A systematic review and meta-analysis of structural magnetic resonance imaging studies investigating cognitive and social activity levels in older adults.
Population aging has prompted considerable interest in identifying modifiable factors that may help protect the brain and its functions. Collectively, epidemiological studies show that leisure activities with high mental and social demands are linked with better cognition in old age. The extent to which socio-intellectual activities relate to the brain's structure is, however, not yet fully understood. This systematic review and meta-analysis summarizes magnetic resonance imaging studies that have investigated whether cognitive and social activities correlate with measures of gray and white matter volume, white matter microstructure and white matter lesions. Across eighteen included studies (total n = 8429), activity levels were associated with whole-brain white matter volume, white matter lesions and regional gray matter volume, although effect sizes were small. No associations were found for global gray matter volume and the evidence concerning white matter microstructure was inconclusive. While the causality of the reviewed associations needs to be established, our findings implicate socio-intellectual activity levels as promising targets for interventions aimed at promoting healthy brain aging.


Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome.
To determine the genetic basis for long QT syndrome (LQTS) in a cohort of patients with a personal history or an extended family history of a swimming-triggered cardiac event. After review of the Mayo Clinic unit medical record system, blood samples or archived autopsy tissue samples were obtained from a retrospective cohort of 35 cases diagnosed as having autosomal dominant LQTS. Exon-specific amplification by polymerase chain reaction and direct sequence analyses were performed on the entire KVLQT1 gene. Six cases had a personal history or an extended family history of a near drowning or drowning. In all 6 cases, LQTS-causing mutations in KVLQT1 gene were identified: 3 deletion mutations, 2 donor splice site mutations, and 1 missense mutation. One of the mutations, a novel donor splicing defect, was determined by postmortem molecular analysis of a paraffin-embedded tissue block from a 12-year-old girl who died in 1976. Distinct KVLQT1 mutations were demonstrated in 3 of the remaining 29 cases. The overall frequency of KVLQT1 defects in LQTS was 100% (6/6) in those with and 10% (3/29) in those without a personal history or an extended family history of drowning or near drowning (P<.001). Swimming appears to be a gene-specific (KVLQT1) arrhythmogenic trigger for LQTS. This study provides proof of principle that an unexplained drowning or near drowning may have a genetic basis.


Characterization of the Antitumor Potential of Extracts of Cannabis sativa Strains with High CBD Content in Human Neuroblastoma.
Cannabis has been used for decades as a palliative therapy in the treatment of cancer. This is because of its beneficial effects on the pain and nausea that patients can experience as a result of chemo/radiotherapy. Tetrahydrocannabinol and cannabidiol are the main compounds present in Cannabis sativa, and both exert their actions through a receptor-mediated mechanism and through a non-receptor-mediated mechanism, which modulates the formation of reactive oxygen species. These oxidative stress conditions might trigger lipidic changes, which would compromise cell membrane stability and viability. In this sense, numerous pieces of evidence describe a potential antitumor effect of cannabinoid compounds in different types of cancer, although controversial results limit their implementation. In order to further investigate the possible mechanism involved in the antitumoral effects of cannabinoids, three extracts isolated from Cannabis sativa strains with high cannabidiol content were analyzed. Cell mortality, cytochrome c oxidase activity and the lipid composition of SH-SY5Y cells were determined in the absence and presence of specific cannabinoid ligands, with and without antioxidant pre-treatment. The cell mortality induced by the extracts in this study appeared to be related to the inhibition of the cytochrome c oxidase activity and to the THC concentration. This effect on cell viability was similar to that observed with the cannabinoid agonist WIN55,212-2. The effect was partially blocked by the selective CB1 antagonist AM281, and the antioxidant α-tocopherol. Moreover, certain membrane lipids were affected by the extracts, which demonstrated the importance of oxidative stress in the potential antitumoral effects of cannabinoids.


Re-Examining the Evidence for School-Based Comprehensive Sex Education: A Global Research Review.
To evaluate the global research on school-based comprehensive sex education (CSE) by applying rigorous and meaningful criteria to outcomes of credible studies in order to identify evidence of real program effectiveness. We examined 120 studies of school-based sex education contained in the reviews of research sponsored by three authoritative agencies: the United Nations Educational, Scientific and Cultural Organization, the U.S. federal Teen Pregnancy Prevention Program, and the Centers for Disease Control and Prevention. Their reviews screened more than 600 hundred studies and accepted only those that reached a threshold of adequate scientific rigor. These included 60 U.S. studies and 43 non-U.S. studies of school-based CSE plus 17 U.S. studies of school-based abstinence education (AE). We evaluated these studies for evidence of effectiveness using criteria grounded in the science of prevention research: sustained positive impact (at least 12 months post-program), on a key protective indicator (abstinence, condom use-especially consistent use, pregnancy, or STDs), for the main (targeted) teenage population, and without negative/harmful program effects. Worldwide, six out of 103 school-based CSE studies (U.S. and non-U.S. combined) showed main effects on a key protective indicator, sustained at least 12 months post-program, excluding programs that also had negative effects. Sixteen studies found harmful CSE impacts. Looking just at the U.S., of the 60 school-based CSE studies, three found sustained main effects on a key protective indicator (excluding programs with negative effects) and seven studies found harmful impact. For the 17 AE studies in the U.S., seven showed sustained protective main effects and one study showed harmful effects. Some of the strongest, most current school-based CSE studies worldwide show very little evidence of real program effectiveness. In the U.S., the evidence, though limited, appeared somewhat better for abstinence education.


Whole genome sequencing based characterization of extensively drug-resistant Mycobacterium tuberculosis isolates from Pakistan.
Improved molecular diagnostic methods for detection drug resistance in Mycobacterium tuberculosis (MTB) strains are required. Resistance to first- and second- line anti-tuberculous drugs has been associated with single nucleotide polymorphisms (SNPs) in particular genes. However, these SNPs can vary between MTB lineages therefore local data is required to describe different strain populations. We used whole genome sequencing (WGS) to characterize 37 extensively drug-resistant (XDR) MTB isolates from Pakistan and investigated 40 genes associated with drug resistance. Rifampicin resistance was attributable to SNPs in the rpoB hot-spot region. Isoniazid resistance was most commonly associated with the katG codon 315 (92%) mutation followed by inhA S94A (8%) however, one strain did not have SNPs in katG, inhA or oxyR-ahpC. All strains were pyrazimamide resistant but only 43% had pncA SNPs. Ethambutol resistant strains predominantly had embB codon 306 (62%) mutations, but additional SNPs at embB codons 406, 378 and 328 were also present. Fluoroquinolone resistance was associated with gyrA 91-94 codons in 81% of strains; four strains had only gyrB mutations, while others did not have SNPs in either gyrA or gyrB. Streptomycin resistant strains had mutations in ribosomal RNA genes; rpsL codon 43 (42%); rrs 500 region (16%), and gidB (34%) while six strains did not have mutations in any of these genes. Amikacin/kanamycin/capreomycin resistance was associated with SNPs in rrs at nt1401 (78%) and nt1484 (3%), except in seven (19%) strains. We estimate that if only the common hot-spot region targets of current commercial assays were used, the concordance between phenotypic and genotypic testing for these XDR strains would vary between rifampicin (100%), isoniazid (92%), flouroquinolones (81%), aminoglycoside (78%) and ethambutol (62%); while pncA sequencing would provide genotypic resistance in less than half the isolates. This work highlights the importance of expanded targets for drug resistance detection in MTB isolates.


Mechanisms, Consequences, and Prevention of Coronary Graft Failure.
Graft failure occurs in a sizeable proportion of coronary artery bypass conduits. We herein review relevant current evidence to give an overview of the incidence, pathophysiology, and clinical consequences of this multifactorial phenomenon. Thrombosis, endothelial dysfunction, vasospasm, and oxidative stress are different mechanisms associated with graft failure. Intrinsic morphological and functional features of the bypass conduits play a role in determining failure. Similarly, characteristics of the target coronary vessel, such as the severity of stenosis, the diameter, the extent of atherosclerotic burden, and previous endovascular interventions, are important determinants of graft outcome and must be taken into consideration at the time of surgery. Technical factors, such as the method used to harvest the conduits, the vasodilatory protocol, the storage solution, and the anastomotic technique, also play a major role in determining graft success. Furthermore, systemic atherosclerotic risk factors, such as age, sex, diabetes mellitus, hypertension, and dyslipidemia, have been variably associated with graft failure. The failure of a coronary graft is not always correlated with adverse clinical events, which vary according to the type, location, and reason for failed graft. Intraoperative flow verification and secondary prevention using antiplatelet and lipid-lowering agents can help reducing the incidence of graft failure.


Activatable iRGD-based peptide monolith: Targeting, internalization, and fluorescence activation for precise tumor imaging.
A disulfide-bridged cyclic RGD peptide, named iRGD (internalizing RGD, c(CRGDK/RGPD/EC)), is known to facilitate tumor targeting as well as tissue penetration. After the RGD motif-induced targeting on αv integrins expressed near tumor tissue, iRGD encounters proteolytic cleavage to expose the CendR motif that promotes penetration into cancer cells via the interaction with neuropilin-1. Based on these proteolytic cleavage and internalization mechanism, we designed an iRGD-based monolithic imaging probe that integrates multiple functions (cancer-specific targeting, internalization and fluorescence activation) within a small peptide framework. To provide the capability of activatable fluorescence signaling, we conjugated a fluorescent dye to the N-terminal of iRGD, which was linked to the internalizing sequence (CendR motif), and a quencher to the opposite C-terminal. It turned out that fluorescence activation of the dye/quencher-conjugated monolithic peptide probe requires dual (reductive and proteolytic) cleavages on both disulfide and amide bond of iRGD peptide. Furthermore, the cleavage of the iRGD peptide leading to fluorescence recovery was indeed operative depending on the tumor-related angiogenic receptors (αvβ3 integrin and neuropilin-1) in vitro as well as in vivo. Compared to an 'always fluorescent' iRGD control probe without quencher conjugation, the dye/quencher-conjugated activatable monolithic peptide probe visualized tumor regions more precisely with lower background noise after intravenous injection, owing to the multifunctional responses specific to tumor microenvironment. All these results, along with minimal in vitro and in vivo toxicity profiles, suggest potential of the iRGD-based activatable monolithic peptide probe as a promising imaging agent for precise tumor diagnosis.


Mechanisms and kinetics for sorption of CO2 on bicontinuous mesoporous silica modified with n-propylamine.
We studied equilibrium adsorption and uptake kinetics and identified molecular species that formed during sorption of carbon dioxide on amine-modified silica. Bicontinuous silicas (AMS-6 and MCM-48) were postsynthetically modified with (3-aminopropyl)triethoxysilane or (3-aminopropyl)methyldiethoxysilane, and amine-modified AMS-6 adsorbed more CO(2) than did amine-modified MCM-48. By in situ FTIR spectroscopy, we showed that the amine groups reacted with CO(2) and formed ammonium carbamate ion pairs as well as carbamic acids under both dry and moist conditions. The carbamic acid was stabilized by hydrogen bonds, and ammonium carbamate ion pairs formed preferably on sorbents with high densities of amine groups. Under dry conditions, silylpropylcarbamate formed, slowly, by condensing carbamic acid and silanol groups. The ratio of ammonium carbamate ion pairs to silylpropylcarbamate was higher for samples with high amine contents than samples with low amine contents. Bicarbonates or carbonates did not form under dry or moist conditions. The uptake of CO(2) was enhanced in the presence of water, which was rationalized by the observed release of additional amine groups under these conditions and related formation of ammonium carbamate ion pairs. Distinct evidence for a fourth and irreversibly formed moiety was observed under sorption of CO(2) under dry conditions. Significant amounts of physisorbed, linear CO(2) were detected at relatively high partial pressures of CO(2), such that they could adsorb only after the reactive amine groups were consumed.


Polyethyleneimine functionalized platinum superstructures: enhancing hydrogen evolution performance by morphological and interfacial control.
The electrocatalytic hydrogen evolution reaction (HER) is a highly promising green method for sustainable and efficient hydrogen production. So far, Pt nanocrystals are still the most active electrocatalysts for the HER in acidic media, although a tremendous search for alternatives has been done in the past decade. In this work, we synthesize polyethyleneimine (PEI) functionalized Pt superstructures (Pt-SSs@PEI) with tetragonal, hierarchical, and branched morphologies with a facile wet chemical reduction method. A series of physical characterizations are conducted to investigate the morphology, electronic structure, surface composition, and formation mechanism of Pt-SSs@PEI. Impressively, the as-prepared Pt-SSs@PEI show an unprecedented onset reduction potential (+64.6 mV vs. reversible hydrogen electrode) for the HER in strong acidic media due to the protonation of -NH2 groups in the PEI adlayers on the Pt surface, and they outperform all currently reported HER electrocatalysts. The work highlights a highly effective interface-engineering strategy for improving the electrocatalytic performance of Pt nanocrystals for the HER.


Uncontrolled organ donation after circulatory death: potential donors in the emergency department.
The continuing shortfall of organs for transplantation has led to interest in Maastricht Category II (uncontrolled) Donation after Circulatory Death (DCD) organ donation. As preparation for a proposed pilot, this study aimed to explore the potential of uncontrolled DCD organ donation from patients presenting in cardiac arrest to the emergency department (ED) who are unsuccessfully resuscitated. We identified all patients who died in our ED following unsuccessful resuscitation after cardiac arrest who were aged between 16 years and 60 years, whose collapse was witnessed, in whom the paramedics arrived within 15 min, whose death in the ED was less than 2 h after their collapse, who were on the organ donation register and who arrived in the ED during the working week (Monday to Friday between 9:00 and 17:00). During a 14-month period from 1 August 2008 to 30 September 2009, 564 patients had a cardiac arrest in the Lothian region. Four patients may have been eligible to participate in an uncontrolled DCD organ donation programme. Identifying potential organ donors in the ED who are unsuccessfully resuscitated from cardiac arrest may contribute to reducing the shortfall of organs for transplantation, although numbers are likely to be small. If such a programme was to be introduced during weekday working hours, there may be around four donors a year. However, even one additional donor per year from hospitals across the UK with an ED and a transplantation service would add considerably to the overall organ donation rate.


Peritumoral and intratumoral hemorrhage after stereotactic radiosurgery for renal cell carcinoma metastasis to the brain.
Stereotactic Radiosurgery (SRS), provides in a single session, a high dose of radiation to a localized brain tumor volume. Acute adverse reactions after treatment are not uncommon, but are usually transient and generally are well controlled by medication. The authors wish to report this rare complication of intratumoral and peritumoral hemorrhage immediately after LINAC SRS treatment of single temporal lobe metastasis from renal cell carcinoma and discuss plausible causes for this case and its management. A review of the literature on acute intracranial hemorrhage after radiosurgery for metastatic lesions is provided. A 68-year-old man underwent SRS treatment for a single left temporal lobe metastasis. No complications were noticed during frame fixation, treatment itself, or frame removal. Thirty minutes after the end of treatment session the patient acutely became aphasic and right hemiplegic. An urgent CT-scan revealed peritumoral and intratumoral hemorrhage. Patient underwent urgent surgical treatment during which was performed gross total excision of the brain metastasis and total removal of the clot. The patient had a good recovery after surgery and he was discharged with moderate aphasia but able to walk with no other neurological deficits. Stereotactic radiosurgery for metastatic brain tumors should not be considered as a risk-free procedure, especially in cases of neoplasms with high propensity for intratumoral bleeding and, while extremely rare, hemorrhagic complications can occur after treatment. The possibility of acute complications and their consequences have to be discussed with the patient and his or her relatives before radiosurgical treatment.


The Ethanolic Extract of Taiwanofungus camphoratus (Antrodia camphorata) Induces Cell Cycle Arrest and Enhances Cytotoxicity of Cisplatin and Doxorubicin on Human Hepatocellular Carcinoma Cells.
Taiwanofungus camphoratus (synonym Antrodia camphorata) is a widely used medicinal fungus in the folk medicine of Taiwan with several pharmacological features such as anti-inflammatory, liver protection, antihypertensive, and antioxidative activities. The ethanolic extract of T. camphoratus (TCEE) which contains abundant bioactive compounds including triterpenoids and polysaccharides also has antitumor effects in various human cancer cell lines. The aims of this study are to clarify the antitumor effects of TCEE on human hepatocellular carcinoma cells and also evaluate the combination drug effects with conventional chemotherapy agents, cisplatin and doxorubicin. In the present study, the TCEE treatment induced cell cycle arrest and suppressed cell growth on both Hep3B and HepJ5 cells. Expression of cell cycle inhibitors, P21 and P27, and activation of apoptosis executer enzyme, caspase-3, were also induced by TCEE. In combination with the chemotherapy agents, TCEE treatment further enhanced the tumor suppression efficiency of cisplatin and doxorubicin. These results together suggested that TCEE is a potential ingredient for developing an integrated chemotherapy for human liver cancer.


A polymer of caffeyl alcohol in plant seeds.
Lignins are complex phenylpropanoid polymers mostly associated with plant secondary cell walls. Lignins arise primarily via oxidative polymerization of the three monolignols, p-coumaryl, coniferyl, and sinapyl alcohols. Of the two hydroxycinnamyl alcohols that represent incompletely methylated biosynthetic products (and are not usually considered to be monolignols), 5-hydroxyconiferyl alcohol is now well established as incorporating into angiosperm lignins, but incorporation of caffeyl alcohol has not been shown. We report here the presence of a homopolymer of caffeyl alcohol in the seed coats of both monocot and dicot plants. This polymer (C-lignin) is deposited to high concentrations in the seed coat during the early stages of seed development in the vanilla orchid (Vanilla planifolia), and in several members of the Cactaceae. The lignin in other parts of the Vanilla plant is conventionally biosynthesized from coniferyl and sinapyl alcohols. Some species of cacti contain only C-lignin in their seeds, whereas others contain only classical guaiacyl/syringyl lignin (derived from coniferyl and sinapyl alcohols). NMR spectroscopic analysis revealed that the Vanilla seed-coat polymer was massively comprised of benzodioxane units and was structurally similar to the polymer synthesized in vitro by peroxidase-catalyzed polymerization of caffeyl alcohol. CD spectroscopy did not detect any optical activity in the seed polymer. These data support the contention that the C-lignin polymer is produced in vivo via combinatorial oxidative radical coupling that is under simple chemical control, a mechanism analogous to that theorized for classical lignin biosynthesis.


The status and future of acupuncture clinical research.
On November 8-9, 2007, the Society for Acupuncture Research (SAR) hosted an international conference to mark the tenth anniversary of the landmark National Institutes of Health Consensus Development Conference on Acupuncture. More than 300 acupuncture researchers, practitioners, students, funding agency personnel, and health policy analysts from 20 countries attended the SAR meeting held at the University of Maryland School of Medicine, Baltimore, MD. This paper summarizes important invited lectures in the area of clinical research. Specifically, included are: a review of the recently conducted German trials and observational studies on low-back pain (LBP), gonarthrosis, migraine, and tension-type headache (the Acupuncture Research Trials and the German Acupuncture Trials, plus observational studies); a systematic review of acupuncture treatment for knee osteoarthritis (OA); and an overview of acupuncture trials in neurologic conditions, LBP, women's health, psychiatric disorders, and functional bowel disorders. A summary of the use of acupuncture in cancer care is also provided. Researchers involved in the German trials concluded that acupuncture is effective for treating chronic pain, but the correct selection of acupuncture points seems to play a limited role; no conclusions could be drawn about the placebo aspect of acupuncture, due to the design of the studies. Overall, when compared to sham, acupuncture did not show a benefit in treating knee OA or LBP, but acupuncture was better than a wait-list control and standard of care, respectively. In women's health, acupuncture has been found to be beneficial for patients with premenstrual syndrome, dysmenorrhea, several pregnancy-related conditions, and nausea in females who have cancers. Evidence on moxibustion for breech presentation, induction of labor, and reduction of menopausal symptoms is still inconclusive. In mental health, evidence for acupuncture's efficacy in treating neurologic and functional bowel disorder is still inconclusive. For chronic cancer-related problems such as pain, acupuncture may work well in stand-alone clinics; however, for acute or treatment-related symptoms, integration of acupuncture care into a busy and complex clinical environment is unlikely, unless compelling evidence of a considerable patient benefit can be established.


Hedgehog signaling and response to cyclopamine differ in epithelial and stromal cells in benign breast and breast cancer.
The hedgehog pathway regulates epithelial-mesenchymal interactions, differentiation, proliferation and survival during development. Stimulation of hedgehog signaling induces carcinogenesis or promotes cell survival in cancers of multiple organs. Using real-time, quantitative PCR, laser capture microdissection, and immunohistochemistry, distinctive patterns of expression of the hedgehog pathway members patched 1 (PTCH1), smoothened, GLI1, GLI2 and the 3 hedgehog ligands were identified for epithelial cells and stromal fibroblasts in benign breast and breast cancer. Hedgehog ligands were expressed at higher levels in some cancer epithelial cell lines compared to noncancerous epithelial cells. Correspondingly, expression of GLI1, a transcription factor and transcriptional product of hedgehog signaling, was increased 8-fold in cancer epithelial cell lines; however, PTCH1, also a transcriptional target of hedgehog signaling in many cell types, was not increased. GLI1 protein and mRNA, and PTCH1 and sonic hedgehog (SHH) proteins were elevated in 3 of 10 breast cancers; however, PTCH1 transcripts were not consistently increased. Hedgehog-mediated transcription, as indicated by a reporter of GLI-dependent promoter activity and by expression of GLI1 transcripts, was reduced by the hedgehog pathway inhibitor cyclopamine in both MDA-MB-435 cancer epithelial cells and MCF10AT epithelial cells, a cell line derived from benign breast. However, cyclopamine reduced viability of cancer epithelial cell lines, including MDA-MB-435, but did not specifically affect fibroblasts or epithelial cells from benign breast, including MCF10AT. Treatment with sonic hedgehog ligand diminished the cyclopamine-induced reduction in GLI-dependent promoter activity in MCF10AT and MDA-MB-435 and viability of MDA-MB-435. These results demonstrate modulation of GLI-mediated transcription in both cancer and benign-derived epithelial cells by cyclopamine and sonic hedgehog, and further suggest that hedgehog signaling contributes to the survival of only the cancer epithelial cells. Determination as to whether the increase in GLI1 and SHH expression in breast cancer indicates a significant increase in hedgehog signaling will require further evaluation.


Chronic Ankle Instability Does Not Affect Lower Extremity Functional Performance.
OBJECTIVE: To determine if functional performance is impaired in individuals with self-reported chronic ankle instability. DESIGN AND SETTING: We used a between-groups design to assess 3 functional variables. All data were collected at a Division III college and a military academy. Before testing, all subjects performed a 5-minute warm-up, followed by a series of stretches for the lower extremity muscles. Subjects then performed cocontraction, shuttle run, and agility hop tests in a counterbalanced fashion. Three trials for each functional test were completed and averaged for analysis. SUBJECTS: Twenty men with a history of at least 1 significant ankle sprain and episodes of at least 1 repeated ankle injury or feelings of instability or "giving way" were compared with 20 men with no prior history of ankle injury. Subjects were matched by age, height, weight, and activity level. MEASUREMENTS: Time to completion was measured in seconds for the cocontraction and the shuttle run tests. The agility hop test was measured on an error point scale. RESULTS: Using 3 separate, independent, 2-tailed t tests, we found no significant difference between groups for the cocontraction (P =.452), shuttle run (P =.680), or agility hop (P =.902) tests. CONCLUSIONS: Chronic ankle instability is a subjectively reported phenomenon defined as the tendency to "give way" during normal activity. Although athletes commonly complain of subjective symptoms associated with chronic ankle instability, our findings suggest that these symptoms do not negatively influence actual functional performance. Future researchers should evaluate other, more demanding functional-performance tests to further substantiate these findings.


Longitudinal associations between teen dating violence victimization and adverse health outcomes.
To determine the longitudinal association between teen dating violence victimization and selected adverse health outcomes. Secondary analysis of Waves 1 (1994-1995), 2 (1996), and 3 (2001-2002) of the National Longitudinal Study of Adolescent Health, a nationally representative sample of US high schools and middle schools. Participants were 5681 12- to 18-year-old adolescents who reported heterosexual dating experiences at Wave 2. These participants were followed-up ~5 years later (Wave 3) when they were aged 18 to 25. Physical and psychological dating violence victimization was assessed at Wave 2. Outcome measures were reported at Wave 3, and included depressive symptomatology, self-esteem, antisocial behaviors, sexual risk behaviors, extreme weight control behaviors, suicidal ideation and attempt, substance use (smoking, heavy episodic drinking, marijuana, other drugs), and adult intimate partner violence (IPV) victimization. Data were analyzed by using multivariate linear and logistic regression models. Compared with participants reporting no teen dating violence victimization at Wave 2, female participants experiencing victimization reported increased heavy episodic drinking, depressive symptomatology, suicidal ideation, smoking, and IPV victimization at Wave 3, whereas male participants experiencing victimization reported increased antisocial behaviors, suicidal ideation, marijuana use, and IPV victimization at Wave 3, controlling for sociodemographics, child maltreatment, and pubertal status. The results from the present analyses suggest that dating violence experienced during adolescence is related to adverse health outcomes in young adulthood. Findings from this study emphasize the importance of screening and offering secondary prevention programs to both male and female victims.


Flow cytometric analysis of platelet surface glycoproteins in the diagnosis of thirty-two Turkish patients with Glanzmann thrombasthenia: a multicenter experience
Glanzmann thrombasthenia (GT) is a rare autosomal recessively inherited bleeding disorder characterized by the quantitative (type 1 and type 2) or qualitative (type 3) deficiency in platelet membrane glycoprotein (GP) IIb/IIIa (CD41a/CD61) fibrinogen receptors. In type 1, 2, and 3, CD41a/CD61 expression is 5%, 5%–20% and above 20%, respectively. In this study, diagnosis of GT was confirmed and subgroups were identified in 32 Turkish patients by flow cytometry analysis. CD41a/CD61 expression levels in platelet-rich plasma (PRP) obtained from peripheral venous EDTA blood samples were analyzed with a BD FACSCanto II flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA). GT subgroup analysis was performed by counting 50,000 events in the BD FACSDiva Software v6.1.3 program of the instrument. In the present study, in blood samples of 32 patients from 23 families with GT and 22 healthy controls, co-expression levels of CD41a and CD61 in PRP was analyzed. 12 out of 23 families were consistent with type 1 GT (52.2%), 4 were consistent with type 2 GT (17.4%), and 7 were consistent with type 3 GT (30.4%). Especially due to consanguineous marriages, GT with various glycoprotein levels may be detected. As a result of the flow cytometry analysis of the present study with the highest GT patient population in Turkey, type 1 GT patients were the most common subgroup. In the determination of the GT subgroups; especially in the detection of type 3 GT, flow cytometry is the most sensitive glycoprotein analysis method. In addition to light transmission aggregometry, CD41a/CD61 study by flow cytometer confirms diagnosis when mutation analysis cannot be performed.


Complete sequence and analysis of the ovine herpesvirus 2 genome.
Ovine herpesvirus 2 (OvHV-2) is endemic in sheep populations worldwide and causes malignant catarrhal fever (MCF), a lymphoproliferative disease, in cattle, bison and deer. OvHV-2 has been placed in the gammaherpesvirus subfamily and is related closely to Alcelaphine herpesvirus 1 (AlHV-1). Here, the cloning, sequencing and analysis of the complete OvHV-2 genome derived from a lymphoblastoid cell line from an affected cow (BJ1035) are reported. The unique portion of the genome consists of 130,930 bp, with a mean G+C content of 52 mol%. The unique DNA is flanked by multiple copies of terminal repeat elements 4205 bp in length, with a mean G+C content of 72 mol%. Analysis revealed 73 open reading frames (ORFs), the majority (62) of which showed homology to other gammaherpesvirus genes. A further subset of nine ORFs is shared with only the related AlHV-1. Three ORFs are entirely unique to OvHV-2, including a spliced homologue of cellular interleukin-10 that retains the exon structure of the cellular gene. The sequence of OvHV-2 is a critical first step in the study of the pathogenesis and treatment of MCF.


Is adaptation to perceived interocular differences in height explained by vertical fusional eye movements?
To find out whether adaptation to a vertical prism involves more than fusional vertical eye movements. Adaptation to a vertical base-up 3 prism diopter prism was measured in a custom-programmed Maddox test in nine visually normal emmetropic subjects (mean age 27.0 ± 2.8 years). Vertical eye movements were binocularly measured in six of the subjects with a custom-programmed binocular video eye tracker. In the Maddox test, some subjects adjusted the perceived height as expected from the power of the prism while others appeared to ignore the prism. After 15 minutes of adaptation, the interocular difference in perceived height was reduced by on average 51% (from 0.86°-0.44°). The larger the initially perceived difference in height in a subject, the larger the amplitude of adaptation was. Eye tracking showed that the prism generated divergent vertical eye movements of 1.2° on average, which was less than expected from its power. Differences in eye elevation were maintained as long as the prism was in place. Small angles of lateral head tilt generated large interocular differences in eye elevation, much larger than the effects introduced by the prism. Vertical differences in retinal image height were compensated by vertical fusional eye movements but some subjects responded poorly to a vertical prism in both experiments; fusional eye movements were generally too small to realign both foveae with the fixation target; and the prism adaptation in the Maddox test was fully explained by the changes in vertical eye position, suggesting that no further adaptational mechanism may be involved.


Effects of Pomegranate Extract Supplementation on Cardiovascular Risk Factors and Physical Function in Hemodialysis Patients.
The purpose of this study was to evaluate the effects of oral supplementation with pomegranate extract on cardiovascular risk, physical function, oxidative stress, and inflammation in hemodialysis (HD) patients. Thirty-three HD subjects were randomized to the pomegranate (POM) or placebo (CON) group. Patients in POM ingested a 1000 mg capsule of a purified pomegranate polyphenol extract 7 days/week for 6 months. Individuals in CON ingested a noncaloric placebo capsule using the same protocol. Measurements were conducted at baseline and repeated 6 months following the start of the intervention. Brachial blood pressure (BP) was obtained using an automatic digital BP monitor. Cardiovascular risk was assessed using ultrasound and arterial tonometry. Blood samples were collected for the measurements of circulating markers of inflammation, oxidative stress, and antioxidant capacity. Muscle strength and physical function were assessed by isokinetic dynamometry, a validated shuttle walk test, and a battery of tests to assess functional fitness. Systolic blood pressure and diastolic blood pressure were reduced by 24 ± 13.7 and 10 ± 5.3 mmHg, respectively, in POM (P < .05). However, the BP differences in POM were no longer significant after controlling for baseline BP. The paraoxonase-1 activity increased by 26.6% (P < .05) in POM, compared to no significant change in CON. However, pomegranate supplementation had no effect on other markers of cardiovascular disease risk, inflammation and oxidative stress, or measures of physical function and muscle strength. While pomegranate extract supplementation may reduce BP and increase the antioxidant activity in HD patients, it does not improve other markers of cardiovascular risk, physical function, or muscle strength.


The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study.
Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a "main stream" pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ(9)-tetrahydrocannabinol (THC) and 11-hydroxy-Δ(9)-THC were taken at baseline and up to 120 minutes. Pain intensity (0-10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ(9)-THC plasma Cmax ± SD was 38 ± 10 ng/mL, Tmax ± SD was 3 ± 1 minutes, AUC₀→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma Cmax increase per mg Δ(9)-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of Cmax (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15-30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ(9)-THC pharmacokinetic profile with low interindividual variation of Cmax, achieving pharmaceutical standards for inhaled drugs.


Photosynthesis in the fleeting shadows: an overlooked opportunity for increasing crop productivity?
Photosynthesis measurements are traditionally taken under steady-state conditions; however, leaves in crop fields experience frequent fluctuations in light and take time to respond. This slow response reduces the efficiency of carbon assimilation. Transitions from low to high light require photosynthetic induction, including the activation of Rubisco and the opening of stomata, whereas transitions from high to low light require the relaxation of dissipative energy processes, collectively known as non-photochemical quenching (NPQ). Previous attempts to assess the impact of these delays on net carbon assimilation have used simplified models of crop canopies, limiting the accuracy of predictions. Here, we use ray tracing to predict the spatial and temporal dynamics of lighting for a rendered mature Glycine max (soybean) canopy to review the relative importance of these delays on net cumulative assimilation over the course of both a sunny and a cloudy summer day. Combined limitations result in a 13% reduction in crop carbon assimilation on both sunny and cloudy days, with induction being more important on cloudy than on sunny days. Genetic variation in NPQ relaxation rates and photosynthetic induction in parental lines of a soybean nested association mapping (NAM) population was assessed. Short-term NPQ relaxation (<30 min) showed little variation across the NAM lines, but substantial variation was found in the speeds of photosynthetic induction, attributable to Rubisco activation. Over the course of a sunny and an intermittently cloudy day these would translate to substantial differences in total crop carbon assimilation. These findings suggest an unexplored potential for breeding improved photosynthetic potential in our major crops.


Determinants of participation in leisure activities in children and youth with cerebral palsy: systematic review.
Children and youth with cerebral palsy (CP) experience difficulties in their ability to move, problem solve, socialize, and communicate, associated with limitations in activities in all environments. They are at risk for lower participation in social and leisure activities critical in fostering friendships, developing interests, and promoting well-being. Little is known about involvement in leisure activities and their determinants. This systematic review aims to describe participation in leisure activities by children with CP and identify personal and environmental factors that influence participation. The following databases were reviewed--CINAHL, Medline, Cochrane, Web of Science, OT-seeker, and REHABDATA--using the keywords participation, cerebral palsy, leisure, and recreation. The literature to date suggests that children with physical disabilities are less involved in leisure activities than their peers; activities are more passive, home based, and lack variety. Several factors influence participation in leisure activities, including age, gender, activity limitations, family preferences and coping, motivation, and environmental resources and supports.


Central nervous system toxicity of cyclosporine in a rat model.
The central nervous system toxicity of cyclosporine, which is known to be neurotoxic clinically, was investigated in a rat model. Munich-Wistar rats were divided into 3 groups for a 2-week protocol. After baseline EEG and behavioral testing, group 1 (control) received a weight-adjusted volume of parenteral cyclosporine vehicle i.p., group 2 (low-dose) received 5 or 10 mg/kg/day i.p., and group 3 (high-dose) received 20 mg/kg/day i.p. Spontaneous behavior was observed, simple sensorimotor testing performed daily, and awake EEG's recorded 3 times per week. Four of 12 high-dose animals died during study, one after a witnessed tonic-clonic seizure, and two after recording of frankly epileptiform EEG's; there were no deaths in control or low-dose animals. Significant EEG abnormalities developed only at high-dose, with frankly epileptiform EEG's and/or seizures seen in 58 +/- 15% of these rats (P = 0.005, different from controls by life-table analysis). Although some high-dose animals demonstrated hyperirritability and dystonic posturing, behavioral changes were subtle, and animals were often still or rocking slightly during recording of frankly epileptiform EEG's. Walking latency and alley escape behaviors were delayed in high-dose rats, the latter correlating with abnormal EEG's. Serum urea nitrogens were mildly elevated in high-dose animals, but serum creatinine, electrolytes, bilirubin, body magnesium stores, and blood pressure remained normal in all groups. Kidneys showed only mild vacuolation histologically. The brain showed only very focal cortical injury sites related to electrode placement, which did not correlate with EEG changes or mortality. These results suggest that there may be a direct effect of cyclosporine on the central nervous system. This model system should prove useful in defining mechanisms of cyclosporine-related neurotoxicity.


The harmful effects of ventricular distention during postischemic reperfusion.
To assess the effects of left ventricular distention during the early reperfusion period following ischemic arrest, 16 canine heart preparations were subjected to 45 minutes of hypothermic (27 degree C) cardioplegic arrest and normothermic reperfusion. Isovolumic left ventricular developed pressure and rate of rise of left ventricular pressure (dp/dt) were measured with an intraventricular balloon; endocardial/epicardial flow ratios were determined with microspheres; and myocardial gas tensions were monitored with mass spectrometry. During early reperfusion, Group 1 hearts (n = 8) were not distended (end-diastolic pressure = 0). Group 2 hearts (n = 8) were subjected to an enddiastolic pressure of 20 mm Hg for the initial 15 minutes of reperfusion. Group 2 hearts demonstrated impaired subendocardial blood flow after 5 minutes of reflow (0.75 +/- 0.06 vs 0.96 +/- 0.04, endocardial/epicardial flow rates, Group 2 vs Group 1) and persistent elevation of intramyocardial carbon dioxide (CO2) tension (68 +/- 4 vs 51 +/- 4 mm Hg, Group 2 vs Group 1). In addition, postischemic ventricular function was significantly worse in Group 2 hearts (60 +/- 7 vs 79 +/- 3% of control dP/dt, Group 2 vs Group 1, and 53 +/- 6 vs 81 +/- 5% of control left ventricular developed pressure, Group 2 vs Group 1). These data demonstrate that even mild distention during early reperfusion can result in reduced subendocardial perfusion and delayed washout of tissue CO2. Although myocardial blood flow and CO2 tension subsequently returned to normal in the distended hearts, left ventricular performance remained significantly depressed. This injury can occur clinically in nonvented hearts prior to the resumption of effective ventricular contraction.


A long-term study of the antiinflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide in asthma.
Adding inhaled long-acting beta(2)-agonists to a low dose of inhaled corticosteroids (ICS), results in better clinical asthma control than increasing the dose of ICS. However, this approach may mask underlying airway inflammation. In a double-blind parallel-group study, we evaluated the effect of adding formoterol to a low dose of budesonide, compared with a higher dose of budesonide, on the composition of induced sputum. After a 4-wk run-in period of treatment with budesonide (800 microg, twice daily), 60 patients with moderate asthma were randomly assigned to a 1-yr treatment with 400 microg of budesonide plus placebo, twice daily (BUD800), or 100 microg of budesonide plus 12 microg of formoterol, twice daily (BUD200+F). All drugs were administered via Turbuhaler. Budesonide (800 microg, twice daily) during run-in significantly reduced median sputum eosinophils from 4.5 to 0.68%. No significant changes in the proportion of eosinophils, EG2(+) cells, other inflammatory cells, or ECP levels in sputum were observed over the ensuing 1-yr treatment with BUD200+F or BUD800. Clinical asthma control was not significantly different between both groups. In conclusion, no significant differences in sputum markers of airway inflammation were observed during a 1-yr treatment with a low dose of inhaled budesonide plus formoterol compared with a higher dose of budesonide.


Beyond the electric-dipole approximation: A formulation and implementation of molecular response theory for the description of absorption of electromagnetic field radiation.
We present a formulation of molecular response theory for the description of a quantum mechanical molecular system in the presence of a weak, monochromatic, linearly polarized electromagnetic field without introducing truncated multipolar expansions. The presentation focuses on a description of linear absorption by adopting the energy-loss approach in combination with the complex polarization propagator formulation of response theory. Going beyond the electric-dipole approximation is essential whenever studying electric-dipole-forbidden transitions, and in general, non-dipolar effects become increasingly important when addressing spectroscopies involving higher-energy photons. These two aspects are examined by our study of the near K-edge X-ray absorption fine structure of the alkaline earth metals (Mg, Ca, Sr, Ba, and Ra) as well as the trans-polyenes. In following the series of alkaline earth metals, the sizes of non-dipolar effects are probed with respect to increasing photon energies and a detailed assessment of results is made in terms of studying the pertinent transition electron densities and in particular their spatial extension in comparison with the photon wavelength. Along the series of trans-polyenes, the sizes of non-dipolar effects are probed for X-ray spectroscopies on organic molecules with respect to the spatial extension of the chromophore.


Creating Community Resilience Through Elder-Led Physical and Social Infrastructure.
Natural disasters and rapidly aging populations are chronic problems for societies worldwide. We investigated the effects of an intervention in Japan known as Ibasho, which embeds elderly residents in vulnerable areas within larger social networks and encourages them to participate in leadership activities. This project sought to deepen the connections of these elderly residents to society and to build elderly leadership and community capacity for future crises. We carried out surveys of participants and nonparticipant residents across the city of Ofunato in Tohoku, Japan, 1 year after the intervention began. Our surveys included questions assessing participation levels in Ibasho, demographic characteristics, efficacy, social networks, and a sense of belonging. Regression analysis and propensity score matching of more than 1100 respondents showed that regular participation in the Ibasho project had a statistically significant and positive connection with various measures of social capital. Given its relatively low cost and focus on deepening cohesion, we suggest that this community-based project could be replicated and scaled up in other countries to deepen resilience, elder health, and social capital. Moving away from an emphasis on investing in physical infrastructure, we believe that disaster risk reduction strategies should center on social infrastructure. (Disaster Med Public Health Preparedness. 2017;11:120-126).


Conjugacy of torsional eye movements in response to a head tilt paradigm.
Vertically skewed eye movements are induced by head tilt toward the shoulder (roll). Because vertical and torsional eye movements are tightly coupled both mechanically and neuronally, the purpose of the present study was to investigate the conjugacy of torsional eye movements during the Bielschowsky head tilt test (BHTT). Furthermore, the purpose was to investigate the influence of different visual and viewing condition on torsional conjugacy. The issue has clinical relevance in interpreting the outcome of the BHTT. Eye movement recordings were performed using the infrared three-dimensional video-oculography (3D-VOG) technique. Objective cycloposition of 20 healthy individuals was measured in presumed primary position and in head tilt positions of 15 degrees, 30 degrees, and 45 degrees to the right and left, respectively. The same paradigm was performed under three different viewing conditions: binocularly without spatial orientation and both binocularly and monocularly with spatial orientation. The stimulus used with spatial orientation was a photographic picture of a historic building, whereas the stimulus with no spatial cues consisted of concentric circles. Consistent excyclovergence occurred in all subjects in head tilt. The relative amount increased with head tilt, regardless of the visual stimulus. Maximum excyclovergence was 0.7 degrees in 45 degrees head tilt during monocular fixation. Binocular viewing enhanced the torsion conjugacy by means of vergence stability (SD), whereas spatial visual cues improved the torsional conjugacy only slightly. Consistent excyclovergence was induced in head tilt. A vestibular origin seems to provide a plausible explanation of the induced torsional disconjugacy, whereas visual feed-back seems plausible in explaining the better conjugacy in binocular viewing.


Dynamics of Long-Range Temporal Correlations in Broadband EEG During Different Motor Execution and Imagery Tasks.
Brain activity is composed of oscillatory and broadband arrhythmic components; however, there is more focus on oscillatory sensorimotor rhythms to study movement, but temporal dynamics of broadband arrhythmic electroencephalography (EEG) remain unexplored. We have previously demonstrated that broadband arrhythmic EEG contains both short- and long-range temporal correlations that change significantly during movement. In this study, we build upon our previous work to gain a deeper understanding of these changes in the long-range temporal correlation (LRTC) in broadband EEG and contrast them with the well-known LRTC in alpha oscillation amplitude typically found in the literature. We investigate and validate changes in LRTCs during five different types of movements and motor imagery tasks using two independent EEG datasets recorded with two different paradigms-our finger tapping dataset with single self-initiated asynchronous finger taps and publicly available EEG dataset containing cued continuous movement and motor imagery of fists and feet. We quantified instantaneous changes in broadband LRTCs by detrended fluctuation analysis on single trial 2 s EEG sliding windows. The broadband LRTC increased significantly (p < 0.05) during all motor tasks as compared to the resting state. In contrast, the alpha oscillation LRTC, which had to be computed on longer stitched EEG segments, decreased significantly (p < 0.05) consistently with the literature. This suggests the complementarity of underlying fast and slow neuronal scale-free dynamics during movement and motor imagery. The single trial broadband LRTC gave high average binary classification accuracy in the range of 70.54±10.03% to 76.07±6.40% for all motor execution and imagery tasks and hence can be used in brain-computer interface (BCI). Thus, we demonstrate generalizability, robustness, and reproducibility of novel motor neural correlate, the single trial broadband LRTC, during different motor execution and imagery tasks in single asynchronous and cued continuous motor-BCI paradigms and its contrasting behavior with LRTC in alpha oscillation amplitude.


Factors influencing receipt of iron supplementation by young children and their mothers in rural India: local and national cross-sectional studies.
In India, 55% of women and 69.5% of preschool children are anaemic despite national policies recommending routine iron supplementation. Understanding factors associated with receipt of iron in the field could help optimise implementation of anaemia control policies. Thus, we undertook 1) a cross-sectional study to evaluate iron supplementation to children (and mothers) in rural Karnataka, India, and 2) an analysis of all-India rural data from the National Family Health Study 2005-6 (NFHS-3). All children aged 12-23 months and their mothers served by 6 of 8 randomly selected sub-centres managed by 2 rural Primary Health Centres of rural Karnataka were eligible for the Karnataka Study, conducted between August and October 2008. Socioeconomic and demographic data, access to health services and iron receipt were recorded. Secondly, NFHS-3 rural data were analysed. For both studies, logistic regression was used to evaluate factors associated with receipt of iron. The Karnataka Study recruited 405 children and 377 of their mothers. 41.5% of children had received iron, and 11.5% received iron through the public system. By multiple logistic regression, factors associated with children's receipt of iron included: wealth (Odds Ratio (OR) 2.63 [95% CI 1.11, 6.24] for top vs bottom wealth quintile), male sex (OR 2.45 [1.47, 4.10]), mother receiving postnatal iron (OR 2.31 [1.25, 4.28]), mother having undergone antenatal blood test (OR 2.10 [1.09, 4.03]); Muslim religion (OR 0.02 [0.00, 0.27]), attendance at Anganwadi centre (OR 0.23 [0.11, 0.49]), fully vaccinated (OR 0.33 [0.15, 0.75]), or children of mothers with more antenatal health visits (8-9 visits OR 0.25 [0.11, 0.55]) were less likely to receive iron. Nationally, 3.7% of rural children were receiving iron; this was associated with wealth (OR 1.12 [1.02, 1.23] per quintile), maternal education (compared with no education: completed secondary education OR 2.15 [1.17, 3.97], maternal antenatal iron (2.24 [1.56, 3.22]), and child attending an Anganwadi (OR 1.47 [1.20, 1.80]). In rural India, public distribution of iron to children is inadequate and disparities exist. Measures to optimize receipt of government supplied iron to all children regardless of wealth and ethnic background could help alleviate anaemia in this population.


Differential requirement for SUB1 in chromosomal and plasmid double-strand DNA break repair.
Non homologous end joining (NHEJ) is an important process that repairs double strand DNA breaks (DSBs) in eukaryotic cells. Cells defective in NHEJ are unable to join chromosomal breaks. Two different NHEJ assays are typically used to determine the efficiency of NHEJ. One requires NHEJ of linearized plasmid DNA transformed into the test organism; the other requires NHEJ of a single chromosomal break induced either by HO endonuclease or the I-SceI restriction enzyme. These two assays are generally considered equivalent and rely on the same set of NHEJ genes. PC4 is an abundant DNA binding protein that has been suggested to stimulate NHEJ. Here we tested the role of PC4's yeast homolog SUB1 in repair of DNA double strand breaks using different assays. We found SUB1 is required for NHEJ repair of DSBs in plasmid DNA, but not in chromosomal DNA. Our results suggest that these two assays, while similar are not equivalent and that repair of plasmid DNA requires additional factor(s) that are not required for NHEJ repair of chromosomal double-strand DNA breaks. Possible roles for Sub1 proteins in NHEJ of plasmid DNA are discussed.


Clinical utility of a stability-based ankle fracture classification system.
Neither of the ankle fracture classification systems (Lauge-Hansen or Weber) in widespread use today is prognostic. To test the hypothesis that ankle fracture prognosis is dependent on initial biomechanical stability, an alternative classification system created using stability-based treatment criteria was developed on the basis of a structured analysis of the ankle fracture literature. All English-language papers reporting on ankle fractures (searched using the terms "ankle + fracture") published between 1966 and 2005 with available online abstracts via PubMed were screened. Abstracts were manually screened for inclusion using the following criteria: (1) there were at least 2 groups of patients categorized on the basis of either fracture configuration or treatment and (2) data was reported in sufficient detail to permit interstudy comparisons. Each included paper was abstracted into a computerized database for consistent data capture. Data elements included the following: fracture classification, stability definitions, surgical indications, patient follow-up parameters, and outcome measures. Ankle fractures were also stratified into stable and unstable groups using predefined stability criteria, and the outcome measures were re-analyzed. Wilcoxon matched-pairs signed-rank test was used for statistical comparisons, assigning statistical significance to 2-tailed tests with P < 0.05. The results support the hypothesis that a stability-based ankle fracture classification system can be prognostic. For unstable ankle fractures, the radiographic outcomes were better after surgery, when the decision for surgery was made on the basis of stability (P = 0.0173). Overall, non-operative treatment results were also better with stability-based treatment (P = 0.0299).


Change in mental health after smoking cessation: systematic review and meta-analysis.
To investigate change in mental health after smoking cessation compared with continuing to smoke. Systematic review and meta-analysis of observational studies. Web of Science, Cochrane Central Register of Controlled Trials, Medline, Embase, and PsycINFO for relevant studies from inception to April 2012. Reference lists of included studies were hand searched, and authors were contacted when insufficient data were reported. Longitudinal studies of adults that assessed mental health before smoking cessation and at least six weeks after cessation or baseline in healthy and clinical populations. 26 studies that assessed mental health with questionnaires designed to measure anxiety, depression, mixed anxiety and depression, psychological quality of life, positive affect, and stress were included. Follow-up mental health scores were measured between seven weeks and nine years after baseline. Anxiety, depression, mixed anxiety and depression, and stress significantly decreased between baseline and follow-up in quitters compared with continuing smokers: the standardised mean differences (95% confidence intervals) were anxiety -0.37 (95% confidence interval -0.70 to -0.03); depression -0.25 (-0.37 to -0.12); mixed anxiety and depression -0.31 (-0.47 to -0.14); stress -0.27 (-0.40 to -0.13). Both psychological quality of life and positive affect significantly increased between baseline and follow-up in quitters compared with continuing smokers 0.22 (0.09 to 0.36) and 0.40 (0.09 to 0.71), respectively). There was no evidence that the effect size differed between the general population and populations with physical or psychiatric disorders. Smoking cessation is associated with reduced depression, anxiety, and stress and improved positive mood and quality of life compared with continuing to smoke. The effect size seems as large for those with psychiatric disorders as those without. The effect sizes are equal or larger than those of antidepressant treatment for mood and anxiety disorders.


Ocular neuromyotonia in a 15-year-old girl after radiation therapy.
A 15-year-old girl, previously treated with radiation, chemotherapy, and surgery for a posterior fossa medulloblastoma and parasellar metastasis at age 8, presented with a 10-month history of episodic horizontal diplopia. She was diagnosed with ocular neuromyotonia and successfully treated with oral carbamazepine. Given the strong association between peripheral neuromyotonia and the presence of autoimmune antivoltage-gated potassium channels, the patient's blood was tested and found negative for these autoantibodies. This is the first time this has been verified in a person with ocular neuromyotonia.


The effect of layer thickness and immobilization chemistry on the detection of CRP in LSPR assays.
The immobilization of a capture molecule represents a crucial step for effective usage of gold nanoparticles in localized surface plasmon resonance (LSPR)-based bioanalytics. Depending on the immobilization method used, the resulting capture layer is of varying thickness. Thus, the target binding event takes place at different distances to the gold surface. Using the example of a C-reactive protein immunoassay, different immobilization methods were tested and investigated with regard to their resulting target signal strength. The dependency of the target signal on the distance to the gold surface was investigated utilizing polyelectrolyte bilayers of different thickness. It could be experimentally demonstrated how much the LSPR-shift triggered by a binding event on the gold nanoparticles decreases with increasing distance to the gold surface. Thus, the sensitivity of an LSPR assay is influenced by the choice of immobilization chemistry.


The control of ozone uptake by Picea abies (L.) Karst. and P. sitchensis (Bong.) Carr. during drought and interacting effects on shoot water relations.
Exposure to O3 alone has not yet been shown to reproduce the symptoms of the various types of spruce decline which have been identified in Europe. However, there is increasing evidence that this pollutant has physiological effects which interact with those of other environmental factors in ways which may be important in determining tree condition and growth. The effects of O3 episodes and drought on O3 uptake, gas exchange and water relations of Picea abies (L.) Karst. and P. sitchensis (Bong.) Carr. were investigated in two experiments. In the first a rapidly drying soil mixture was used, and seedlings of P. abies were exposed to short (2 h) daily episodes of O3 at 80 nl 1-1 on each day of a 5 d drought. Photosynthesis (A) and stomatal conductance (gs ) were significantly decreased (P= 0.01) by water deficit and as a consequence, uptake of O3 by the plants was also significantly decreased. Exposure to O3 did not affect A or gs for this species. In the second experiment a soil mixture designed to give a slower development of water deficit was used and 1 + 1 transplants of P. sitchensis were exposed to a single O3 episode (up to 100 nl 1-1 for 3 h) after water had been withheld for 7 or 14 d. Hofler diagrams showed that mild water deficits did not affect shoot water relations. However, O3 significantly increased solute potential (Ψs ) after 7 d of drought, an effect which was lost after 14 d of drought. Flux of O3 to the watered plants was greater than to the unwatered plants at all concentrations, the effect being more marked at higher concentrations. This effect was partly attributable to the greater stomatal conductances recorded for the well watered plants, but was also partly due to stomatal opening caused by O3 , an effect which was diminished or reversed for unwatered plants.


Do they work? Regulating for-profit providers in Zimbabwe.
The experience of low- and middle-income countries (LMC) with respect to regulation and legislation in the health sector is in marked contrast to that of Canada and Europe. It is suggested that the degree to which regulatory mechanisms can influence private sector activity in LMC is quite low. However, there has been little work done on exploring just how, and to what extent, these regulations fail. Through the use of stakeholder interviews, this study explored the effectiveness of regulations directed at the private-for-profit sector (general practitioners, private clinics and hospitals) in Zimbabwe. The study found that there was limited and asymmetric knowledge of basic regulations among government bodies and private providers. However, there was a clear feeling that regulations are not being implemented and enforced effectively. A variety of opportunistic practices have been observed among private providers, including: practices of self-referral, where patients are sent to other services the provider has a financial interest in; over-servicing; doctor-patient collusion to collect health insurance payments; and the use of unlicensed staff in private facilities. Key factors limiting effectiveness of regulation in the health sector include the over-centralization and lack of independence of the regulatory body, the absence of legal mechanisms to control the price of care, and the lack of knowledge by patients of their rights. The study also identified a number of potential strategies for improving the current regulatory environment. For example, in order to improve monitoring, 'informal' arrangements between the centralized regulatory body and local authorities developed. There is a need to develop ways to formalize the role of these authorities. In addition, professional associations of private providers are also identified as key players through which to improve the impact of regulation among private providers. Increasing consumer access to information and knowledge is another potential way to improve information within the regulatory process as well as implementation.


A comparative clinical study on the Carisolv caries removal method.
Carisolv is a relatively new chemomechanical method for caries removal. The aim of this clinical study was to compare Carisolv with the conventional drilling technique. Forty-five volunteers, ages 18 to 55 years, each with two contralateral primary coronal mesio-occlusal or disto-occlusal carious lesions, similar in extent, participated in the study. Two calibrated operators treated all lesions. One operator treated both lesions in one visit (one lesion with Carisolv and the other with conventional drilling). Following the filling procedure, the opinion of each patient regarding each caries removal method was recorded. The need for drilling in addition to the Carisolv application, the time required for caries removal, the need for anesthesia, and the gingival reaction to the Carisolv gel were recorded by each operator for each case. The patients found Carisolv treatment more pleasant (82%) and preferable (88%) to drilling. Of the patients treated with drilling, 40% required anesthesia compared to the 8% treated with Carisolv. Additional drilling for complete caries removal was needed in 10% of Carisolv-treated lesions. Carisolv induced no gingival reaction. Significantly longer times were required for caries removal with Carisolv (12.2 +/- 4.1 minutes) compared to drilling (6.8 +/- 2.8 minutes). The Carisolv technique was: (a) accepted by the majority of patients, (b) efficient for caries removal, (c) considered a time-consuming technique for the dentists, and (d) considered less dependent on local anesthesia.


Immunogenicity of the outer domain of a HIV-1 clade C gp120.
The possibility that a sub domain of a C clade HIV-1 gp120 could act as an effective immunogen was investigated. To do this, the outer domain (OD) of gp120CN54 was expressed and characterized in a construct marked by a re-introduced conformational epitope for MAb 2G12. The expressed sequence showed efficient epitope retention on the isolated ODCN54 suggesting authentic folding. To facilitate purification and subsequent immunogenicity ODCN54 was fused to the Fc domain of human IgG1. Mice were immunised with the resulting fusion proteins and also with gp120CN54-Fc and gp120 alone. Fusion to Fc was found to stimulate antibody titre and Fc tagged ODCN54 was substantially more immunogenic than non-tagged gp120. Immunogenicity appeared the result of Fc facilitated antigen processing as immunisation with an Fc domain mutant that reduced binding to the FcR lead to a reduction in antibody titre when compared to the parental sequence. The breadth of the antibody response was assessed by serum reaction with five overlapping fragments of gp120CN54 expressed as GST fusion proteins in bacteria. A predominant anti-inner domain and anti-V3C3 response was observed following immunisation with gp120CN54-Fc and an anti-V3C3 response to the ODCN54-Fc fusion. The outer domain of gp120CN54 is correctly folded following expression as a C terminal fusion protein. Immunogenicity is substantial when targeted to antigen presenting cells but shows V3 dominance in the polyvalent response. The gp120 outer domain has potential as a candidate vaccine component.


Need for quality improvement in renal systematic reviews.
Systematic reviews of clinical studies aim to compile best available evidence for various diagnosis and treatment options. This study assessed the methodologic quality of all systematic reviews relevant to the practice of nephrology published in 2005. We searched electronic databases (Medline, Embase, American College of Physicians Journal Club, Cochrane) and hand searched Cochrane renal group records. Clinical practice guidelines, case reports, narrative reviews, and pooled individual patient data meta-analyses were excluded. Methodologic quality was measured using a validated questionnaire (Overview Quality Assessment Questionnaire). For reviews of randomized trials, we also evaluated adherence to recommended reporting guidelines (Quality of Reporting of Meta-Analyses). Ninety renal systematic reviews were published in year 2005, 60 of which focused on therapy. Many systematic reviews (54%) had major methodologic flaws. The most common review flaws were failure to assess the methodologic quality of included primary studies and failure to minimize bias in study inclusion. Only 2% of reviews of randomized trials fully adhered to reporting guidelines. A minority of journals (four of 48) endorsed adherence to consensus guidelines for review reporting, and these journals published systematic reviews of higher methodologic quality (P < 0.001). The majority of systematic reviews had major methodologic flaws. The majority of journals do not endorse consensus guidelines for review reporting in their instructions to authors; however, journals that recommended such adherence published systemic reviews of higher methodologic quality.


High serum CXCL10 in Rickettsia conorii infection is endothelial cell mediated subsequent to whole blood activation.
The pathophysiological hallmark of Rickettsia conorii (R. conorii) infection comprises infection of endothelial cells with perivascular infiltration of T-cells and macrophages. Although interferon (IFN)-γ-induced protein 10 (IP-10)/CXCL10 is induced during vascular inflammation, data on CXCL10 in R. conorii infection is scarce. Serum CXCL10 was analyzed in two cohorts of southern European patients with R. conorii infection using multiplex cytokine assays. The mechanism of R. conorii-induced CXCL10 release was examined ex vivo using human whole blood interacting with endothelial cells. (i) At admission, R. conorii infected patients had excessively increased CXCL10 levels, similar in the Italian (n=32, ∼56-fold increase vs controls) and the Spanish cohort (n=38, ∼68-fold increase vs controls), followed by a marked decrease after recovery. The massive CXCL10 increase was selective since it was not accompanied with similar changes in other cytokines. (ii) Heat-inactivated R. conorii induced a marked CXCL10 increase when whole blood and endothelial cells were co-cultured. Even plasma obtained from R. conorii-exposed whole blood induced a marked CXCL10 release from endothelial cells, comparable to the levels found in serum of R. conorii-infected patients. Bacteria alone did not induce CXCL10 production in endothelial cells, macrophages or smooth muscle cells. We show a massive and selective serum CXCL10 response in R. conorii-infected patients, likely reflecting release from infected endothelial cells characterized by infiltrating T cells and monocytes. The CXCL10 response could contribute to T-cell infiltration within the infected organ, but the pathologic consequences of CXCL10 in clinical R. conorii infection remain to be defined.


Impact of coronavirus disease 2019 on urgent referrals to secondary care otolaryngology: a prospective case series.
As the novel coronavirus disease 2019 changed patient presentation, this study aimed to prospectively identify these changes in a single ENT centre. A seven-week prospective case series was conducted of urgently referred patients from primary care and accident and emergency department. There was a total of 133 referrals. Referral rates fell by 93 per cent over seven weeks, from a mean of 5.4 to 0.4 per day. Reductions were seen in referrals from both primary care (89 per cent) and the accident and emergency department (93 per cent). Presentations of otitis externa and epistaxis fell by 83 per cent, and presentations of glandular fever, tonsillitis and peritonsillar abscess fell by 67 per cent. Coronavirus disease 2019 has greatly reduced the number of referrals into secondary care ENT. The cause for this reduction is likely to be due to patients' increased perceived risk of the virus presence in a medical setting. The impact of this reduction is yet to be ascertained, but will likely result in a substantial increase in emergency pressures once the lockdown is lifted and the general public's perception of the coronavirus disease 2019 risk reduces.


Recreational Physical Activity Experiences Among Guatemalan Families With Children With Visual Impairments.
Nationwide research indicates that children with visual impairment have limited participation in recreational and sport activities than their peers. This is due in part to the lack of recreational opportunities and facilities, as well as a lack of awareness by parents of how and where their children can participate. The purpose of the current study was to explore the experiences of Latino families of children with visual impairments living in Guatemala regarding physical recreation. Participants were Latino parents (N = 13) who have children with visual impairments recruited from a sport camp. Qualitative data were gathered through one-on-one interviews that were transcribed and analyzed through a constant comparative analysis. Participating Latino families who resided in Guatemala City participated at least once a month in low budget recreational activities with their children with visual impairments. Activities were mostly done in local surroundings and led mainly by their mother. Benefits identified by the participants related to relaxation, socialization, and sense of independence, with minimal mention of health related benefits. There is a need to disseminate information to the Latino community with children with visual impairments regarding the multiple benefits that arise from being involved in recreational physical activities.


Transcription factor KLF4 modulates microRNA-106a that targets Smad7 in gastric cancer.
Mounting evidence has revealed that microRNAs (miRNAs, miRNA) play oncogenic or anti-oncogenic roles in many cancer types. Our previous studies have found the ectopic expression of miR-106a in gastric cancer. However, its deregulation and some potential targets have not yet been fully explored. In this investigation, we identified that the upstream transcriptional factor krüppel-like factor 4 (KLF4), a novel regulator, directly bound to the promoter sequence of miR-106a and was responsible for its deregulation. Using real-time PCR and immunohistochemistry, we further verified that the expression level of KLF4 was negatively correlated with the miR-106a expression in tissue samples. Moreover, the downstream locus was also screened and small mothers against decapentaplegic 7 (Smad7) was revealed to be a direct target of miR-106a, with its 3'-UTR region complementarily bound to miR-106a and the protein expression was mediated by miR-106a in gastric cancer cells, which was confirmed by luciferase assay and Western blot. The role of KLF4-miR-106a-Smad7 in gastric cancer invasion was assessed by real-time PCR and transwell assay. The promoting effect of miR-106a on gastric cancer invasion was significantly abolished by the overexpression of KLF4. The silencing of Smad7 partially promoted the cell invasion when miR-106a was suppressed. In conclusion, we suggest that the ectopic expression of miR-106a is modulated by the upstream transcriptional factor KLF4, which influences the invasive ability of gastric cancer through the downstream target Smad7. MiR-106a should, therefore, be considered as a potential molecular phenotype in gastric cancer.


Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience.
The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg p.o.) on psilocybin-induced (170 µg/kg p.o.) psychological effects in two groups (n=19, n=17) of healthy human subjects. Psychological effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (p<0.001), which was mostly driven by a reduction of the VR item cluster scores for elementary and complex visual hallucinations. Further, buspirone also reduced the main scale score for Oceanic Boundlessness (OB) including derealisation and depersonalisation phenomena at a trend level (p=0.062), whereas ergotamine did not show any effects on the psilocybin-induced 5D-ASC main scale scores. The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurological diseases.


Transition metals in legume root nodules: iron-dependent free radical production increases during nodule senescence.
The cytosol from root nodules of soybean, bean, and cowpea contained Fe and Cu capable of catalyzing the formation of highly reactive free radicals. Specific and sensitive assays based on free radical-mediated DNA degradation revealed that most catalytic Fe and Cu were present as small chelates (300-600 Da). The involvement of catalytic Fe in free radical production during nodule senescence, which was induced by exposure of plants to continuous darkness for 2-4 days, was investigated. (i) Free heme remained at a constant and low concentration (1-4% of total nodule heme) during senescence, indicating that it is not an important constituent of the catalytic Fe pool of nodules. (ii) Catalytic Fe of nodule cytosol promoted deoxyribose degradation and linolenic acid peroxidation in reaction mixtures containing physiological concentrations of ascorbate and H2O2. Deoxyribose degradation but not lipid peroxidation required hydroxyl radicals to proceed. (iii) The cytosol from senescent nodules, particularly of bean and cowpea, sustained in vitro higher rates of deoxyribose degradation and lipid peroxidation than the cytosol from unstressed nodules. Both degradative processes were inhibited by the Fe chelator desferrioxamine and were correlated with the content of catalytic Fe in the nodule cytosol. (iv) Although other transition metals (Cu, Mn, Mo, and Ni) were present in significant amounts in the low molecular mass fraction (<3 kDa) of the nodule cytosol, Fe is most likely the only metal involved in free radical generation in vivo. (v) By using dimethyl sulfoxide as a molecular probe, formation of significant amounts of hydroxyl radical was observed in vivo during senescence of bean and cowpea nodules.


Propofol-based anaesthesia versus sevoflurane-based anaesthesia for living donor kidney transplantation: results of the VAPOR-1 randomized controlled trial.
Kidney transplantation is associated with harmful processes affecting the viability of the graft. One of these processes is associated with the phenomenon of ischaemia-reperfusion injury. Anaesthetic conditioning is a widely described strategy to attenuate ischaemia-reperfusion injury. We therefore conducted the Volatile Anaesthetic Protection of Renal Transplants-1 trial, a pilot project evaluating the influence of two anaesthetic regimens, propofol- vs sevoflurane-based anaesthesia, on biochemical and clinical outcomes in living donor kidney transplantation. Sixty couples were randomly assigned to the following three groups: PROP (donor and recipient propofol), SEVO (donor and recipient sevoflurane), and PROSE (donor propofol and recipient sevoflurane). The primary outcome was renal injury reflected by urinary biomarkers. The follow-up period was 2 yr. Three couples were excluded, leaving 57 couples for analysis. Concentrations of kidney injury molecule-1 (KIM-1), N -acetyl-β- d -glucosaminidase (NAG), and heart-type fatty acid binding protein (H-FABP) in the first urine upon reperfusion showed no differences. On day 2, KIM-1 concentrations were higher in SEVO [952.8 (interquartile range 311.8-1893.0) pg mmol -1 ] compared with PROP [301.2 (202.0-504.7) pg mmol -1 ]. This was the same for NAG: SEVO, 1.835 (1.162-2.457) IU mmol -1 vs PROP, 1.078 (0.819-1.713) IU mmol -1 . Concentrations of H-FABP showed no differences. Measured glomerular filtration rate at 3, 6, and 12 months showed no difference. After 2 yr, there was a difference in the acute rejection rate ( P =0.039). Post hoc testing revealed a difference between PROP (35%) and PROSE (5%; P =0.020). The difference between PROP and SEVO (11%) was not significant ( P =0.110). The SEVO group showed higher urinary KIM-1 and NAG concentrations in living donor kidney transplantation on the second day after transplantation. This was not reflected in inferior graft outcome. NCT01248871.


Older Americans' risk-benefit preferences for modifying the course of Alzheimer disease.
Alzheimer disease (AD) is a progressive, ultimately fatal neurodegenerative illness affecting millions of patients, families, and caregivers. Effective disease-modifying therapies for AD are desperately needed, but none currently exist on the market. Thus, accelerating the discovery, development, and approval of new disease-modifying drugs for AD is a high priority for individuals, physicians, and medical decision makers. Potentially disease-modifying drugs likely will have significant therapeutic benefits but also may have treatment-related risks. We quantified older Americans' treatment-related risk tolerance by eliciting their willingness to accept the risk of treatment-related death or permanent severe disability in exchange for modifying the course of AD. A stated-choice survey instrument was administered to 2146 American residents 60 years of age and older. On average, subjects were willing to accept a 1-year risk of treatment-related death or permanent severe disability from stroke of over 30% for a treatment that prevents AD from progressing beyond the mild stage. Thus, most people in this age cohort are willing to accept considerable risks in return for disease-modifying benefits of new AD drugs. These results are consistent with other studies indicating that individuals view AD as a serious, life threatening illness that imposes heavy burdens on both patients and caregivers.


Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling.
Macropinocytosis is differentiated from other types of endocytosis by its unique susceptibility to inhibitors of Na(+)/H(+) exchange. Yet, the functional relationship between Na(+)/H(+) exchange and macropinosome formation remains obscure. In A431 cells, stimulation by EGF simultaneously activated macropinocytosis and Na(+)/H(+) exchange, elevating cytosolic pH and stimulating Na(+) influx. Remarkably, although inhibition of Na(+)/H(+) exchange by amiloride or HOE-694 obliterated macropinocytosis, neither cytosolic alkalinization nor Na(+) influx were required. Instead, using novel probes of submembranous pH, we detected the accumulation of metabolically generated acid at sites of macropinocytosis, an effect counteracted by Na(+)/H(+) exchange and greatly magnified when amiloride or HOE-694 were present. The acidification observed in the presence of the inhibitors did not alter receptor engagement or phosphorylation, nor did it significantly depress phosphatidylinositol-3-kinase stimulation. However, activation of the GTPases that promote actin remodelling was found to be exquisitely sensitive to the submembranous pH. This sensitivity confers to macropinocytosis its unique susceptibility to inhibitors of Na(+)/H(+) exchange.


Serotype-specific and age-dependent generation of pneumococcal polysaccharide-specific memory B-cell and antibody responses to immunization with a pneumococcal conjugate vaccine.
Glycoconjugate vaccines have dramatically reduced the incidence of encapsulated bacterial diseases in toddlers under 2 years of age, but vaccine-induced antibody levels in this age group wane rapidly. We immunized adults and 12-month-old toddlers with heptavalent pneumococcal conjugate vaccine to determine differences in B-cell and antibody responses. The adults and 12-month-old toddlers received a pneumococcal conjugate vaccine. The toddlers received a second dose at 14 months of age. The frequencies of diphtheria toxoid and serotype 4, 14, and 23F polysaccharide-specific plasma cells and memory B cells were determined by enzyme-linked immunospot assay. The toddlers had no preexisting polysaccharide-specific memory B cells or serum immunoglobulin G (IgG) antibody but had good diphtheria toxoid-specific memory responses. The frequencies of plasma cells and memory B cells increased by day 7 (P < 0.0001) in the adults and the toddlers following a single dose of conjugate, but the polysaccharide responses were significantly lower in the toddlers than in the adults (P = 0.009 to <0.001). IgM dominated the toddler antibody responses, and class switching to the IgG was serotype dependent. A second dose of vaccine enhanced the antibody and memory B-cell responses in the toddlers but not the ex vivo plasma cell responses. Two doses of pneumococcal conjugate vaccine are required in toddlers to generate memory B-cell frequencies and antibody class switching for each pneumococcal polysaccharide equivalent to that seen in adults.


IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.
XIAP prevents apoptosis by binding to and inhibiting caspases, and this inhibition can be relieved by IAP antagonists, such as Smac/DIABLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits postmitochondrial caspases, caspase 8 inhibitors should not block killing by IACs. Instead, we show that apoptosis caused by an IAC is blocked by the caspase 8 inhibitor crmA and that IAP antagonists activate NF-kappaB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-kappaB-stimulated production of TNFalpha that killed cells in an autocrine fashion. Inhibition of NF-kappaB reduced TNFalpha production, and blocking NF-kappaB activation or TNFalpha allowed tumor cells to survive IAC-induced apoptosis. Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFalpha, suggesting novel uses of these compounds in treating cancer.


MRI parcellation of ex vivo medial temporal lobe.
Recent advancements in radio frequency coils, field strength and sophisticated pulse sequences have propelled modern brain mapping and have made validation to biological standards - histology and pathology - possible. The medial temporal lobe has long been established as a pivotal brain region for connectivity, function and unique structure in the human brain, and reveals disconnection in mild Alzheimer's disease. Specific brain mapping of mesocortical areas affected with neurofibrillary tangle pathology early in disease progression provides not only an accurate description for location of these areas but also supplies spherical coordinates that allow comparison between other ex vivo cases and larger in vivo datasets. We have identified several cytoarchitectonic features in the medial temporal lobe with high resolution ex vivo MRI, including gray matter structures such as the entorhinal layer II 'islands', perirhinal layer II-III columns, presubicular 'clouds', granule cell layer of the dentate gyrus as well as lamina of the hippocampus. Localization of Brodmann areas 28 and 35 (entorhinal and perirhinal, respectively) demonstrates MRI based area boundaries validated with multiple methods and histological stains. Based on our findings, both myelin and Nissl staining relate to contrast in ex vivo MRI. Precise brain mapping serves to create modern atlases for cortical areas, allowing accurate localization with important applications to detecting early disease processes.


Drug shortages. Part 2: Trends, causes and solutions.
Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations. In the first part of this review we proposed an operational definition that incorporates the processes by which products are manufactured, the causes of shortages and stock-outs (local shortages), and the contributory factors. Here we discuss causes and possible solutions. Drug shortages have complex causes, and a single cause cannot always be identified. Reasons include lack or shortage of raw materials, manufacturing difficulties, regulatory and political actions, voluntary recalls, just-in-time inventory systems, halts in production for financial or other business reasons, low demand (eg, orphan products, reduced usage), mergers, market shifts (eg, diversion to home markets) and unexpected increases in demand (eg, improved diagnosis, new trial information, epidemics and pandemics, inappropriate use, off-label use). Potential solutions are as diverse as the potential causes. Prevention is hard, because shortages are not easily predicted. Everyone in the supply chain is involved in anticipating and managing shortages, with responsibilities for preventing them or at least trying to mitigate their effects. This includes manufacturers and suppliers, particularly of generic formulations, pharmacists, prescribers, patients and governments. Solutions can therefore be linked to the causes and classified according to where the responsibility for implementing them lies.


The acute physiology and chronic health evaluation III outcome prediction in patients admitted to the intensive care unit after pneumonectomy.
The Acute Physiology and Chronic Health Evaluation (APACHE) III prognostic system has not been previously validated in patients admitted to the intensive care unit (ICU) after pneumonectomy. The purpose of this study was to determine if the APACHE III predicts hospital mortality after pneumonectomy. A retrospective review of all adult patients admitted to a single thoracic surgical intensive care unit after pneumonectomy between October 1994 and December 2004. Patient demographics, ICU admission day APACHE III score, actual and predicted hospital mortality, and length of hospital and ICU stay data were collected. Data on preoperative pulmonary function tests and smoking habits were also collected. Univariate statistical methods and logistic regression were used. The performance of the APACHE III prognostic system was assessed by the Hosmer-Lemeshow statistic for calibration and area under receiver operating characteristic curve (AUC) for discrimination. There were 417 pneumonectomies performed during the study period, of which 281 patients were admitted to the ICU. The mean age was 61.1 years, and 67.2% were men; 88.2% were smokers with a median of 40.0 (interquartile range, 18-62) pack-years of tobacco use. The mean APACHE III score on the day of ICU admission was 37.7 (+/- standard deviation 17.8), and the mean predicted hospital mortality rate was 6.4% (+/-10.4). The median (and interquartile range) lengths of ICU and hospital stay were 1.7 (0.9-3.1) and 9.0 (7.0-17.0) days, respectively. The observed ICU and hospital mortality rates were 4.6% (13/281 patients) and 8.2% (23/281), respectively. The standardized ICU and hospital mortality ratios with their 95% confidence intervals (CIs) were 1.55 (0.71-2.39) and 1.27 (0.75-1.78), respectively. There were significant differences in the mean APACHE III score (p < 0.001) and the predicted mortality rate (p < .001) between survivors and nonsurvivors. In predicting mortality, the AUC of APACHE III prediction was 0.801 (95% CI, 0.711-0.891), and the Hosmer-Lemeshow statistic was 9.898 with a p value of 0.272. Diffusion capacity of the lung for carbon monoxide (DLCO) and percentage predicted DLCO were higher in survivors, but the addition of either of these variables to a logistic regression model did not improve APACHE III mortality prediction. In patients admitted to the ICU after pneumonectomy, the APACHE III discriminates moderately well between survivors and nonsurvivors. The calibration of the model appears to be good, although the low number of deaths limits the power of the calibration analysis. The use of APACHE III data in outcomes research involving patients who have undergone pneumonectomy is acceptable.


Navigating abstract virtual environment: an eeg study.
Perceptions of different environments are different for different people. An abstract designed environment, with a degree of freedom from any visual reference in the physical world requests a completely different perception than a fully or semi-designed environment that has some correlation with the physical world. Maximal evidence on the manner in which the human brain is involved/operates in dealing with such novel perception comes from neuropsychology. Harnessing the tools and techniques involved in the domain of neuropsychology, the paper presents nee evidence on the role of pre-central gyrus in the perception of abstract spatial environments. In order to do so, the research team developed three different categories of designed environment with different characteristics: (1) Abstract environment, (2) Semi-designed environment, (3) Fully designed environment, as experimental sample environments. Perception of Fully-designed and semi-designed environments is almost the same, [maybe] since the brain can find a correlation between designed environments and already experienced physical world. In addition to this, the response to questionnaires accompanied with a list of buzzwords that have been provided after the experiments, also describe the characteristics of the chosen sample environments. Additionally, these results confirm the suitability of continuous electroencephalography (EEG) for studying Perception from the perspective of architectural environments.