescent sign were both significantly associated with delayed ischemic events (p < 0.001 and p = 0.002, respectively). Incomplete stent apposition is a temporally persistent phenomenon, which resolves spontaneously in only a small minority of cases and appears to be a risk factor for delayed ischemic events. Although further follow-up is needed, these results suggest that longer duration of antiplatelet therapy and clinical follow-up may be warranted in cases of recognized incomplete stent apposition.


A national collaborative for reducing health care‒associated infections: current initiatives, challenges, and opportunities.
There has been increasing interest and an upsurge in efforts to prevent hospital-associated infections (HAIs), a leading cause of death in the United States. This study was conducted to assess current strategies and efforts of HAI reduction initiatives in hospitals. HAI reduction initiatives and factors influencing institutional participation in these initiatives were categorized. Data were collected via open-ended questions on surveys performed in 5 different HAI collaboratives. Thematic analysis of the coded qualitative data was conducted. A total of 1,212 health care professionals from 33 different hospitals participated. Improving hand hygiene was the most frequently mentioned HAI reduction initiative implemented in the previous year. Initiatives for reducing central line or central venous catheter infections and ventilator-associated pneumonia also were commonly cited. The most frequently mentioned challenges to implementing HAI reduction initiatives included poor adherence, insufficient resources, staffing problems, lack of culture change, no impetus to change, and issues related to staff and patient education. Many respondents identified engaging physicians as particularly challenging.These findings suggest that consistently improving hand hygiene remains a widespread problem for reducing HAIs and sustaining this type of behavioral change is difficult. Furthermore, ensuring staff and physician engagement and compliance in HAI reduction efforts remains challenging for most hospitals.


"Seeing the baby": pleasures and dilemmas of ultrasound technologies for primiparous Australian women.
The practice of obstetric ultrasound scans has undergone significant expansion in the last two decades and is now a standard part of many women's antenatal care in Australia as elsewhere. This article reviews recent evidence about the value of obstetric ultrasound, summarizing debates and contradictions in research literature and practitioner guidelines. Pregnant women's interpretations of the significance of ultrasound are examined through multiple interviews with 34 study participants. We find that ultrasound has become an integral part of women's embodied experience of pregnancy, with its own pleasures and dilemmas. The increasing use of the technology has augmented the role of scientific biomedicine in the government of pregnancy. This must be understood in the light of trends toward individualized risk management in which the pregnant woman increasingly takes responsibility for the successful outcome of the pregnancy, in a context where pregnancy is discursively constructed as a risky domain of gendered experience in contemporary Australian society.


Relationship between native and recombinant cholecystokinin receptors: role of differential glycosylation.
In an attempt to establish the relationship between the protein encoded by the recently cloned type A cholecystokinin (CCK) receptor cDNA and the two distinct plasmalemmal proteins on the rat pancreatic acinar cell that were previously described as candidates to represent this receptor, we have established a Chinese hamster ovary (CHO) cell line stably expressing large amounts of this recombinant protein and have used biochemical methods to characterize it directly. Upon affinity labeling, this protein migrated faster on a sodium dodecyl sulfate-polyacrylamide gel than the M(r) 85,000-95,000 molecule previously felt to represent the best candidate. However, deglycosylation with endoglycosidase F demonstrated that it had the same size core protein as that candidate, and this identification was further supported by protease peptide mapping. We postulated that the structural differences between the recombinant and the native proteins related to differences in glycosylation. Consistent with this, lectin-binding experiments demonstrated that both represented complex glycoproteins but that only the native receptor-bound Ulex europeus agglutinin I. Since this lectin binds to fucose residues that are added late in glycoprotein biosynthesis, it is possible that the distinct processing observed affected only that step. In spite of this structural difference, the type A CCK receptor-bearing CHO cell CCK receptor was functionally indistinguishable from the native acinar cell receptor. This included its ability to initiate signaling cascades, its sensitivity to stable GTP analogues, and its binding affinities for agonists and antagonists. The fidelity of this receptor expression system, while representing a 25-fold increase in receptor density over the native pancreatic acinar cell, should provide an ideal substrate for the examination of structure-function relationships within this molecule.


[Evaluation of quality of epidemiological and demographic variables in the Live Births Information System, 2002].
This study evaluates the quality of data in the Brazilian Live Births Information System (SINASC), focusing on the methodological clarity of documentation and adequate data completeness and consistency at the national, regional, and State levels in 2002. The variables analyzed were: skin color/race of newborn, maternal schooling, maternal marital status, maternal occupation, maternal age, prenatal visits, live births, stillbirths, and birth weight. For most of the variables, SINASC shows good data completeness and consistency, but there were serious problems with the quality of data on previous children and maternal occupation. Related to race, there were some methodological problems in the definition and incomplete filling-in for the Federal District (Brasília) and the States of São Paulo, Bahia, and Sergipe. Statistical analysis confirmed a significant association between data completeness and indicators of poverty and inequality. The study showed that improvements in SINASC data quality could make this system a good epidemiological source for identifying risk factors and socioeconomic conditioning factors.


Comparison of injecting drug users who obtain syringes from pharmacies and syringe exchange programs in Tallinn, Estonia.
Both syringe exchange programs (SEPs) and pharmacy sales of syringes are available in Estonia, though the current high incidence and high prevalence of HIV among injection drug users (IDUs) in Tallinn, Estonia requires large-scale implementation of additional harm reduction programs as a matter of great urgency. The aims of this report were to compare risk behavior and HIV infection and to assess the prevention needs among IDUs who primarily use pharmacies as their source of sterile syringes with IDUs who primarily use SEPs in Tallinn. A cross-sectional study using respondent-driven sampling was used to recruit 350 IDUs for an interviewer-administered survey and HIV testing. IDUs were categorized into two groups based on their self-reported main source for syringes within the last six months. Odds ratios with 95% CI were used to compare characteristics and risk factors between the groups. The main sources of sterile needles for injection drug users were SEP/SEP outreach (59%) and pharmacies (41%). There were no differences in age, age at injection drug use initiation, the main drug used or experiencing overdoses. Those IDUs using pharmacies as a main source of sterile needles had lower odds for being infected with either HIV (AOR 0.54 95% CI 0.33-0.87) or HCV (AOR 0.10 95% CI 0.02-0.50), had close to twice the odds of reporting more than one sexual partner within the previous 12 months (AOR 1.88 95% CI 1.17-3.04) and engaging in casual sexual relationships (AOR 2.09 95% CI 1.24-3.53) in the last six months. The data suggest that the pharmacy users were at a less "advanced" stage of their injection career and had lower HIV prevalence than SEP users. This suggests that pharmacies could be utilized as a site for providing additional HIV prevention messages, services for IDUs and in linking IDUs with existing harm reduction services.


Directed percolation and numerical stability of simulations of digital memcomputing machines.
Digital memcomputing machines (DMMs) are a novel, non-Turing class of machines designed to solve combinatorial optimization problems. They can be physically realized with continuous-time, non-quantum dynamical systems with memory (time non-locality), whose ordinary differential equations (ODEs) can be numerically integrated on modern computers. Solutions of many hard problems have been reported by numerically integrating the ODEs of DMMs, showing substantial advantages over state-of-the-art solvers. To investigate the reasons behind the robustness and effectiveness of this method, we employ three explicit integration schemes (forward Euler, trapezoid, and Runge-Kutta fourth order) with a constant time step to solve 3-SAT instances with planted solutions. We show that (i) even if most of the trajectories in the phase space are destroyed by numerical noise, the solution can still be achieved; (ii) the forward Euler method, although having the largest numerical error, solves the instances in the least amount of function evaluations; and (iii) when increasing the integration time step, the system undergoes a "solvable-unsolvable transition" at a critical threshold, which needs to decay at most as a power law with the problem size, to control the numerical errors. To explain these results, we model the dynamical behavior of DMMs as directed percolation of the state trajectory in the phase space in the presence of noise. This viewpoint clarifies the reasons behind their numerical robustness and provides an analytical understanding of the solvable-unsolvable transition. These results land further support to the usefulness of DMMs in the solution of hard combinatorial optimization problems.


EHD2 and the novel EH domain binding protein EHBP1 couple endocytosis to the actin cytoskeleton.
Here we identified two novel proteins denoted EH domain protein 2 (EHD2) and EHD2-binding protein 1 (EHBP1) that link clathrin-mediated endocytosis to the actin cytoskeleton. EHD2 contains an N-terminal P-loop and a C-terminal EH domain that interacts with NPF repeats in EHBP1. Disruption of EHD2 or EHBP1 function by small interfering RNA-mediated gene silencing inhibits endocytosis of transferrin into EEA1-positive endosomes as well as GLUT4 endocytosis into cultured adipocytes. EHD2 localizes with cortical actin filaments, whereas EHBP1 contains a putative actin-binding calponin homology domain. High expression of EHD2 or EHBP1 in intact cells mediates extensive actin reorganization. Thus EHD2 appears to connect endocytosis to the actin cytoskeleton through interactions of its N-terminal domain with membranes and its C-terminal EH domain with the novel EHBP1 protein.


A Phase-Changing Polymer Film for Broadband Smart Window Applications.
Smart windows (SWs) with tunable opacity are sought to regulate solar-irradiation and privacy protection. A new smart window material based on a phase-changing polymer that can be reversibly switched between a semicrystalline, opaque state and an amorphous, transparent state is introduced. The polymer film is a network of the phase-changing poly(stearyl acrylate) crosslinked with a poly(ethylene oxide) oligomer. The two constituent polymers show strong phase separation. The transmission switching of the resulting copolymer film is resulted from the combination of three different mechanisms: reversible phase changing of the poly(stearyl acrylate) component, phase separation between the two distinct constituent polymers, and a large change of refractive index of the phase-changing polymer during the amorphous-to-semicrystalline transition. The opaqueness switching can be reversed and repeated for more than 500 cycles of heating and cooling. A silver nanowire (AgNW)-based transparent heater is combined with the SW film to control the semicrystalline-to-amorphous phase transition. The resulting smart window exhibits a high infrared transmittance modulation (ΔTIR ) of 80.4% and solar transmittance modulation (ΔTsolar ) of 70.2%, which significantly outperform existing thermochromic smart windows.


Implementation of standardized follow-up care significantly reduces peritonitis in children on chronic peritoneal dialysis.
The Standardizing Care to improve Outcomes in Pediatric End stage renal disease (SCOPE) Collaborative aims to reduce peritonitis rates in pediatric chronic peritoneal dialysis patients by increasing implementation of standardized care practices. To assess this, monthly care bundle compliance and annualized monthly peritonitis rates were evaluated from 24 SCOPE centers that were participating at collaborative launch and that provided peritonitis rates for the 13 months prior to launch. Changes in bundle compliance were assessed using either a logistic regression model or a generalized linear mixed model. Changes in average annualized peritonitis rates over time were illustrated using the latter model. In the first 36 months of the collaborative, 644 patients with 7977 follow-up encounters were included. The likelihood of compliance with follow-up care practices increased significantly (odds ratio 1.15, 95% confidence interval 1.10, 1.19). Mean monthly peritonitis rates significantly decreased from 0.63 episodes per patient year (95% confidence interval 0.43, 0.92) prelaunch to 0.42 (95% confidence interval 0.31, 0.57) at 36 months postlaunch. A sensitivity analysis confirmed that as mean follow-up compliance increased, peritonitis rates decreased, reaching statistical significance at 80% at which point the prelaunch rate was 42% higher than the rate in the months following achievement of 80% compliance. In its first 3 years, the SCOPE Collaborative has increased the implementation of standardized follow-up care and demonstrated a significant reduction in average monthly peritonitis rates.


Decreased immunoreactivities of neocortical AMPA receptor subunits correlate with motor disability in Lewy body dementias.
Dementia with Lewy bodies and Parkinson's disease dementia are different clinical phenotypes of Lewy body dementias differentiated by the temporal relationship between parkinsonism and dementia onset. At present, it is unclear whether the glutamatergic system is affected in these disorders. In this study, we measured α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA subunits in the postmortem neocortex of a cohort of prospectively studied Lewy body dementia cases, as well as age-matched controls by immunoblotting. We found losses of GluA2/3/4 immunoreactivities in Lewy body dementias which correlated with higher pre-death Hoehn and Yahr scores and with longer Parkinson's disease duration before dementia onset, but not with dementia severity, cortical Lewy body burden, or amyloid plaque and neurofibrillary tangle burden. Our study suggests that GluA2/3/4 losses may be a neurochemical marker of motor disability in Lewy body dementias.


Theory of enhanced optical transmission through a metallic nano-slit surrounded with asymmetric grooves under oblique incidence.
A metallic nano-slit surrounded with asymmetric grooves is proposed as the plasmonic concentrator for oblique incident light. A theoretical model based on the surface plasmon polariton (SPP) coupled-mode method is derived for the extraordinary optical transmission (EOT) through such a structure under oblique incidence. The model is quantitatively validated with the finite element method. With the model, the physical insight of the EOT is then interpreted, i.e., the major contributions to the transmission include the vertical Fabry-Perot resonance of the slit, and the interference among slit modes excited by the incident light, by SPPs generated from groove arrays and their first-order reflections. This is quite different from the EOT through a nano-slit surrounded with symmetric grooves under normal incidence.


Chronic low back pain: new perspectives and treatment guidelines for primary care: Part II.
Low back pain is a leading cause of work-related disability and has important socioeconomic consequences. Although there is little evidence to determine the optimal treatment of chronic low back pain, treatment goals can be established. Primary care providers should focus simultaneously on pain management, improvement of activity and functional level, and fostering a greater understanding of chronic low back pain. This two-part article summarizes consensus guidelines developed by practitioners with expertise in pain management, family medicine, internal medicine, physical therapy, rheumatology, and managed care and provides direction for primary care providers on a multidisciplinary approach to the patient with chronic low back pain. This part examines pharmacologic methods.


Measured GFR does not outperform estimated GFR in predicting CKD-related complications.
Although many assume that measurement of glomerular filtration rate (GFR) using a marker such as iothalamate (iGFR) is superior to equation-estimated GFR (eGFR), each of these methods has distinct disadvantages. Because physicians often use renal function to guide the screening for various CKD-associated complications, one method to compare the clinical utility of iGFR and eGFR is to determine the strength of their association with CKD-associated comorbidities. Using a subset of 1214 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study, we determined the cross-sectional associations between known complications of CKD and iGFR, eGFR estimated from serum creatinine (eGFR_Cr), and eGFR estimated from cystatin C (eGFR_cysC). We found that none of the measures of renal function strongly associated with CKD complications and that the relative strengths of associations varied according to the outcome of interest. For example, iGFR demonstrated better discrimination than eGFR_Cr and eGFR_cysC for outcomes of anemia and hemoglobin concentration; however, both eGFR_Cr and eGFR_cysC demonstrated better discrimination than iGFR for outcomes of hyperphosphatemia and phosphorus level. iGFR and eGFR had similar strengths of association with hyperkalemia/potassium level and with metabolic acidosis/bicarbonate level. In conclusion, iothalamate measurement of GFR is not consistently superior to equation-based estimations of GFR in explaining CKD-related comorbidities. These results raise questions regarding the conventional view that iGFR is the "gold standard" measure of kidney function.


Targeting adenoviruses with factor x-single-chain antibody fusion proteins.
Abstract It has been shown that blood clotting factors, including factor X (FX), bind to the adenovirus serotype 5 (Ad5) hexon protein and target the virus to liver hepatocytes after intravenous injection. These factors bind to hexon via their conserved vitamin K-dependent gamma-carboxyglutamic acid (GLA) domains with subnanomolar affinity. In this work, we have used this strong interaction to retarget Ad to new receptors, using the GLA domain of FX fused to single-chain antibody variable fragment (ScFv). We demonstrate that fusion of the GLA domain of human FX to receptor-specific ScFvs will target Ad5 vectors to cells expressing these receptors. Fusion of an alphaHer2 ScFv to GLA increased in vitro transduction of Her2-positive versus Her2-negative cells when compared with untargeted virus. Similar results were obtained with ScFvs against the epidermal growth factor receptor (EGFR) and against the stem cell marker ATP-binding cassette protein G2 (ABCG2). Direct expression of GLA fusion protein from replication-defective or replication-competent Ad increased infection and killing of cancer cells in vitro and in vivo. These data demonstrate the potential of using GLA domains to bridge secreted ligands with intracellularly produced Ad5 vectors for vector targeting.


Randomly phase-locked microlaser arrays and fuzzy eigenmodes with stochastic phasing.
Deviations in the cold cavity parameters, random or systematic, produce incoherently phased-locked laser arrays with unevenly distributed phase difference and intensity. The collective radiation fields constitute "fuzzy" eigenmodes; the phasing among cavities is constant in time but changes randomly from site-to-site. The existence and structure of such eigenmodes is demonstrated numerically and analyzed theoretically using the rate equations for coupled semiconductor laser cavities. Active coupling, whereby one cavity's radiation field modulates the complex gain of nearby cavities (cross-cavity hole burning), is essential for the frequency pulling allowing synchronization of the laser operating frequencies.


Periodic extraction of interstitial fluid from the site of subcutaneous insulin infusion for the measurement of glucose: a novel single-port technique for the treatment of type 1 diabetes patients.
Treatment of type 1 diabetes patients could be simplified if the site of subcutaneous insulin infusion could also be used for the measurement of glucose. This study aimed to assess the agreement between blood glucose concentrations and glucose levels in the interstitial fluid (ISF) that is extracted from the insulin infusion site during periodic short-term interruptions of continuous subcutaneous insulin infusion (CSII). A perforated cannula (24 gauge) was inserted into subcutaneous adipose tissue of C-peptide-negative type 1 diabetes subjects (n=13) and used alternately to infuse rapid-acting insulin (100 U/mL) and to extract ISF glucose during a fasting period and after ingestion of a standard oral glucose load (75 g). Although periodically interrupted for extracting glucose (every hour for approximately 10 min), insulin infusion with the cannula was adequate to achieve euglycemia during fasting and to restore euglycemia after glucose ingestion. Furthermore, the ISF-derived estimates of plasma glucose levels agreed well with plasma glucose concentrations. Correlation coefficient and median absolute relative difference values were found to be 0.95 and 8.0%, respectively. Error grid analysis showed 99.0% of all ISF glucose values within clinically acceptable Zones A and B (83.5% Zone A, 15.5% Zone B). Results show that ISF glucose concentrations measured at the insulin infusion site during periodic short-term interruptions of CSII closely reflect blood glucose levels, thus suggesting that glucose monitoring and insulin delivery may be performed alternately at the same tissue site. A single-port device of this type could be used to simplify and improve glucose management in diabetes.


Superfocusing effect in the chain of silver nanorods.
A chain of three silver nanorods with progressively decreasing sizes and separations is designed to focus the electric fields around the small nanorods. The optical properties of the chain of silver nanorods are investigated by the discrete dipole approximation method. The results show that, compared with the individual small nanorod and the chain of two nanorods, many enhanced electric fields are focused around the small nanorod of the chain of three nanorods due to the electric field couplings between adjacent nanorods. Therefore, the design of the chain of three nanorods provides a way to obtain stronger electric fields. In addition, how the structural parameters of the chain of three nanorods affect their optical properties is also studied.


What Exactly Is Shared Decision-Making? A Qualitative Study of Shared Decision-Making in Lung Cancer Screening.
Shared decision-making (SDM) is widely recommended and required by the Centers for Medicare and Medicaid for patients considering lung cancer screening (LCS). We examined clinicians' communication practices and perceived barriers of SDM for LCS at three medical centers with established screening programs. Multicenter qualitative study of clinicians participating in LCS. We performed semi-structured interviews, which were transcribed and analyzed using directed content analysis, guided by a theoretical model of patient-clinician communication. We interviewed 24 clinicians including LCS coordinators (2), pulmonologists (3), and primary care providers (17), 4 of whom worked for the LCS program, a thoracic surgeon, and a radiologist. All clinicians agreed with the goal of SDM, to ensure the screening decision was congruent with the patient's values. The depth and type of information presented by each clinician role varied considerably. LCS coordinators presented detailed information including numeric estimates of benefit and harm. Most PCPs explained the process more generally, focusing on logistics and the high rate of nodule detection. No clinician explicitly elicited values or communication preferences. Many PCPs tailored the conversation based on their implicit understanding of patients' values and preferences, gained from past experiences. PCPs reported that time, lack of detailed personal knowledge of LCS, and patient preferences were barriers to SDM. Many clinicians perceived that a significant proportion of patients were not interested in specific percentages and preferred to receive a clinician recommendation. Our results suggest that clinicians support the goal of SDM for LCS decisions but PCPs may not perform some of its elements. The lack of completion of some elements, such as PCPs' lack of in-depth information exchange, may reflect perceived patient preferences for communication. As LCS is implemented, further research is needed to support a personalized, patient-centered approach to produce better outcomes.


MALDI imaging mass spectrometry: spatial molecular analysis to enable a new age of discovery.
Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) combines the sensitivity and selectivity of mass spectrometry with spatial analysis to provide a new dimension for histological analyses to provide unbiased visualization of the arrangement of biomolecules in tissue. As such, MALDI IMS has the capability to become a powerful new molecular technology for the biological and clinical sciences. In this review, we briefly describe several applications of MALDI IMS covering a range of molecular weights, from drugs to proteins. Current limitations and challenges are discussed along with recent developments to address these issues. This article is part of a Special Issue entitled: 20years of Proteomics in memory of Viatliano Pallini. Guest Editors: Luca Bini, Juan J. Calvete, Natacha Turck, Denis Hochstrasser and Jean-Charles Sanchez.


A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme.
Twenty patients who suffered from more than four attacks of erythema multiforme (EM) per year were enrolled in a 6-month double-blind, placebo-controlled trial of acyclovir 400 mg twice daily. Fifteen patients had disease precipitated by recurrent herpes simplex. In the acyclovir-treated group the median number of EM attacks during the treatment period was zero, compared with three in the placebo-treated group (P < 0.0005, Wilcoxon rank sum test). Seven of the 11 patients treated with continuous acyclovir did not have any attacks of EM while taking the drug, and one showed almost complete disease suppression. Following treatment with acyclovir, two patients went into complete remission, whereas all individuals in the placebo group continued to have attacks. In the acyclovir-treated group nine of the 11 patients had herpes simplex-precipitated disease. One of the two patients with idiopathic disease showed complete disease suppression while on acyclovir, lending support to the view that idiopathic recurrent EM may be related to subclinical herpetic infection. In this study, we have shown that continuous acyclovir therapy can completely suppress attacks of recurrent EM and, in some cases, may induce disease remission.