Syncytium biogenesis: It's all about maintaining good connections.
At the end of mitosis, cells typically complete their division with cytokinesis. In certain tissues however, incomplete cytokinesis can give rise to cells that remain connected by intercellular bridges, thus forming a syncytium. Examples include the germline of many species, from fruitfly to humans, yet the mechanisms regulating syncytial formation and maintenance is unclear, and the biological relevance of syncytial organization remains largely speculative. To better understand these processes, we recently used the germline of Caenorhabditis elegans as a model for syncytium development. Analysis of the germline syncytial architecture throughout development revealed that it arises progressively during larval growth and that it relies on the activity of 2 actomyosin scaffold proteins of the Anillin family. Our work also showed that the gonad can sustain elastic deformation when under mechanical stress and that this property may be conferred by the malleability of syncytial openings. We suggest that elasticity and resistance to mechanical stress constitutes a general property of syncytial tissues.


Recovery of infectious respiratory syncytial virus expressing an additional, foreign gene.
A previous report described the recovery from cDNA of infectious recombinant respiratory syncytial virus (RSV) strain A2 (P. L. Collins, M. G. Hill, E. Camargo, H. Grosfeld, R. M. Chanock, and B. R. Murphy, Proc. Natl. Acad. Sci. USA, 92:11563-11567, 1995). Here, the system was used to construct recombinant RSV containing an additional gene encoding chloramphenicol acetyltransferase (CAT). The CAT coding sequence was flanked by RSV-specific gene-start and gene-end motifs, the transcription signals for the viral RNA-dependent RNA polymerase. The RSV-CAT chimeric transcription cassette was inserted into the region between the G and F genes of the complete cDNA-encoded positive-sense RSV antigenome, and infectious CAT-expressing recombinant RSV was recovered. Transcription of the inserted gene into the predicted subgenomic polyadenylated mRNA was demonstrated by Northern (RNA) blot hybridization analysis, and the encoded protein was detected by enzyme assay and by radioimmunoprecipitation. Quantitation of intracellular CAT, SH, G, and F mRNAs showed that the CAT mRNA was efficiently expressed and that the levels of the G and F mRNAs (which represent the genes on either side of the inserted CAT gene) were comparable to those expressed by a wild-type recombinant RSV. Consistent with this finding, the CAT-containing and wild-type viruses were very similar with regard to the levels of synthesis of the major viral proteins. Each of 25 RSV isolates obtained by plaque purification following eight serial passages expressed CAT, showing that the foreign gene was faithfully maintained in functional form. Analysis by reverse transcription and PCR did not reveal evidence of deletion of the foreign sequence. This finding demonstrated that the RSV genome can accept and maintain an increase in length of 762 nucleotides of foreign sequence and can be engineered to encode an additional, 11th mRNA. The presence of the additional gene resulted in a 10% decrease in plaque diameter and was associated with delay in virus growth and 20-fold decrease in virus yield in vitro. Thus, introduction of an additional gene into the RSV genome might represent a method of attenuation. The ability to express foreign genes by recombinant RSV has implications for basic studies as well as for the development of live recombinant vaccines.


A computational study on a multimode spin conductance switching by coordination isomerization in organometallic single-molecule junctions.
Single-molecule junctions provide the additional flexibility of tuning the on/off conductance states through molecular design. Here, we focus on a family of organometallic complexes with a conjugated curved buckybowl as the ligand. Using first-principles calculations, a multi-mode reversible spin switching based on the CpFe·corannulene complex is predicted by the temperature control of the CpFe+ coordination position in corannulene. The different spin conductance states for three coordinated modes are ascribed to the different electronic spin states of the organometallic complex due to crystal field effects. The predicted relative stabilities of isomers and the energy barriers of isomerization reactions can ensure that the conversion among the three isomers can occur quickly and, at a specific temperature, a dominant isomer has a higher proportion than the other two isomers. This provides a new framework for understanding transport in organometallic complexes with localized d states. This presents an exciting opportunity for exploiting junctions involving molecular spin switching.


Non-terminal blood sampling techniques in guinea pigs.
Guinea pigs possess several biological similarities to humans and are validated experimental animal models(1-3). However, the use of guinea pigs currently represents a relatively narrow area of research and descriptive data on specific methodology is correspondingly scarce. The anatomical features of guinea pigs are slightly different from other rodent models, hence modulation of sampling techniques to accommodate for species-specific differences, e.g., compared to mice and rats, are necessary to obtain sufficient and high quality samples. As both long and short term in vivo studies often require repeated blood sampling the choice of technique should be well considered in order to reduce stress and discomfort in the animals but also to ensure survival as well as compliance with requirements of sample size and accessibility. Venous blood samples can be obtained at a number of sites in guinea pigs e.g., the saphenous and jugular veins, each technique containing both advantages and disadvantages(4,5). Here, we present four different blood sampling techniques for either conscious or anaesthetized guinea pigs. The procedures are all non-terminal procedures provided that sample volumes and number of samples do not exceed guidelines for blood collection in laboratory animals(6). All the described methods have been thoroughly tested and applied for repeated in vivo blood sampling in studies within our research facility.


Speciation reversal in European whitefish (Coregonus lavaretus (L.)) caused by competitor invasion.
Invasion of exotic species has caused the loss of biodiversity and imparts evolutionary and ecological changes in the introduced systems. In northern Fennoscandia, European whitefish (Coregonus lavaretus (L.)) is a highly polymorphic species displaying adaptive radiations into partially reproductively isolated and thus genetically differentiated sympatric morphs utilizing the planktivorous and benthivorous food niche in many lakes. In 1993, Lake Skrukkebukta was invaded by vendace (Coregonus albula (L.)) which is a zooplanktivorous specialist. The vendace displaced the densely rakered whitefish from its preferred pelagic niche to the benthic habitat harbouring the large sparsely rakered whitefish. In this study, we investigate the potential influence of the vendace invasion on the breakdown of reproductive isolation between the two whitefish morphs. We inferred the genotypic and phenotypic differentiation between the two morphs collected at the arrival (1993) and 15 years after (2008) the vendace invasion using 16 microsatellite loci and gill raker numbers, the most distinctive adaptive phenotypic trait between them. The comparison of gill raker number distributions revealed two modes growing closer over 15 years following the invasion. Bayesian analyses of genotypes revealed that the two genetically distinct whitefish morphs that existed in 1993 had collapsed into a single population in 2008. The decline in association between the gill raker numbers and admixture values over 15 years corroborates the findings from the Bayesian analysis. Our study thus suggests an apparent decrease of reproductive isolation in a morph-pair of European whitefish within 15 years (≃ 3 generations) following the invasion of a superior trophic competitor (vendace) in a subarctic lake, reflecting a situation of "speciation in reverse".


Endolymphatic sac decompression as a treatment for Meniere's disease.
Endolymphatic sac decompression is a surgical treatment option for patients with medically intractable Meniere's disease. However, effectiveness is debated because published data show great variability. Outcome-based research studies are useful in incorporating the patient's perspective on the success of treatment. To further assess effectiveness of endolymphatic sac decompression, we performed a prospective study to examine both symptom-specific and general health outcomes. Prospective, observational outcome study. Nineteen patients with endolymphatic sac decompression responded to symptom-specific questionnaires and the Medical Outcomes Short-Form 36 Health Survey (SF-36) before and after surgery. Follow-up ranged from 6 to 58 months with a mean duration of 50 months. Overall measures of physical health were significantly improved following endolymphatic sac decompression (P = .04), whereas overall measures of mental health were unchanged (P = .74). Role Physical and Social Functioning scores were significantly improved following endolymphatic sac decompression (P = .04 and P = .03, respectively). Study patients scored significantly lower (P < .05) than SF-36 normative data in 6 of 10 categories before endolymphatic sac decompression but patient scores were not significantly different from normal scores in all but one category (General Health) following endolymphatic sac decompression. The mean number of vertigo episodes was significantly reduced from an average of 8.3 times per month to an average of 2.6 times per month following endolymphatic sac decompression (P = .006). Ninety-five percent of patients (18 of 19 patients) reported improvement in symptoms (frequency, duration, or intensity) of vertigo and 37% (7 of 19 patients) reported complete resolution of vertigo. Endolymphatic sac decompression significantly improved perception of physical health, as well as symptom-specific outcomes, in patients with medically intractable Meniere's disease.


Non-exercise activity thermogenesis.
Non-exercise activity thermogenesis (NEAT) is the energy expended that is not from sleeping, eating or sports-like exercise. It ranges from the energy expended walking to work, typing, performing yard work, undertaking agricultural tasks and fidgeting. NEAT can be measured by one of two approaches. The first approach is to measure or estimate total NEAT. Here, total daily energy expenditure is measured and from it is subtracted BMR + thermic effect of food. The second is the factoral approach whereby the components of NEAT are quantified and total NEAT calculated by summing these components. The amount of NEAT that human subjects perform represents the product of the amount and types of physical activities and the thermogenic cost of each activity. The factors that affect the NEAT of a human subject are readily divisible into biological factors, such as weight, gender and body composition, and environmental factors, such as occupation or dwelling within a 'concrete jungle'. The combined impact of these factors explains the substantial variance in human NEAT. The variability in NEAT might be viewed as random but human data contradict this perception. It appears that changes in NEAT subtly accompany experimentally-induced changes in energy balance and are important in the physiology of weight change. NEAT and sedentariness may thus be important in obesity. It then becomes intriguing to dissect mechanistic studies that delineate how NEAT is regulated by neural, peripheral and humoral factors. NEAT may be a carefully-regulated 'tank' of physical activity that is crucial for weight control.


Comparative analyses of host responses upon infection with moderately virulent classical swine fever virus in domestic pigs and wild boar.
Classical swine fever (CSF) is one of the most important viral diseases of pigs. Clinical signs may vary from almost inapparent infection to a hemorrhagic fever like illness. Among the host factors leading to different disease courses are age, breed, and immune status. The aim of this study was to compare host responses of different pig breeds upon infection with a recent moderately virulent CSF virus (CSFV) strain, and to assess their impact on the clinical outcome and the efficiency of immune responses. To this means, two domestic pig types (German Landrace and hybrids), were compared to European wild boar. Along with clinical and pathological assessments and routine virological and serological methods, kinetics of immune-cellular parameters were evaluated. All animals were susceptible to infection and despite clinical differences, virus could be detected in all infected animals to similar amounts. All but one animal developed an acute disease course, two landrace animals recovered after a transient infection. One wild boar got chronically infected. Changes in the percentages of lymphocyte subsets in peripheral blood did not show a clear correlation with the clinical outcome. High and early titers of neutralizing antibodies were especially detected in wild boar and German Landrace pigs. While differences among breeds did not have the expected impact on course and outcome of CSFV infection, preload with facultative pathogens and even small differences in age seemed to be more relevant. Future studies will target the characterization of responses observed during different disease courses including cytokine reactions and further analyses of lymphocyte subsets.


Prevalence of Systemic Atherosclerosis Burdens and Overlapping Stroke Etiologies and Their Associations With Long-term Vascular Prognosis in Stroke With Intracranial Atherosclerotic Disease.
Patients who have experienced stroke with intracranial atherosclerotic disease (ICAD) may also have concomitant atherosclerosis in different arterial beds and other possible causes for ischemic stroke. However, little is known about the frequency and prognostic effect of such overlapping diseases. To describe the prevalence of systemic atherosclerotic burdens and overlapping stroke etiologies and their contributions to long-term prognoses among patients who have experienced stroke with ICAD. The Asymptomatic Myocardial Ischemia in Stroke and Atherosclerotic Disease study is a single-center prospective study in which 405 patients with acute ischemic stroke within 10 days of onset were consecutively enrolled between June 2005 and December 2008 and followed up for 4 years. After excluding 2 patients because of incomplete investigations, 403 were included in this analysis. Significant ICAD was defined as having 50% or greater stenosis/occlusion by contrast-enhanced/time-of-flight magnetic resonance angiography, computed tomography angiography, and/or transcranial Doppler ultrasonography. Systemic vascular investigations on atherosclerotic disease were performed with ultrasonography in carotid arteries, aorta and femoral arteries, and by angiography in coronary arteries. Coexistent stroke etiologies were assessed using the atherosclerosis, small-vessel disease, cardiac pathology, other cause, and dissection (ASCOD) grading system. We estimated the 4-year risk of major adverse cardiovascular events (MACE), including vascular death, nonfatal cardiac events, nonfatal stroke, and major peripheral arterial events. Of 403 participants, 298 (74%) were men and the mean (SD) age was 62.6 (13.1) years. Significant ICAD was found in 146 (36.2%). Patients with significant ICAD more often had aortic arch (70 [60.9%] vs 99 [49.0%]; P = .04) and coronary artery (103 [76.9%] vs 153 [63.2%]; P = .007) atherosclerosis than those without. Among patients with ICAD, concurrent stenosis in the extracranial carotid artery (24 [23.4%] vs 3 [9.0%]; P = .08; adjusted hazard ratio[aHR] = 2.12) and the coronary artery (19 [29.9%] vs 8 [12.8%]; P = .01; aHR = 1.90) increased the MACE risk. Furthermore, patients with ICAD who also had any cardiac pathology (ASCOD grade C1-3) were at a higher MACE risk than others (grade C0) (20 [28.2%] vs 7 [11.4%]; P = .01; aHR = 2.24). By contrast, patients with ICAD with any form of small vessel disease (grade S1-3) had a lower MACE risk than those without (grade S0) (20 [17.3%] vs 6 [34.6%]; P = .05; aHR = 0.23). Patients with ICAD often have coexisting systemic atherosclerosis and multiple potential stroke mechanisms that affect their prognosis, suggesting that extensive evaluations of overlapping diseases may allow better risk stratification.


MicroRNA profiles of t(14;18)-negative follicular lymphoma support a late germinal center B-cell phenotype.
A total of 90% of follicular lymphomas (FLs) harbor the translocation t(14;18) leading to deregulated BCL2 expression. Conversely, 10% of FLs lack the t(14;18), and the majority of these FLs do not express BCL2. The molecular features of t(14;18)-negative FLs remain largely unknown. We performed microRNA expression analysis in 32 FL grades 1 to 3A, including 17 t(14;18)-positive FLs, 9 t(14;18)-negative FLs without BCL2 expression, and 6 t(14;18)-negative FLs with BCL2 expression. MicroRNA profiles were correlated with corresponding mRNA expression patterns, and potential targets were investigated by quantitative PCR and immunohistochemistry in an independent validation series of 83 FLs. Statistical analysis identified 17 microRNAs that were differentially expressed between t(14;18)-positive FLs and t(14;18)-negative FLs. The down-regulation of miR-16, miR-26a, miR-101, miR-29c, and miR138 in the t(14;18)-negative FL subset was associated with profound mRNA expression changes of potential target genes involving cell cycle control, apoptosis, and B-cell differentiation. miR-16 target CHEK1 showed increased expression in t(14;18)-negative FLs, whereas TCL1A expression was reduced, in line with a partial loss of the germinal center B-cell phenotype in this FL subset. In conclusion, t(14;18)-negative FL have distinct microRNA profiles that are associated with an increased proliferative capacity and a "late" germinal center B-cell phenotype.


Anterior Petrosectomy: Consecutive Series of 46 Patients with Attention to Approach-Related Complications.
Objective Anterior petrosectomy(AP) was popularized in the 1980s and 1990s as micro-neurosurgery proliferated. Original reports concentrated on the anatomy of the approach and small case series. Recently, with the advent of additional endonasal approaches to the petrous apex, the morbidity of AP remains unclear. This report details approach-related morbidity around and under the temporal lobe. Methods A total of 46 consecutive patients identified from our surgical database were reviewed retrospectively. Results Of the 46 patients, 61% were women. Median age of the patients was 50 years (mean: 48 ± 2 years). Median follow-up of this cohort was 66 months. Most procedures dealt with intradural pathology (n = 40 [87%]). Approach-related morbidity consisted of only two patients (4%) with new postoperative seizures. There were only two significant postoperative hemorrhages (4%). Cerebrospinal fluid leakage occurred in two patients (4%) requiring reoperation. Conclusion Approach-related complications such as seizures and hematoma were infrequent in this series, < 4%. This report describes a contemporary group of patients treated with open AP and should serve as a comparison for approach-related morbidity of endoscopic approaches. Given the pathologies treated with this approach, the morbidity appears acceptable.


Self-selection into payments for ecosystem services programs.
Designers and funders of payments for ecosystem services (PES) programs have long worried that payments flow to landholders who would have conserved forests even without the program, undermining the environmental benefits ("additionality") and cost-effectiveness of PES. If landholders self-select into PES programs based on how much conservation they were going to undertake anyway, then those who were planning to conserve should always enroll. This paper discusses the less-appreciated fact that enrollment is often based on other factors too. The hassle of signing up or financial costs of enrollment (e.g., purchasing seedlings) can affect who participates in a PES program. These enrollment costs reduce overall take-up, and, importantly, they can also influence the composition of landholders who select into the program-and thereby the program's environmental benefits per enrollee. Enrollment costs can increase a program's benefits per enrollee if they are systematically higher for (and thus deter enrollment by) landholders who would have conserved anyway. Alternatively, enrollment costs can dampen per-enrollee benefits if their correlation with status-quo conservation is in the opposite direction. We illustrate these points with evidence from two studies of randomized trials of PES programs aimed at increasing forest cover in Uganda and Malawi. We also discuss how in other sectors, such as social welfare, policy designers have purposefully adjusted the costs of program enrollment to influence the composition of participants and improve cost-effectiveness. We propose that these ideas for targeting could be incorporated into the design of PES programs.


Frequency and impact of active clinical issues and new impairments on hospital discharge in patients with hip fracture.
Hip fracture is associated with significant mortality and disability. Patients who are discharged from the hospital with active clinical problems may have worse outcomes than those patients without active clinical problems. To assess the frequency and impact of clinical problems at discharge on clinical and functional hip fracture outcomes. Detailed clinical data were collected from 559 patients in a prospective, multicenter observational cohort study. Active clinical issues (ACIs) on discharge included the following: temperature of 38.3 degrees C or higher, heart rate of more than 100/min or less than 60/min, systolic blood pressure higher than 180 mm Hg or lower than 90 mm Hg, diastolic blood pressure higher than 110 mm Hg or lower than 60 mm Hg, respiratory rate of more than 24/min, oxygen saturation of less than 90%, altered mental status, no oral intake, shortness of breath, chest pain, arrhythmias, or wound infection. New impairments (NIs) included bowel and bladder incontinence, inability to get out of bed, and decubitus ulcer. Outcomes were deaths, readmissions, and functional mobility 60 days after discharge. Overall, 94 patients (16.8%) had 1 or more ACIs, and 229 (41.0%) had 1 or more NIs on discharge. Both ACIs and NIs on discharge were associated with increased risk-adjusted rates of death (odds ratio, 1.8; 95% confidence interval, 1.2-2.8) or readmission (odds ratio, 1.7; 95% confidence interval, 1.2-2.3). The NIs on discharge were also associated with worse functional mobility (P<.004). These relationships persisted in multivariate analyses that controlled for a previously validated, hip fracture-specific risk adjustment measure. Clinicians should consider information about ACIs and NIs when deciding readiness for discharge and planning post-acute care.


Muscle Logic: New Knowledge Resource for Anatomy Enables Comprehensive Searches of the Literature on the Feeding Muscles of Mammals.
In recent years large bibliographic databases have made much of the published literature of biology available for searches. However, the capabilities of the search engines integrated into these databases for text-based bibliographic searches are limited. To enable searches that deliver the results expected by comparative anatomists, an underlying logical structure known as an ontology is required. Here we present the Mammalian Feeding Muscle Ontology (MFMO), a multi-species ontology focused on anatomical structures that participate in feeding and other oral/pharyngeal behaviors. A unique feature of the MFMO is that a simple, computable, definition of each muscle, which includes its attachments and innervation, is true across mammals. This construction mirrors the logical foundation of comparative anatomy and permits searches using language familiar to biologists. Further, it provides a template for muscles that will be useful in extending any anatomy ontology. The MFMO is developed to support the Feeding Experiments End-User Database Project (FEED, https://feedexp.org/), a publicly-available, online repository for physiological data collected from in vivo studies of feeding (e.g., mastication, biting, swallowing) in mammals. Currently the MFMO is integrated into FEED and also into two literature-specific implementations of Textpresso, a text-mining system that facilitates powerful searches of a corpus of scientific publications. We evaluate the MFMO by asking questions that test the ability of the ontology to return appropriate answers (competency questions). We compare the results of queries of the MFMO to results from similar searches in PubMed and Google Scholar. Our tests demonstrate that the MFMO is competent to answer queries formed in the common language of comparative anatomy, but PubMed and Google Scholar are not. Overall, our results show that by incorporating anatomical ontologies into searches, an expanded and anatomically comprehensive set of results can be obtained. The broader scientific and publishing communities should consider taking up the challenge of semantically enabled search capabilities.


Dietary PUFA and the metabolic syndrome in Indian Asians living in the UK.
Indian Asians living in the UK have a 50% higher CHD mortality rate compared with the indigenous Caucasian population, which cannot be attributed to traditional risk factors. Instead, features of the metabolic syndrome, including raised plasma triacylglycerol, reduced HDL-cholesterol (HDL-C) and an increased proportion of small dense LDL particles, together with insulin resistance and central obesity, are prevalent among this population. The present review examines evidence to support the hypothesis that an imbalance in dietary PUFA intake, specifically a higher intake of n-6 PUFA in combination with the lower intake of the long-chain (LC) n-3 PUFA, plays an important role in the prevalence of the metabolic syndrome observed in Indian Asians. Data are presented to illustrate the impact of manipulation of the background n-6 PUFA intake (moderate or high n-6 PUFA) and the subsequent response to supplementation with LC n-3 PUFA on blood lipids and insulin action in a group of Indian Asian volunteers. The results demonstrate that supplementation with LC n-3 PUFA had no impact on insulin action in those subjects consuming either the moderate- or high-n-6 PUFA diet. In the postprandial phase reductions in plasma triacylglycerol concentrations were greater in those consuming the high-n-6 PUFA background diet subsequent to fish oil supplementation. The present study concludes that, contrary to the central hypothesis, the prevalence of metabolic abnormalities in Indian Asians compared with Caucasians may not be attributable to differences in intakes of n-6 and n-3 PUFA.


Clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma: interim analysis.
To report an unplanned interim analysis of a prospective, one-armed, single center phase I/II trial (NCT01566123). Between 2007 and 2013, 27 patients (pts) with primary/recurrent retroperitoneal sarcomas (size > 5 cm, M0, at least marginally resectable) were enrolled. The protocol attempted neoadjuvant IMRT using an integrated boost with doses of 45-50 Gy to PTV and 50-56 Gy to GTV in 25 fractions, followed by surgery and IOERT (10-12 Gy). Primary endpoint was 5-year-LC, secondary endpoints included PFS, OS, resectability, and acute/late toxicity. The majority of patients showed high grade lesions (FNCLCC G1:18%, G2:52%, G3:30%), predominantly liposarcomas (70%). Median tumor size was 15 cm (6-31). Median follow-up was 33 months (5-75). Neoadjuvant IMRT was performed as planned (median dose 50 Gy, 26-55) in all except 2 pts (93%). Gross total resection was feasible in all except one patient. Final margin status was R0 in 6 (22%) and R1 in 20 pts (74%). Contiguous-organ resection was needed in all grossly resected patients. IOERT was performed in 23 pts (85%) with a median dose of 12 Gy (10-20 Gy).We observed 7 local recurrences, transferring into estimated 3- and 5-year-LC rates of 72%. Two were located outside the EBRT area and two were observed after more than 5 years. Locally recurrent situation had a significantly negative impact on local control. Distant failure was found in 8 pts, resulting in 3- and 5-year-DC rates of 63%. Patients with leiomyosarcoma had a significantly increased risk of distant failure. Estimated 3- and 5-year-rates were 40% for PFS and 74% for OS. Severe acute toxicity (grade 3) was present in 4 pts (15%). Severe postoperative complications were found in 9 pts (33%), of whom 2 finally died after multiple re-interventions. Severe late toxicity (grade 3) was scored in 6% of surviving patients after 1 year and none after 2 years. Combination of neoadjuvant IMRT, surgery and IOERT is feasible with acceptable toxicity and yields good results in terms of LC and OS in patients with high-risk retroperitoneal sarcomas. Long term follow-up seems mandatory given the observation of late recurrences. Accrual of patients will be continued with extended follow-up. NCT01566123.


Advances in the genetics of cerebrovascular disease and stroke.
MEDLINE searches identified epidemiologic, experimental, and clinical studies on the genetics of cerebrovascular disease and stroke, including the following topics: genetic epidemiology of stroke; genetics of systemic disorders that cause ischemic stroke, including coagulation disorders, connective tissue disorders, vasculopathies, metabolic disorders, and disorders of unknown etiology; and genetics of systemic disorders that cause hemorrhagic stroke. Recent discoveries in stroke genetics involve the genetic basis of monogenic disorders such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and sickle cell disease. Reproducing similar advances in other forms of cerebrovascular disease and stroke will be more difficult because their inheritance is complex, multigenic, and heterogeneous. However, the future is promising with the application of molecular genetic approaches such as linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses as well as the transmission/disequilibrium test--a statistical method for detection of linkage between a marker and a disease-susceptibility locus.


A critical stem-loop structure in the CR4-CR5 domain of mammalian telomerase RNA.
Telomerase is an enzyme that maintains telomere length by adding telomeric sequence repeats onto chromosome ends. The telomerase ribonucleoprotein complex consists of two essential components, a reverse transcriptase and an RNA molecule that provides the template for telomeric repeat synthesis. A common secondary structure of vertebrate telomerase RNA has been proposed based on a phylogenetic comparative analysis of 35 sequences. Here we report the identification of an additional essential base-paired region in the CR4-CR5 domain of mammalian telomerase RNA, termed P6.1. Mouse telomerase RNAs with mutations that disrupted base pairings in the P6.1 helix were unable to reconstitute telomerase activity in vivo. In contrast, an RNA mutant with compensatory mutations that restored base pairings in the P6.1 helix restored telomerase activity. In an in vitro reconstitution system stable base pairing of the P6.1 stem was required for the RNA-protein interaction between the CR4-CR5 domain and the telomerase reverse transcriptase (TERT) protein. Interestingly, two RNA mutations, one that extends the P6.1 stem and one that alters the conserved nucleotides of the L6.1 loop, allowed RNA-protein binding but significantly impaired telomerase activity. These data establish the presence of the P6.1 stem-loop and its importance for the assembly and enzymatic activity of the mammalian telomerase complex.


Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation.
Dabigatran etexilate is a prodrug whose absorption is opposed by intestinal P-glycoprotein and which is converted by carboxylesterase to its active form, dabigatran. Unlike other statins, simvastatin and lovastatin are potent inhibitors of P-glycoprotein and carboxylesterase, and might either increase the risk of hemorrhage with dabigatran etexilate or decrease its effectiveness. We conducted 2 population-based, nested case-control studies involving Ontario residents 66 years of age and older who started dabigatran etexilate between May 1, 2012, and Mar. 31, 2014. In the first study, cases were patients with ischemic stroke; in the second, cases were patients with major hemorrhage. Each case was matched with up to 4 controls by age and sex. All cases and controls received a single statin in the 60 days preceding the index date. We determined the association between each outcome and the use of simvastatin or lovastatin, relative to other statins. Among 45 991 patients taking dabigatran etexilate, we identified 397 cases with ischemic stroke and 1117 cases with major hemorrhage. After multivariable adjustment, use of simvastatin or lovastatin was not associated with an increased risk of stroke (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 0.88 to 2.01). In contrast, use of simvastatin and lovastatin were associated with a higher risk of major hemorrhage (adjusted OR 1.46, 95% CI 1.17 to 1.82). In patients receiving dabigatran etexilate, simvastatin and lovastatin were associated with a higher risk of major hemorrhage relative to other statins. Preferential use of the other statins should be considered in these patients.


[New indications for transcranial Doppler--huge steps forward].
Huge steps forward in understanding and treatment of ischemic stroke happened in the last several decades. Significant part of this progress is due to advances in diagnostic possibilities, with the leading role of transcranial Doppler (TCD). The American Academy of Neurology has recently published new guidelines and indications for TCD use. Indications with the highest rank, when TCD is able to provide information with established clinical utility, are designated as follows: (1) screening of children aged 2 to 16 years with sickle cell disease for assessing the stroke risk, and (2) detection and monitoring of vasospasm in spontaneous subarachnoid hemorrhage. TCD indications in setting where this examination provides important information but with still indefinite clinical utility are: (1) intracranial steno-occlusive disease, with data insufficient to recommend replacement of conventional angiography with TCD, despite obvious TCD usefulness and precision, and (2) cerebral circulatory arrest detection, as confirmatory test in support of clinical diagnosis of brain death. The major limiting factor of TCD application is dependence on an examiner's training and skills. Only strict application of diagnostic protocols and accepted criteria, with knowledge of pathophysiologic basis of cerebrovascular diseases and TCD principles, can result in conclusive findings. TCD is the source of valuable information for neurologists and other specialty physicians. This text presents review of other TCD indications and their application in everyday practice.


Flail arm-like syndrome associated with HIV-1 infection.
During the last 20 years at least 23 cases of motor neuron disease have been reported in HIV-1 seropositive patients. In this report we describe the clinical picture of a young man with HIV-1 clade C infection and flail arm-like syndrome, who we were able to follow-up for a long period. We investigated and prospectively monitored a 34-year-old man with features of flail arm syndrome, who developed the weakness and wasting 1 year after being diagnosed with HIV-1 infection after a routine blood test. He presented in 2003 with progressive, symmetrical wasting and weakness of the proximal muscles of the upper limb of 2 years' duration. He had severe wasting and weakness of the shoulder and arm muscles. There were no pyramidal signs. He has been on HAART for the last 4 years and the weakness or wasting has not worsened. At the last follow-up in July 2007, the patient had the same neurological deficit and no other symptoms or signs of HIV-1 infection. MRI of the spinal cord in 2007 showed characteristic T2 hyperintense signals in the central part of the spinal cord, corresponding to the central gray matter. Thus, our patient had HIV-1 clade C infection associated with a 'flail arm-like syndrome.' The causal relationship between HIV-1 infection and amyotrophic lateral sclerosis (ALS)-like syndrome is still uncertain. The syndrome usually manifests as a lower motor neuron syndrome, as was seen in our young patient. It is known that treatment with antiretroviral therapy (ART) stabilizes/improves the condition. In our patient the weakness and atrophy remained stable over a period of 3.5 years after commencing HAART regimen.


Engagement in dance is associated with emotional competence in interplay with others.
This study has explored the relation between dance achievement and alexithymia in a larger Swedish population sample (Swedish Twin Registry) with a study sample of 5431 individuals. Dance achievement (CAQ) was assessed in relation to Alexithymia (Toronto Alexithymia Scale, TAS-20) including the three subscales: Difficulty Identifying Feelings (DIF), Difficulty Describing Feelings (DDF), and Externally Oriented Thinking (EOT). The results show a significant negative association between the TAS subscale (EOT) and creative achievement in dance. A high EOT score corresponds to poor ability to communicate feelings to the environment. There was no consistent association between the other factors DIF and DDF and dance achievement. Dance activity and training seem to be involved in the body's emotional interplay with others. Embodied cognition, emotional perception, and action are discussed as factors relevant to measuring the skill of a dancer.


Subjective and objective evaluations of health among middle-aged and older veterans with hypertension.
The congruence between self-rated health and objective health was examined for associations with health factors related to hypertension (health behaviors, medication barriers, and perceived blood-pressure control). The Charlson Comorbidity Index was cross classified with self-rated health, producing four health-congruence groups: good health realists, poor health realists, health optimists, and health pessimists. Data for this study were obtained from 588 hypertensive veterans (mean age = 63) at baseline of a clinical trial to improve blood-pressure control before randomization to an intervention. Optimists had higher perceived control of their hypertension when compared to pessimists. Additionally, optimists had higher levels of exercise and fewer medication barriers when compared to poor health realists. Health congruence classification could be a useful tool to alert practitioners of patients who may be having difficulties managing their hypertension.


Use of a Boari flap and renal descensus as treatment for proximal ureteral rupture in a cat.
CASE DESCRIPTION A 6-year-old neutered male domestic shorthair cat was evaluated because of signs of abdominal pain and anuria of 12 hours' duration after vehicular trauma. CLINICAL FINDINGS Lethargy, mydriasis, bradycardia, abdominal distension, and signs of pain on abdominal palpation were observed. Abdominal ultrasonography revealed moderate urinary bladder distension without evidence of free abdominal fluid; hematologic evaluation revealed leukocytosis with high BUN and serum creatinine concentrations. TREATMENT AND OUTCOME The patient was hospitalized, medical stabilization was attempted, and an indwelling urinary catheter was placed. Urinary output was < 1 mL/kg/h (< 0.45 mL/lb/h), and signs of abdominal pain persisted despite treatment. The next day, ultrasonographic examination revealed fluid in the retroperitoneal space, and ureteral rupture was suspected. Exploratory laparotomy confirmed retroperitoneal fluid accumulation; a large hematoma surrounded the right kidney and perirenal structures. An abdominal drain was placed to aid patient stabilization. Three days later, IV pyelography revealed rupture of the proximal part of the right ureter. Ureteroneocystostomy was performed with elongated cystoplasty through a Boari flap and caudal transposition of the right kidney (renal descensus). On follow-up examination 18 months after treatment, the cat was free of clinical signs, and results of ultrasonography, CBC, and serum biochemical analysis were unremarkable. CLINICAL RELEVANCE Results suggested that a Boari flap procedure with renal descensus could be a feasible alternative in the management of proximal ureteral rupture in cats, but research is needed in this area.


The analysis of record-linked data using multiple imputation with data value priors.
Probabilistic record linkage techniques assign match weights to one or more potential matches for those individual records that cannot be assigned 'unequivocal matches' across data files. Existing methods select the single record having the maximum weight provided that this weight is higher than an assigned threshold. We argue that this procedure, which ignores all information from matches with lower weights and for some individuals assigns no match, is inefficient and may also lead to biases in subsequent analysis of the linked data. We propose that a multiple imputation framework be utilised for data that belong to records that cannot be matched unequivocally. In this way, the information from all potential matches is transferred through to the analysis stage. This procedure allows for the propagation of matching uncertainty through a full modelling process that preserves the data structure. For purposes of statistical modelling, results from a simulation example suggest that a full probabilistic record linkage is unnecessary and that standard multiple imputation will provide unbiased and efficient parameter estimates.


Salvage chemotherapy and autologous stem cell transplantation for peripheral T-cell lymphoma: a subset analysis of the Canadian Cancer Trials Group LY.12 randomized phase 3 study.
Peripheral T-cell lymphoma (PTCL) is a rare, heterogeneous malignancy. Of the 619 patients with relapsed and refractory (R/R) aggressive lymphoma enrolled in the Canadian Cancer Trials Group LY.12 phase 3 trial, 59 (9.5%) had PTCL. Among these, 81% had advanced stage disease, 41% had an International Prognostic Score ≥3, and 41% were refractory to primary therapy. Within the PTCL cohort, the overall response rate after two cycles of salvage chemotherapy was 36%; no difference was observed between dexamethasone, cytarabine, cisplatin (10/30, 33%), and gemcitabine, cisplatin, dexamethasone (11/29, 38%) therapy. At one year, event-free survival (EFS) was 16% and overall survival (OS) was 28%. For PTCL patients, who received autologous stem cell transplant, two-year EFS and OS were 21% and 42%, respectively. Patients with PTCL had inferior OS (HR 0.49, p < .0001) and EFS (HR 0.53, p < .0001) compared to B-cell lymphoma. Outcomes for patients with R/R PTCL are poor with currently available therapies.


Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase.
Protein acetylation has emerged as a major mechanism in regulating cellular metabolism. Whereas most glycolytic steps are reversible, the reaction catalyzed by pyruvate kinase is irreversible, and the reverse reaction requires phosphoenolpyruvate carboxykinase (PEPCK1) to commit for gluconeogenesis. Here, we show that acetylation regulates the stability of the gluconeogenic rate-limiting enzyme PEPCK1, thereby modulating cellular response to glucose. High glucose destabilizes PEPCK1 by stimulating its acetylation. PEPCK1 is acetylated by the P300 acetyltransferase, and this acetylation stimulates the interaction between PEPCK1 and UBR5, a HECT domain containing E3 ubiquitin ligase, therefore promoting PEPCK1 ubiquitinylation and degradation. Conversely, SIRT2 deacetylates and stabilizes PEPCK1. These observations represent an example that acetylation targets a metabolic enzyme to a specific E3 ligase in response to metabolic condition changes. Given that increased levels of PEPCK are linked with type II diabetes, this study also identifies potential therapeutic targets for diabetes.


MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets.
ChIP-Seq is widely used to characterize genome-wide binding patterns of transcription factors and other chromatin-associated proteins. Although comparison of ChIP-Seq data sets is critical for understanding cell type-dependent and cell state-specific binding, and thus the study of cell-specific gene regulation, few quantitative approaches have been developed. Here, we present a simple and effective method, MAnorm, for quantitative comparison of ChIP-Seq data sets describing transcription factor binding sites and epigenetic modifications. The quantitative binding differences inferred by MAnorm showed strong correlation with both the changes in expression of target genes and the binding of cell type-specific regulators.


Remission of collagen-induced arthritis is associated with high levels of transforming growth factor-beta expression in the joint.
Immunization of genetically susceptible strains of mice with heterologous type II collagen leads to the induction of a self-limiting polyarthritis that begins to subside around 10 days after onset of clinical disease. The aims of this study were to compare pro- and anti-inflammatory cytokine expression in the joints during the course of arthritis in order to identify cytokines involved in spontaneous remission of arthritis. DBA/1 mice were immunized with type II collagen and an immunohistochemical analysis of expression of proinflammatory cytokines [tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6] and anti-inflammatory cytokines [IL-10, IL-1ra, transforming growth factor (TGF)-beta1, TGF-beta2 and TGF-beta3] in joints was carried out over the course of the disease. Both pro- and anti-inflammatory cytokines were found to be expressed in early arthritis. However, around 10 days after onset of arthritis, the level of expression of proinflammatory cytokines declined while the level of expression of anti-inflammatory cytokines, particularly TGF-beta1 and TGF-beta2, increased. Surprisingly, TNF-alpha continued to be expressed at low levels during the period of disease remission (30 days after onset). Blockade of TNF-alpha during the period of disease remission had no effect on TGF-beta expression. This study confirms that the level of inflammation in arthritis correlates strongly with the balance of pro- and anti-inflammatory cytokine expression in the joints. Of the anti-inflammatory cytokines studied, TGF-beta1 and TGF-beta2 predominate during the time of disease remission, suggesting that these cytokines are involved in regulating disease activity.


Glycomic profiling of targeted serum haptoglobin for gastric cancer using nano LC/MS and LC/MS/MS.
Gastric cancer has one of the highest cancer mortality rates worldwide, largely because of difficulties in early-stage detection. Aberrant glycosylation in serum proteins is associated with many human diseases including inflammation and various types of cancer. Serum-based global glycan profiling using mass spectrometry has been explored and has already led to several potential glycan markers for several disease states. However, localization of the aberrant glycosylation is desirable in order to improve the specificity and sensitivity for clinical use. Here, we combined protein-specific immunoaffinity purification, glycan release, and MS analysis to examine haptoglobin glycosylation of gastric cancer patients for glyco-markers. Age- and sex-matched 60 serum samples (30 cancer patients and 30 healthy controls) were used to profile and quantify haptoglobin N-glycans. A T-test based statistical analysis was performed to identify potential glyco-markers for gastric cancer. Interestingly, abundances of several tri- and tetra-antennary fucosylated N-glycans were increased in gastric cancer patients. Additionally, structural analysis via LC/MS/MS indicated that the fucosylated complex type N-glycans were primarily decorated with antenna fucose, which can be categorized as sialyl-Lea or sialyl-Lex type structures. This platform demonstrates quantitative, structure-specific profiling of haptoglobin glycosylation for the purposes of biomarker discovery for gastric cancer.


Coassembly of big conductance Ca2+-activated K+ channels and L-type voltage-gated Ca2+ channels in rat brain.
Based on electrophysiological studies, Ca(2+)-activated K(+) channels and voltage-gated Ca(2+) channels appear to be located in close proximity in neurons. Such colocalization would ensure selective and rapid activation of K(+) channels by local increases in the cytosolic calcium concentration. The nature of the apparent coupling is not known. In the present study we report a direct coassembly of big conductance Ca(2+)-activated K(+) channels (BK) and L-type voltage-gated Ca(2+) channels in rat brain. Saturation immunoprecipitation studies were performed on membranes labeled for BK channels and precipitated with antibodies against alpha(1C) and alpha(1D) L-type Ca(2+) channels. To confirm the specificity of the interaction, precipitation experiments were carried out also in reverse order. Also, additive precipitation was performed because alpha(1C) and alpha(1D) L-type Ca(2+) channels always refer to separate ion channel complexes. Finally, immunochemical studies showed a distinct but overlapping expression pattern of the two types of ion channels investigated. BK and L-type Ca(2+) channels were colocalized in various compartments throughout the rat brain. Taken together, these results demonstrate a direct coassembly of BK channels and L-type Ca(2+) channels in certain areas of the brain.


Large-scale zygosity testing using single nucleotide polymorphisms.
A requirement for performing robust genetic and statistical analyses on twins is correctly assigned zygosities. In order to increase the power to detect small risk factors of disease, zygosity testing should also be amenable for high throughput screening. In this study we validate and implement the use of a panel of 50 single nucleotide polymorphisms (SNPs) for reliable high throughput zygosity testing and compare it to a panel of 16 short tandem repeats (STRs). We genotyped both genomic (gDNA) and whole genome amplified DNA (WGA DNA), ending up with 47 SNP and 11 STR markers fulfilling our quality criteria. Out of 99 studied twin pairs, 2 were assigned a different zygosity using SNP and STR data as compared to self reported zygosity in a questionnaire. We also performed a sensitivity analysis based on simulated data where we evaluated the effects of genotyping error, shifts in allele frequencies and missing data on the qualitative zygosity assignments. The frequency of false positives was less than 0.01 when assuming a 1% genotyping error, a decrease of 10% of the observed minor allele frequency compared to the actual values and up to 10 missing markers. The SNP markers were also successfully genotyped on both gDNA and WGA DNA from whole blood, saliva and filter paper. In conclusion, we validate a robust panel of 47 highly multiplexed SNPs that provide reliable and high quality data on a range of different DNA templates.


Scattering and Recoiling Spectrometry: An Ion's Eye View of Surface Structure.
Recent developments in ion-scattering spectrometry have led to a surface crystallography that is sensitive to all elements, including hydrogen. Time-of-flight techniques for the detection of atoms scattered and recoiled from surfaces in simple collision sequences, together with calculations of shadowing and blocking cones, can be used to make direct measurements of interatomic spacings and adsorption sites within an accuracy of </=0.1 angstrom. Time-of-flight detection of both neutrals and ions provides the high sensitivity necessary for nondestructive analysis. Structures are determined by monitoring the angular anisotropies in the scattered primary and recoiled target atom flux. Such surface and adsorption site determinations find application in such fields as catalysis, thin film growth, and interfaces.


Who is in control? Clinicians' view on their role in self-management approaches: a qualitative metasynthesis.
To explore clinician perceptions of involvement in delivery of self-management approaches. All healthcare settings. EBSCO, Scopus and AMED databases were searched, in July 2013, for peer-reviewed studies in English reporting original qualitative data concerning perceptions of clinicians regarding their involvement in or integration of a self-management approach. Of 1930 studies identified, 1889 did not meet the inclusion criteria. Full text of 41 studies were reviewed by two independent reviewers; 14 papers were included for metasynthesis. Findings and discussion sections were imported into Nvivo-10 and coded line-by-line. Codes were organised into descriptive themes and cross-checked against original sources to check interpretation, and refined iteratively until findings represented an agreed understanding. Studies were appraised for quality. Delivering self-management in practice appeared to be a complex process for many clinicians. The issue of 'control' arose in all studies, both in the qualitative data and authors' interpretations. The first theme: Who is in control?--represented ways clinicians talked of exercising control over patients and the control they expected patients to have over their condition. The second theme: Changing clinician views--reflected what appeared to be an essential transformation of practice experienced by some clinicians in the process of integrating self-management approaches into the practice. A range of challenges associated with shifting towards a self-management approach were reflected in the third theme, Overcoming challenges to change. Tensions appeared to exist around forming partnerships with patients. Strategies found helpful in the process of change included: dedicating time to practice reciprocity in communication style, peer support and self-reflection. A consistent finding across studies is that 'control' is a key feature of how self-management is viewed by clinicians. They described challenges associated with the paradigm shift required to share or let go of control. Future research should identify whether strategies described by clinicians are key to successful self-management.


The influence of lifestyle and gender on sickness absence in Brazilian workers.
Despite an increasing body of knowledge concerning gender and lifestyle factors as determinants of sickness absence in well-developed countries, the relationship between these variables has not been elucidated in emerging economic power countries, where the burden of non-communicable diseases is particularly high. This study aimed to analyze the relationships among lifestyle-related factors and sick leave and to examine whether gender differences in sickness absence can be explained by differences in socio-demographic, work and lifestyle-related factors among Brazilian workers. In this longitudinal study with a one year follow-up among 2.150 employees of a Brazilian airline company, sick leave was the primary outcome of interest. Independent variables collected by interview at enrolment in the study were gender, age, educational level, type of work, stress, and lifestyle-related factors (body mass index, physical activity and smoking). In addition, the risk for coronary heart disease was determined based on measurement of blood pressure, total cholesterol and glucose levels. The total number of days on sick leave during 12 months follow-up was available from the company register. Logistic regression analysis was used to determine the influence of socio-demographic, type of work and lifestyle-related factors on sick leave. Younger employees, those with lower educational level, those who worked as air crew members and those with higher levels of stress were more likely to have sick leave. Body mass index and level of physical activity were not associated with sick leave. After adjustment by socio-demographic variables, increased odds for 10 or more days of sick leave were found in smokers (OR=1.51, CI=1.05-2.17), and ex-smokers (OR=1.45, CI=1.01-2.10). Women were more likely to have 10 or more days of sick leave. Gender differences were reduced mainly when adjusted for type of work (15%) and educational level (7%). The higher occurrence of sick leave among women than among men was partly explained by type of work and educational level. Our results suggest that type of work, a stressful life, and smoking are important targets for health promotion in this study population.


Hope, recovery and symptoms: the importance of hope for people living with severe mental illness.
Hope is an important part of recovery from severe mental illness. Our aim was to assess hope and its correlation with symptoms in people living with severe mental illness. We used validated questionnaires to assess hope, social isolation, quality of life and symptoms among 60 people living with severe mental illness. Hope scores were significantly lower than those reported for many community groups. There was a negative association between psychiatric symptoms and levels of hope. Some people living with enduring severe mental illness in the Australian community feel hopeless. Being hopeful and initiating recovery are evidently difficult when symptoms remain severe. Appropriate acknowledgement and support for patients and their families is required.


[Environmental chemical hazards and child health].
To review the recent medical literature on environmental chemical hazards to child health. Articles published on this subject between 1999 and 2005 were searched in the MEDLINE database. Books, manuals and statements on child environmental health, issued by institutions such as the American Academy of Pediatrics and the World Health Organization, were also reviewed. There has been a growing concern in the last few years with the exposure of children to environmental chemicals. Around 85,000 synthetic chemicals are produced today, and 2,800 of them are mass-produced. There is little knowledge regarding their effects on developing organisms. Children have a greater exposure to environmental pollutants than adults, because their metabolic needs and behaviors (e.g.: crawling, bringing objects to the mouth, playing closer to the ground) put them at special risk of contact with chemicals when they breathe, eat, drink or play. Heavy metals, pesticides, persistent organic pollutants and, at home, environmental tobacco smoke have been associated with the increasing number of diseases such as asthma, neurodevelopmental disorders and childhood cancer. Screening of risk situations using tools such as Environmental History has been stimulated alongside a greater commitment of pediatricians towards measures that can reduce the exposure of children and adolescents to environmental chemicals.


Neutrophil adherence to isolated adult cardiac myocytes. Induction by cardiac lymph collected during ischemia and reperfusion.
Canine neutrophils can be induced to adhere in vitro to isolated adult cardiac myocytes by stimulation of the neutrophils with chemotactic factors such as zymosan-activated serum (ZAS) only if the myocytes have been previously exposed to cytokines such as interleukin 1 (IL-1) or tumor necrosis factor-alpha. These cytokines induce synthesis and surface expression of intercellular adhesion molecule-1 (ICAM-1) on the myocyte, and neutrophil adhesion is almost entirely CD18 and ICAM-1 dependent. The present study examines cardiac-specific lymph collected from awake dogs during 1-h coronary occlusion and 3 d of reperfusion for its ability to induce both ICAM-1 expression in cardiac myocytes, and neutrophil-myocyte adherence. Reperfusion lymph induced ICAM-1 expression in isolated myocytes, and myocyte adherence to ZAS-stimulated neutrophils that was completely inhibited by anti-CD18 and anti-ICAM-1 monoclonal antibodies. This activity peaked at 90 min of reperfusion and persisted for up to 72 h. Preischemic lymph was not stimulatory. IL-1 appeared not to be a stimulating factor in lymph in that dilutions of lymph were found to inhibit the stimulatory effects of recombinant IL-1 beta. However, investigation of interleukin 6 (IL-6) revealed that recombinant IL-6 stimulated myocyte adhesiveness for ZAS-stimulated neutrophils (ED50 = 0.002 U/ml) and expression of ICAM-1 by isolated myocytes. IL-6 neutralizing antibody markedly reduced the ability of reperfusion lymph to stimulate adhesion and ICAM-1 expression, and estimates of levels of IL-6 in reperfusion lymph ranged from 0.035 to 0.14 U/ml. These results indicate that cytokines capable of promoting neutrophil-myocyte adhesion occur in extracellular fluid during reperfusion of ischemic myocardium, and that one of these cytokines is IL-6. Neutrophil-myocyte adhesion may be of pathogenic significance because it may enhance the cytotoxic activity of the neutrophil.


Randomised controlled trial of the effect of long-term selenium supplementation on plasma cholesterol in an elderly Danish population.
Although cross-sectional studies have shown a positive association between Se and cholesterol concentrations, a recent randomised controlled trial in 501 elderly UK individuals of relatively low-Se status found that Se supplementation for 6 months lowered total plasma cholesterol. The Danish PRECISE (PREvention of Cancer by Intervention with Selenium) pilot study (ClinicalTrials.gov ID: NCT01819649) was a 5-year randomised, double-blinded, placebo-controlled trial with four groups (allocation ratio 1:1:1:1). Men and women aged 60-74 years (n 491) were randomised to 100 (n 124), 200 (n 122) or 300 (n 119) μg Se-enriched yeast or matching placebo-yeast tablets (n 126) daily for 5 years. A total of 468 participants continued the study for 6 months and 361 participants, equally distributed across treatment groups, continued for 5 years. Plasma samples were analysed for total and HDL-cholesterol and for total Se concentrations at baseline, 6 months and 5 years. The effect of different doses of Se supplementation on plasma lipid and Se concentrations was estimated by using linear mixed models. Plasma Se concentration increased significantly and dose-dependently in the intervention groups after 6 months and 5 years. Total cholesterol decreased significantly both in the intervention groups and in the placebo group after 6 months and 5 years, with small and nonsignificant differences in changes in plasma concentration of total cholesterol, HDL-cholesterol, non-HDL-cholesterol and total:HDL-cholesterol ratio between intervention and placebo groups. The effect of long-term supplementation with Se on plasma cholesterol concentrations or its sub-fractions did not differ significantly from placebo in this elderly population.


Effect of Instability and Bodyweight Neuromuscular Training on Dynamic Balance Control in Active Young Adults.
The aims of this study were to analyse the effects of unstable and stable bodyweight neuromuscular training on dynamic balance control and to analyse the between-group differences after the training period. Seventy-seven physically active young adults (48 males, 29 females, 19.1 ± 1.1 years, 170.2 ± 9.2 cm, 64.1 ± 10.7 kg) were distributed into an unstable training group (UTG), a stable training group (STG), and a control group (CG). Training was conducted three times a week for nine weeks. Pre-intervention and post-intervention measures included dynamic balance control using a Y Balance Test (YBT), anterior (A), posteromedial (PM), and posterolateral (PL) reach direction. A mixed ANOVA was executed to test the within-subjects factor and the between-subjects factor. Statistically significant differences were found for all YBT measures within groups (p = 0.01) and between groups (p = 0.01). After the intervention, UTG and STG presented meaningfully improved results in all YBT measures (A: 7%, p = 0.01; 4%, p = 0.02, PM: 8%, p = 0.01; 5%, p = 0.01, PL: 8%, p = 0.01; 4%, p = 0.04, respectively). No statistical changes were found for any of the measures in the CG. After the intervention, significant differences were observed between the UTG and CG for the YBTA and PM (p = 0.03; p = 0.01). The results suggest that neuromuscular training using an unstable surface had similar effects on dynamic balance control as training using a stable surface. When compared to CG, UTG showed better performance in YBTA and PM.


Interface/defect-tuneable macro and micro photoluminescence behaviours of trivalent europium ions in electrospun ZrO2/ZnO porous nanobelts.
It was demonstrated that suitable interfaces between two materials can enhance the separation of photogenerated carriers. In this study, ZrO2/ZnO interfaces with type I structure were designed and prepared by the electrospinning technique. The obtained ZrO2/ZnO:Eu3+ (ZZOE) composites are highly porous in the form of nanobelts with width of 600-700 nm, comprising ZnO and ZrO2 nanocrystals, and the Eu doping can hinder the t-m phase transition of ZrO2. By tuning the annealing temperature, the inner stress and defects can be well controlled to improve the photoluminescence (PL) of the ZZOE porous nanobelts. Macro- and micro-PL spectra indicated that the body oxygen vacancies benefit the PL from Eu3+ ions, whereas the surficial ones do not. The optimal parameters for the preparation of ZZOE porous nanobelts were also investigated. Finally, a charge transfer mechanism was proposed to illuminate the PLs from the ZZOE porous nanobelts.


Drugs for preventing lung cancer in healthy people.
This is an updated version of the original review published in Issue 2, 2003. Some studies have suggested a protective effect of antioxidant nutrients on lung cancer. Observational epidemiological studies suggest an association between higher dietary levels of fruits and vegetables containing beta-carotene and a lower risk of lung cancer. To determine whether vitamins, minerals and other potential agents, alone or in combination, reduce incidence and mortality from lung cancer in healthy people. For this update we have used a search strategy adapted from the design in the original review. The following electronic databases have been searched up to December 2011: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). References included in published studies and reviews were also screened. Included studies were randomised controlled clinical trials comparing different vitamins, mineral supplements or supplements with placebo, administered to healthy people with the aim of preventing lung cancer. Two authors independently selected the trials to be included in the review, assessed the methodological quality of each trial and extracted data using a standardised form. For each study, relative risk and 95% confidence limits were calculated for dichotomous outcomes and pooled results were calculated using the random-effect model. In the first version of this review four studies were included; in this review update, an additional five studies have been included. Four studies included only males and two only females; two studies included only participants considered at high risk, namely smokers or exposed to asbestos, and one study included people deficient in many micronutrients. Six studies analysed vitamin A, three vitamin C, four vitamin E, one selenium supplements, and six studied combinations of two or more products. All the RCTs included in this review were classified as being of low risk of bias.For people not at high risk of lung cancer and compared to placebo, none of the supplements of vitamins or minerals or their combinations resulted in a statistically significant difference in lung cancer incidence or mortality, except for a single study that included 7627 women and found a higher risk of lung cancer incidence for those taking vitamin C but not for total cancer incidence, but that effect was not seen in males or when the results for males and females were pooled.For people at high risk of lung cancer, such as smokers and those exposed to asbestos and compared to placebo, beta-carotene intake showed a small but statistically significant higher risk of lung cancer incidence, lung cancer mortality and for all-causes mortality. There is no evidence for recommending supplements of vitamins A, C, E, selenium, either alone or in different combinations, for the prevention of lung cancer and lung cancer mortality in healthy people. There is some evidence that the use of beta-carotene supplements could be associated with a small increase in lung cancer incidence and mortality in smokers or persons exposed to asbestos.


Clomipramine vs desipramine crossover trial in body dysmorphic disorder: selective efficacy of a serotonin reuptake inhibitor in imagined ugliness.
Body dysmorphic disorder (preoccupation with an imagined or slight defect in appearance) is a common and disabling disorder associated with high rates of delusional symptoms and suicide attempts. Although preliminary studies suggest that serotonin reuptake inhibitors may be effective for body dysmorphic disorder, to date no controlled treatment studies have been published. Forty patients were enrolled and 29 were randomized into a 16-week, double-blind, crossover-design study of clomipramine, a potent serotonin reuptake inhibitor, and active control desipramine, a selective norepinephrine reuptake inhibitor. Outcome measures included specific ratings of body dysmorphic disorder severity, delusionality, and functional impairment. Clomipramine was superior to desipramine in the acute treatment of body dysmorphic disorder symptoms as measured by assessment of patients' obsessive preoccupation with perceived body defects, repetitive behaviors in response to this preoccupation, and global ratings of symptom severity. Treatment efficacy was independent of the presence or severity of comorbid diagnoses of obsessive-compulsive disorder, depression, or social phobia. Likewise, clomipramine was equally effective regardless of whether the patients had insight or held their dysmorphic misperception with delusional intensity. Clomipramine was also superior to desipramine in improving functional disability. Clomipramine is more effective than desipramine in the treatment of body dysmorphic disorder and is effective even among those patients who are delusional.


A two-step procedure for efficient electrotransfer of both high-molecular-weight (greater than 400,000) and low-molecular-weight (less than 20,000) proteins.
We have developed conditions for the efficient electrotransfer from polyacrylamide gels to nitrocellulose sheets of a broad size range of proteins (Mr 8,000 to Mr greater than 400,000). The important features of this procedure include a two-step electrotransfer, beginning with elution of low-molecular-weight polypeptides at a low current density (approximately 1 mA/cm2) for 1 h, followed by prolonged electrotransfer (16-20 h) at high current density (approximately 3.5-7.5 mA/cm2) in conditions that favor the elution of high-molecular-weight proteins. The transfer buffer includes 0.01% sodium dodecyl sulfate to enhance protein elution, and 20% methanol to improve the retention of proteins on the nitrocellulose sheet. The nitrocellulose is air-dried after transfer is complete to eliminate loss of proteins during subsequent processing. This transfer procedure works well with proteins prepared from many different cell types, and is suitable for use with all polyacrylamide gel systems tested. With little or no modification, our method should also be applicable to transfer membranes other than nitrocellulose.


ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.


Neither insects nor wind: ambophily in dioecious Chamaedorea palms (Arecaceae).
Pollination of Neotropical dioecious trees is commonly related to generalist insects. Similar data for non-tree species with separated genders are inconclusive. Recent studies on pollination of dioecious Chamaedorea palms (Arecaceae) suggest that species are either insect- or wind-pollinated. However, the wide variety of inflorescence and floral attributes within the genus suggests mixed pollination mode involving entomophily and anemophily. To evaluate this hypothesis, we studied the pollination of Chamaedorea costaricana, C. macrospadix, C. pinnatifrons and C. tepejilote in two montane forests in Costa Rica. A complementary morphological analysis of floral traits was carried out to distinguish species groups within the genus according to their most probable pollination mechanism. We conducted pollinator exclusion experiments, field observations on visitors to pistillate and staminate inflorescences, and trapped airborne pollen. A cluster analysis using 18 floral traits selected for their association with wind and insect pollination syndromes was carried out using 52 Chamaedorea species. Exclusion experiments showed that both wind and insects, mostly thrips (Thysanoptera), pollinated the studied species. Thrips used staminate inflorescences as brood sites and pollinated pistillate flowers by deception. Insects caught on pistillate inflorescences transported pollen, while traps proved that pollen is wind-borne. Our empirical findings clearly suggest that pollination of dioecious Chamaedorea palms is likely to involve both insects and wind. A cluster analysis showed that the majority of studied species have a combination of floral traits that allow for both pollination modes. Our pollination experiments and morphological analysis both suggest that while some species may be completely entomophilous or anemophilous, ambophily might be a common condition within Chamaedorea. Our results propose a higher diversity of pollination mechanisms of Neotropical dioecious species than previously suggested.


Plasma and rhADAMTS13 reduce trauma-induced organ failure by restoring the ADAMTS13-VWF axis.
Trauma-induced organ failure is characterized by endothelial dysfunction. The aim of this study was to investigate the role of von Willebrand factor (VWF) and its cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) in the occurrence of endothelial permeability and organ failure in trauma. In an observational study in a level-1 trauma center, 169 adult trauma patients with clinical signs of shock and/or severe injuries were included. Trauma was associated with low ADAMTS13 and high VWF antigen levels, thus generating an imbalance of ADAMTS13 to VWF. Patients who developed organ failure (23%) had greater ADAMTS13-to-VWF imbalances, persistently lower platelet counts, and elevated levels of high-molecular-weight VWF multimers compared with those without organ failure, suggesting microthrombi formation. To investigate the effect of replenishing low ADAMTS13 levels on endothelial permeability and organ failure using either recombinant human ADAMTS13 (rhADAMTS13) or plasma transfusion, a rat model of trauma-induced shock and transfusion was used. Rats in traumatic hemorrhagic shock were randomized to receive crystalloids, crystalloids supplemented with rhADAMTS13, or plasma transfusion. A 70-kDa fluorescein isothiocyanate-labeled dextran was injected to determine endothelial leakage. Additionally, organs were histologically assessed. Both plasma transfusion and rhADAMTS13 were associated with a reduction in pulmonary endothelial permeability and organ injury when compared with resuscitation with crystalloids, but only rhADAMTS13 resulted in significant improvement of a trauma-induced decline in ADAMTS13 levels. We conclude that rhADAMTS13 and plasma transfusion can reduce organ failure following trauma. These findings implicate the ADAMTS13-VWF axis in the pathogenesis of organ failure.


The clinical consequences of hemizygosity across 2 MB of 10q23 are restricted to Cowden syndrome.
Cowden syndrome is caused by germline mutations in PTEN and clinically characterized by hamartomas, macrocephaly, classic dermatologic stigmata, and an estimated 85 % lifetime risk of female breast cancer. A young woman with macrocephaly, tricholemmomas, AV malformations, and mammary papillomatosis was found to be hemizygous for PTEN in her germline DNA. Using MLPA, comparative genomic hybridization, and DNA sequencing, we identified a 2-Mb deletion in chromosome 10 spanning 344-kb centromeric and 1.7-Mb telomeric of PTEN. Her father who has a clinical history including macrocephaly, Hashimoto's thyroiditis, colonic polyposis, acral keratoses, and goiter was also found to have the same deletion. In benign breast tissue from the hemizygous female, PTEN protein expression was significantly reduced in luminal and stromal cells but present in the myoepithelium. Compared with a typical papilloma of the breast which had intense cytoplasmic PTEN staining, the majority of the patient's papilloma had significantly decreased PTEN expression while some cells had mislocalized perinuclear PTEN expression. In addition to PTEN, 22 other protein-coding genes were deleted including two predicted haploinsufficient genes and five additional genes that have previously been associated with hereditary predispositions to certain diseases. However, because all significant clinical features of the proband and her father are common to patients with genetic alterations in PTEN, the other 22 hemizygous protein-coding genes appear to be haplosufficient.


Neuromuscular Adaptations to Low-Load Blood Flow Restricted Resistance Training.
Low-load blood flow restricted (BFR) resistance exercise has been suggested to be as effective as moderate and high-load resistance training for increasing muscle size and strength. The purpose of the study was to evaluate the effects of 6 weeks of HL or low-load BFR resistance training on neuromuscular function, strength, and hypertrophy of the knee extensors. Eighteen participants aged 18-22 years old were randomized to one of three training groups: moderate load (ML: 70% of 1 repetition maximum [1-RM]); BFR (20% 1-RM with a vascular restriction set to ~180 mmHg); and a control group (CON) that did not exercise. Participants performed leg extension (LE) and leg press exercises 3 times per week for 6 weeks. Measurements of isometric torque, LE 1-RM, central activation, electrically evoked torque, and muscle volume of the knee extensors were obtained before and after training. Isometric peak torque did not change following the training (p = 0.13). LE 1-RM improved in the ML (34 ± 20%; d = 0.78) and BFR (14 ± 5%; d = 0.67) groups compared to the CON group (0.6 ± 8%; d = 0.09; time x group interaction p = 0.02). Muscle volume increased in the ML (5.6%; d = 0.19) and BFR groups (2.5%; d = 0.09) with no change in the CON group (time x group interaction p = 0.001). There were no changes in central activation and evoked torque in any groups following the training (p > 0.05). Strength and hypertrophy were evident following ML and BFR resistance training programs indicating that both modalities are effective, although ML training appears to be a more potent and efficient. Neuromuscular changes were not evident and warrant more research.


Clocks and meals keep mice from being cool.
Daily torpor is used by small mammals to reduce daily energy expenditure in response to energetic challenges. Optimizing the timing of daily torpor allows mammals to maximize its energetic benefits and, accordingly, torpor typically occurs in the late night and early morning in most species. However, the regulatory mechanisms underlying such temporal regulation have not been elucidated. Direct control by the circadian clock and indirect control through the timing of food intake have both been suggested as possible mechanisms. Here, feeding cycles outside of the circadian range and brain-specific mutations of circadian clock genes (Vgat-Cre+ CK1δfl/fl εfl/+ ; Vgat-Cre+ Bmal1fl/fl ) were used to separate the roles of the circadian clock and food timing in controlling the timing of daily torpor in mice. These experiments revealed that the timing of daily torpor is transiently inhibited by feeding, while the circadian clock is the major determinant of the timing of torpor. Torpor never occurred during the early part of the circadian active phase, but was preferentially initiated late in the subjective night. Food intake disrupted torpor in the first 4-6 h after feeding by preventing or interrupting torpor bouts. Following interruption, re-initiation of torpor was unlikely until after the next circadian active phase. Overall, these results demonstrate that feeding transiently inhibits torpor while the central circadian clock gates the timing of daily torpor in response to energetic challenges by restricting the initiation of torpor to a specific circadian phase.


Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency.
Inappropriate accumulation of the misfolded Z variant of alpha1-antitrypsin in the hepatocyte endoplasmic reticulum (ER) is a risk factor for the development of end-stage liver disease. However, the genetic and environmental factors that contribute to its etiology are poorly understood. ER mannosidase I (ERManI) is a quality control factor that plays a critical role in the sorting and targeting of misfolded glycoproteins for proteasome-mediated degradation. In this study, we tested whether genetic variations in the human ERManI gene influence the age at onset of end-stage liver disease in patients homozygous for the Z allele (ZZ). We sequenced all 13 exons in a group of unrelated Caucasian ZZ transplant recipients with different age at onset of the end-stage liver disease. Homozygosity for the minor A allele at 2484G/A (refSNP ID number rs4567) in the 3'-untranslated region was prevalent in the infant ZZ patients. Functional studies indicated that rs4567(A), but not rs4567(G), suppresses ERManI translation under ER stress conditions. These findings suggest that the identified single-nucleotide polymorphism can accelerate the onset of the end-stage liver disease associated with alpha1-antitrypsin deficiency and underscore the contribution of biosynthetic quality control as a modifier of genetic disease.


Identification of Biomarkers for PKD1 Using Urinary Exosomes.
Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of ESRD. Affected individuals inherit a defective copy of either PKD1 or PKD2, which encode polycystin-1 (PC1) or polycystin-2 (PC2), respectively. PC1 and PC2 are secreted on urinary exosome-like vesicles (ELVs) (100-nm diameter vesicles), in which PC1 is present in a cleaved form and may be complexed with PC2. Here, label-free quantitative proteomic studies of urine ELVs in an initial discovery cohort (13 individuals with PKD1 mutations and 18 normal controls) revealed that of 2008 ELV proteins, 9 (0.32%) were expressed at significantly different levels in samples from individuals with PKD1 mutations compared to controls (P<0.03). In samples from individuals with PKD1 mutations, levels of PC1 and PC2 were reduced to 54% (P<0.02) and 53% (P<0.001), respectively. Transmembrane protein 2 (TMEM2), a protein with homology to fibrocystin, was 2.1-fold higher in individuals with PKD1 mutations (P<0.03). The PC1/TMEM2 ratio correlated inversely with height-adjusted total kidney volume in the discovery cohort, and the ratio of PC1/TMEM2 or PC2/TMEM2 could be used to distinguish individuals with PKD1 mutations from controls in a confirmation cohort. In summary, results of this study suggest that a test measuring the urine exosomal PC1/TMEM2 or PC2/TMEM2 ratio may have utility in diagnosis and monitoring of polycystic kidney disease. Future studies will focus on increasing sample size and confirming these studies. The data were deposited in the ProteomeXchange (identifier PXD001075).


Vertical transmission of SARS CoV-2: a systematic review.
The aim of this study is to review the current evidence on the vertical transmission of SARS CoV-2. Combination of the following keywords; COVID-19, SARS CoV-2, placenta, vertical transmission, intrauterine infection, breast milk were searched in databases. In the 50 studies included, 17 newborns testing positive for SARS CoV-2 by RT-PCR were reported. In three neonates, SARS-CoV-2 IgG and IgM levels were elevated. Eight placental tissues testing positive for the virus were reported. Three positive RT-PCR results of test of breast milk have been reported recently. One amniotic fluid testing positive was reported. Possible vertical transmission of SARS CoV-2 has been observed in some studies currently. More RT-PCR tests on amniotic fluid, placenta, breast milk and cord blood are required.


Machine Learning Classifiers for Endometriosis Using Transcriptomics and Methylomics Data.
Endometriosis is a complex and common gynecological disorder yet a poorly understood disease affecting about 176 million women worldwide and causing significant impact on their quality of life and economic burden. Neither a definitive clinical symptom nor a minimally invasive diagnostic method is available, thus leading to an average of 4 to 11 years of diagnostic latency. Discovery of relevant biological patterns from microarray expression or next generation sequencing (NGS) data has been advanced over the last several decades by applying various machine learning tools. We performed machine learning analysis using 38 RNA-seq and 80 enrichment-based DNA methylation (MBD-seq) datasets. We experimented how well various supervised machine learning methods such as decision tree, partial least squares discriminant analysis (PLSDA), support vector machine, and random forest perform in classifying endometriosis from the control samples trained on both transcriptomics and methylomics data. The assessment was done from two different perspectives for improving classification performances: a) implication of three different normalization techniques and b) implication of differential analysis using the generalized linear model (GLM). Several candidate biomarker genes were identified by multiple machine learning experiments including NOTCH3, SNAPC2, B4GALNT1, SMAP2, DDB2, GTF3C5, and PTOV1 from the transcriptomics data analysis and TRPM6, RASSF2, TNIP2, RP3-522J7.6, FGD3, and MFSD14B from the methylomics data analysis. We concluded that an appropriate machine learning diagnostic pipeline for endometriosis should use TMM normalization for transcriptomics data, and quantile or voom normalization for methylomics data, GLM for feature space reduction and classification performance maximization.


Quantum mechanical investigation of aqueous desferrioxamine B metal complexes: trends in structure, binding, and infrared spectroscopy.
A systematic density functional theory study supported by extended X-ray absorption fine structure (EXAFS) and infrared spectroscopic data was conducted to elucidate how structure and vibrational spectra of aqueous desferrioxamine B (DFOB) metal complexes vary with the metal ion identity. Structural parameters derived from EXAFS analyses and trends in metal binding constants are well reproduced and validated by the applied computational model. Vibrational mode analysis guides determination and recognition of crucial structure- and metal-sensitive infrared marker bands. The key marker bands, CO and CN stretching modes, dominate the infrared spectra in the 1400-1650cm(-1) region. The modes are sensitive to the stability and size of the metal core (first coordination shell) and indicative of its deformation from the octahedral symmetry. The results shed light on the fundamental structural and electronic factors that control metal binding by siderophores, and drive their potentially rich and largely unexplored interactions with trace metals.


Deep brain stimulation for generalised dystonia and spasmodic torticollis.
Dystonia appears distinct from the other tremulous disorders in that improvement following deep brain stimulation frequently appears in a delayed and progressive manner. The rate of this improvement and the point at which no further progress can be expected are presently unknown. The establishment of these parameters is important in the provision of accurate and relevant prognostic information to these patients, their carers, and their treating physicians. We studied 12 consecutive patients with generalised dystonia (n=6) and spasmodic torticollis (n=6) who underwent bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) and were followed up for a minimum of 2 years postoperatively. Standard rating scales were used to quantify their neurological improvement. Both groups experienced a statistically significant improvement in their rating scores at both one and two years following surgery. At 2 years follow-up, the spasmodic torticollis group exhibited a 59% improvement in their total Toronto Western Spasmodic Torticoilis Rating Scale (TWSTRS) rating score and the generalised dystonia group attained a 46% improvement in their overall Burke, Fahn and Marsden Dystonia Rating Scale (BFMDRS) evaluation. Ninety-five percent of the final improvement was attained by 6.4 months in the generalised dystonia group and by 6.6 months in those with spasmodic torticollis. There was no significant improvement after one year postoperatively. These findings add further support to GPi DBS as an effective treatment for generalised dystonia and spasmodic torticollis, and furnish important information as to the expected rate of improvement and the point at which no further gains can be reasonably anticipated.


Decision Support System for Lymphoma Classification.
The diffuse lymphoma is a malignant tumor of lymphoid tissues. It is associated with abnormal, unlimited and uncontrolled proliferation of lymphoid cells. Until now, expert pathologists have identified diffuse lymphoma cells disease manually. This paper introduces automatic system with a friendly user interface to differentiate between the categories of the diffuse lymphoma cells. This research is based on the morphological features such as size, perimeter and circularity. The cell size is a critical element in the classification of diffuse lymphoma according to international formulation standards. Therefore, the applied procedures identify lymphoid cell population in digital microscopic images. The cells are classified using their morphological data according to the characteristics of each cell such as: circularity, perimeter, area, and color density. The number of cells is taken into consideration in the developed approach. Image processing techniques are applied to digital microscopic images to measure morphological parameters and to overcome image problems such as overlapping and cell distortion that affect the sensitivity of the measured data. The developed procedures help the pathologists to come to a decision regarding the classification of diffuse lymphoma. Moreover, it can be used to train medical students and young pathologists.


Increased risk for malaria in chronically malnourished children under 5 years of age in rural Gambia.
Malaria and malnutrition cause high morbidity and mortality in rural sub-Saharan Africa. To explore the relationship between nutritional status and malaria, a cohort of Gambian children under 5 years of age was followed weekly during one malaria season. Anthropometric measurements were made at the beginning and at the end of the season. A total of 55/107 (51.4 per cent) children with baseline stunting, defined as having a height-for-age z-score below -2 standard deviations, subsequently experienced malaria episodes, compared to 145/380 (38.2 per cent) children who were not stunted (RR = 1.35; 95 per cent CI, 1.08-1.69; p value = 0.01). Neither wasting (weight-for-height z-score below -2 standard deviations) nor undernutrition (weight-for-age z-score below -2 standard deviations) influenced susceptibility to malaria. Adjustment for characteristics of age, sex, and ethnicity did not significantly change the risk ratios. Malaria had no effect on the nutritional status from the beginning to the end of the malaria season. Our findings suggest that chronically malnourished children may be at higher risk for developing malaria episodes.


Synthesis and investigation of intra-molecular charge transfer state properties of novel donor-acceptor-donor pyridine derivatives: the effects of temperature and environment on molecular configurations and the origin of delayed fluorescence.
A novel series of donor-acceptor-donor (D-A-D) structured pyridine derivatives were synthesised and detailed photo-physical investigations were made using mainly steady-state and time-resolved spectroscopy techniques at varying temperatures. The investigations showed that the molecules have solvent polarity and temperature dependent excited-state configurations, confirmed in two different polarity solvents (295-90 K), i.e. methyl cyclohexane (MCH) and 2-methyltetrahdrofurane (2-MeTHF). In MCH, the investigations revealed dual fluorescence over the temperature range of 295-90 K. At 295 K, the ground-state configuration of the molecules has a partially twisted geometry as determined by DFT calculation, yet the emission originates totally from a locally excited (LE) state, however once the temperature is lowered to 90 K, the twisted molecular configuration is stabilised, and the emission originates from a fully-relaxed intramolecular charge transfer state (ICT), this is contrary to the systems where structural reorganisation stabilises ICT and this is frozen out at low temperatures. The DFT calculations revealed different ground state molecular configurations due to the presence of different electron-donating groups, e.g. the molecule including anthracene groups has a near 90° twisted geometry whereas the triphenylamine including molecule has a pyramidal geometrical folding, therefore, the decrease in temperature restricts the donor degree of rotational freedom. In 2-MeTHF solution, the fluorescence spectrum of both molecules is always of ICT character, but gradually red-shifts through the fluid to glass transition temperature (∼135 K), in this case, the fluorescence occurs after structural and solvent-shell relaxations, however, upon cooling below 135 K, the spectra dramatically shift back to blue giving rise to strong emission from an ICT excited-state (but not the LE state) where the molecules have unrelaxed geometries. This significant change in the nature of the emitting species was explained with specific solvent-solute dynamic interactions in the vicinity of the solvation shell and the effect of thermal excitation of molecular vibrational modes of the C-C bond linking donor and acceptor units. Finally, we confirmed that the molecules have ICT ground-state geometry in the solid-state phase (spin-coated films), and the time-resolved decay dynamics were investigated comparing the spin-coated films (at RT and 25 K) and MCH solutions (at 295 K and 90 K).