Polarization-beam-splitter-less integrated dual-polarization coherent receiver.
Conventional dual-polarization coherent receivers require polarization beam splitters for either the signal or the local oscillator path. This severely hinders monolithic integration, since integrated polarization splitting devices often exhibit stringent fabrication tolerances. Here we propose a dual-polarization monolithically integrated coherent receiver architecture that completely avoids the use of polarization splitting elements. Polarization management is instead achieved by adequately engineering the birefringence of the interconnecting waveguides. The resultant receiver is highly tolerant to fabrication deviations and thus offers a completely new route for monolithic integration of dual-polarization receivers without any type of active tuning.


Mendelian inheritance revisited: dominance and recessiveness in medical genetics.
Understanding the consequences of genotype for phenotype (which ranges from molecule-level effects to whole-organism traits) is at the core of genetic diagnostics in medicine. Many measures of the deleteriousness of individual alleles exist, but these have limitations for predicting the clinical consequences. Various mechanisms can protect the organism from the adverse effects of functional variants, especially when the variant is paired with a wild type allele. Understanding why some alleles are harmful in the heterozygous state - representing dominant inheritance - but others only with the biallelic presence of pathogenic variants - representing recessive inheritance - is particularly important when faced with the deluge of rare genetic alterations identified by high throughput DNA sequencing. Both awareness of the specific quantitative and/or qualitative effects of individual variants and the elucidation of allelic and non-allelic interactions are essential to optimize genetic diagnosis and counselling.


Cytomegalovirus in human brain tumors: Role in pathogenesis and potential treatment options.
During the last years increasing evidence implies that human cytomegalovirus (CMV) can be attributed to human malignancies arising from numerous tissues. In this perspective, we will review and discuss the potential mechanisms through which CMV infection may contribute to brain tumors by affecting tumor cell initiation, progression and metastasis formation. Recent evidence also suggests that anti-CMV treatment results in impaired tumor growth of CMV positive xenografts in animal models and potentially increased survival in CMV positive glioblastoma patients. Based on these observations and the high tumor promoting capacity of this virus, the classical and novel antiviral therapies against CMV should be revisited as they may represent a great promise for halting tumor progression and lower cancer deaths.


What happens next?: a claims database study of second-line pharmacotherapy in patients with major depressive disorder (MDD) who initiate selective serotonin reuptake inhibitor (SSRI) treatment.
The objective of this research was to examine treatment patterns and health-care costs associated with second-step pharmacotherapy in patients with major depressive disorder (MDD) who initiated monotherapy with a selective serotonin reuptake inhibitor (SSRI) in 2010. This claims database study analyzed patients diagnosed with MDD who were prescribed a monotherapy SSRI, with the first prescription identified as the index date. Patients were required to be ≥18 years old, to have continuous insurance coverage from 1 year prior (pre-index) through 1 year post (post-index) from the index date, and to have not received an antidepressant in the pre-index period. The analyses are descriptive of the patient characteristics, initial SSRI prescribed, most commonly prescribed second-step therapies, and annualized health-care costs. The identified patients (N = 5,012) were predominantly female (65.2%) with a mean age of 41.9 years. The most frequent index SSRIs were citalopram (30.1%) and sertraline (27.5%), and 52.9% of patients were prescribed a second-step pharmacotherapy during the post-index period. Add-on therapy occurred twice more frequently than switching treatments, with either anxiolytics (40.2%) or antidepressants (37.1%) as the most common classes of add-on pharmacological therapies. Patients who added a second medication or switched therapies had higher annualized medical costs compared with patients who continued their index SSRI or discontinued treatment. For patients who were initially treated with an SSRI therapy, approximately half were prescribed a second-step treatment. In this comprehensive claims analysis, many of these patients experienced the addition of second medication, rather than switching to a new therapy. Given the type of medications used, it is possible that second-step interventions were targeted toward resolution of residual symptoms; however, this work is limited by the use of claims data without information on dosing or clinical symptoms, side effects, or response. Findings from this study set the expectation that physicians and patients will most likely need to partner for additional interventions in order to achieve remission.


Waiting times for radiotherapy after breast-conserving surgery and the association with survival: a path analysis.
To investigate the association between radiotherapy waiting times and survival in women who have undergone breast-conserving surgery using data from two English cancer registry regions. The data were analysed using path analysis to account for the complex variable interrelationships within the data. Cases of female invasive breast cancer diagnosed during the period 1 January 1998 to 31 December 2005 were identified and linked to an extract of Hospital Episode Statistics data. A subset of these linked records where women underwent breast-conserving surgery was extracted (n=18,158). Patient, tumour and treatment information were extracted. A path model was developed with three outcome variables: survival, time to receive radiotherapy and receipt of chemotherapy before radiotherapy. During the study period, the median radiotherapy waiting time in region 1 increased from 70 days to 128.5 days. In region 2, the median wait increased from 44 days in 1998 to 68 days in 2001, then decreased to 42 days by 2005. In the path model, radiotherapy waiting time was not associated with survival (hazard ratio=1.00, 95% confidence interval 0.99-1.01 per week increase in both regions). Patients receiving chemotherapy before radiotherapy waited 12.3 weeks (region 1) and 6.3 weeks (region 2) longer for their radiotherapy than those not receiving chemotherapy. Patients with stage II/III disease waited longer than patients with stage I disease. Younger age, diagnosis of stage II/III disease and presence of co-morbidities were associated with increased odds of receiving chemotherapy before radiotherapy. This study found no association between waiting times for radiotherapy and survival in two regions of England, despite increases in waiting times over the study period. Such an association, if real, may only become apparent after a longer period of follow-up.


Comparisons of ultrafine and fine particles in their associations with biomarkers reflecting physiological pathways.
Using a quasi-experimental opportunity offered by greatly restricted air pollution emissions during the Beijing Olympics compared to before and after the Olympics, we conducted the current study to compare ultrafine particles (UFPs) and fine particles (PM2.5) in their associations with biomarkers reflecting multiple pathophysiological pathways linking exposure and cardiorespiratory events. Number concentrations of particles (13.0-764.7 nm) and mass concentrations of PM2.5 were measured at two locations within 9 km from the residence and workplace of 125 participating Beijing residents. Each participant was measured 6 times for biomarkers of autonomic function (heart rate, systolic and diastolic blood pressures), hemostasis (von Willebrand factor, soluble CD40 ligand, and P-selectin), pulmonary inflammation and oxidative stress (exhaled nitric oxide and exhaled breath condensate pH, malondialdehyde, and nitrite), and systemic inflammation and oxidative stress (urinary malondialdehyde and 8-hydroxy-2'-deoxyguanosine, plasma fibrinogen, and white blood cells). Linear mixed models were used to estimate associations of biomarkers with UFPs and PM2.5 measured 1-7 days prior to biomarker measurements (lags). We found that the correlation coefficient for UFPs at two locations (∼ 9 km apart) was 0.45, and at the same location, the correlation coefficient for PM2.5 vs UFPs was -0.18. Changes in biomarker levels associated with increases in UFPs and PM2.5 were comparable in magnitude. However, associations of certain biomarkers with UFPs had different lag patterns compared to those with PM2.5, suggesting that the ultrafine size fraction (≤ 100 nm) and the fine size fraction (∼ 100 nm to 2.5 μm) of PM2.5 are likely to affect PM-induced pathophysiological pathways independently.


The effects of prolonged running on foot posture: a repeated measures study of half marathon runners using the foot posture index and navicular height.
Different foot postures are associated with alterations in foot function, kinetics and the subsequent occurrence of injury. Little is known about changes in foot posture following prolonged weightbearing exercise. This study aimed to identify changes in foot posture after running a half marathon. Foot posture was measured using the Foot Posture Index (FPI-6) and navicular height in thirty volunteer participants before and after running a half marathon. FPI-6 scores were converted to Rasch logit values and means compared for these and navicular height using an ANOVA. There was a 5 mm drop in navicular height in both feet when measured after the half marathon (P < 0.05). The FPI-6 showed a side x time interaction with an increase in score indicating a more 'pronated' position in the left foot of + 2 [Rasch value + 1.7] but no change in the right foot (+ 0.4 [+ 0.76]) following the half marathon. The apparent differences between the FPI-6 and navicular height on the right foot may be because the FPI-6 takes soft tissue contour changes into consideration whilst the navicular height focuses on skeletal changes. The changes in foot posture towards a more pronated position may have implications for foot function, and therefore risk of injury; shoe fit and comfort and also the effect of therapeutic orthoses worn during prolonged running.


A randomized trial of preexercise stretching for prevention of lower-limb injury.
This study investigated the effect of muscle stretching during warm-up on the risk of exercise-related injury. 1538 male army recruits were randomly allocated to stretch or control groups. During the ensuing 12 wk of training, both groups performed active warm-up exercises before physical training sessions. In addition, the stretch group performed one 20-s static stretch under supervision for each of six major leg muscle groups during every warm-up. The control group did not stretch. 333 lower-limb injuries were recorded during the training period, including 214 soft-tissue injuries. There were 158 injuries in the stretch group and 175 in the control group. There was no significant effect of preexercise stretching on all-injuries risk (hazard ratio [HR] = 0.95, 95% CI 0.77-1.18), soft-tissue injury risk (HR = 0.83, 95% CI 0.63-1.09), or bone injury risk (HR = 1.22, 95% CI 0.86-1.76). Fitness (20-m progressive shuttle run test score), age, and enlistment date all significantly predicted injury risk (P < 0.01 for each), but height, weight, and body mass index did not. A typical muscle stretching protocol performed during preexercise warm-ups does not produce clinically meaningful reductions in risk of exercise-related injury in army recruits. Fitness may be an important, modifiable risk factor.


B Vitamins Can Reduce Body Weight Gain by Increasing Metabolism-related Enzyme Activities in Rats Fed on a High-Fat Diet.
B vitamins are enzyme cofactors that play an important role in energy metabolism. The aim of this study was to elucidate whether B vitamin administration can reduce body weight (BW) gain by improving energy metabolism-related enzyme activities in rats fed on a highfat diet. Fifty rats were randomly assigned to one of the following five groups: control group (C), including rats fed on standard rat chow; four treatment groups (HO, HI, H2, and H3), in which rats were fed on a high-fat diet. Rats in the HI group were treated daily with 100 mg/kg BW thiamine (VB1), 100 mg/kg BW riboflavin (VB2), and 250 mg/kg BW niacin (VPP); rats in the H2 group were treated daily with 100 mg/kg BW pyridoxine (VB6), 100 mg/kg BW cobalamin (VB12), and 5 mg/kg BW folate (FA); and rats in the H3 group were treated daily with all of the B vitamins administered to the HI and H2 groups. After 12 weeks, the BW gains from the initial value were 154.5±58.4 g and 159.1±53.0 g in the HI and C groups, respectively, which were significantly less than the changes in the HO group (285.2±14.8 g, P<0.05). In the HO group, the plasma total cholesterol (CHO) and triglyceride (TG) levels were 1.59±0.30 mmol/L and 1,55±0.40 mmol/L, respectively, which were significantly greater than those in the HI group (1.19±0.18 mmol/L and 0.76±0.34 mmol/L, respectively, P<0.05). The activities of transketolase (TK), glutathione reductase, and Na+/K+ adenosine triphosphatase were significantly increased in the B vitamin-treated groups and were significantly greater than those in the HO group (P<0.05). Furthermore, the glucose-6-phosphate dehydrogenase, pyruvic acid kinase, and succinate dehydrogenase activities also were increased after treatment with B vitamins. Supplementation with B vitamins could effectively reduce BW gain and plasma levels of lipids by improving energy metabolism-related enzyme activities in rats, thus possibly providing potential benefits to humans.


Changes in cerebral blood flow during a migraine attack.
Regional cerebral blood flow studies during a typical prodromal phase of a migraine attack in a young woman showed a global decrease of cerebral blood flow in the carotid artery territory. These studies were repeated during the subsequent headache phase of the same attack and hemispheric blood flow increased considerably. Ergotamine tartrate was then administered intramuscularly which brought definite relief of symptoms but no change in cerebral blood flow. Carotid angiography performed immediately afterwards showed retrograde filling of the proximal portion of the basilar artery, which suggested that the brain stem was the site of hyper-perfusion. These findings illustrate certain features underlying both the pathophysiology of migraine itself and its response to ergotamine preparations.


Organization of cytokeratin bundles by desmosomes in rat mammary cells.
In a rat mammary epithelial cell line, LA-7, cytokeratin bundles recognized in immunofluorescence by a monoclonal antibody (24B42) disappear after trypsinization of cultures and are gradually reformed after replating. We have followed the time course of cytokeratin filament reappearance by growing cells in low calcium medium (0.1 mM) which prevents desmosome formation, and then shifting to high calcium (1.8 mM) to start the process. By fixing the cells at various intervals and staining them in immunofluorescence for 24B42 cytokeratin and for desmosomal proteins, we found that cell to cell contact and desmosome formation are prerequisites for keratin filament formation in these cells. EGTA treatment, by disassembling desmosomes, causes the cytokeratin filaments to disappear and the 24B42 protein to pass into a soluble form in this cell line, as ascertained by 100,000 g fractionation and immunoenzymatic assay. Cycloheximide treatment also causes cytokeratin filaments to disappear, indicating that protein synthesis is needed for normal filament maintenance. In another related cell line (106A-10a) and in HeLa cells, trypsinization and EGTA exposure do not cause a complete loss of 24B42 immunofluorescence, although distinct filaments disappear, indicating the presence in these cells of different organizing centers, besides desmosomes, for cytokeratin bundle formation. LA7 cells therefore seem to have a cytokeratin system strictly dependent on the presence of desmosomes, which act as an organizing center for filament assembly. 106A-10a cells (also rich in desmosomes) and HeLa cells (showing instead a reduced number of desmosomes) have a cytokeratin system partially or totally independent from that of desmosomes, with different organizing centers.


Translation of science to surgery: linking emerging concepts in biological cartilage repair to surgical intervention.
Orthopaedic surgery is in an exciting transitional period as modern surgical interventions, implants and scientific developments are providing new therapeutic options. As advances in basic science and technology improve our understanding of the pathology and repair of musculoskeletal tissue, traditional operations may be replaced by newer, less invasive procedures which are more appropriately targeted at the underlying pathophysiology. However, evidence-based practice will remain a basic requirement of care. Orthopaedic surgeons can and should remain at the forefront of the development of novel therapeutic interventions and their application. Progression of the potential of bench research into an improved array of orthopaedic treatments in an effective yet safe manner will require the development of a subgroup of specialists with extended training in research to play an important role in bridging the gap between laboratory science and clinical practice. International regulations regarding the introduction of new biological treatments will place an additional burden on the mechanisms of this translational process, and orthopaedic surgeons who are trained in science, surgery and the regulatory environment will be essential. Training and supporting individuals with these skills requires special consideration and discussion by the orthopaedic community. In this paper we review some traditional approaches to the integration of orthopaedic science and surgery, the therapeutic potential of current regenerative biomedical science for cartilage repair and ways in which we may develop surgeons with the skills required to translate scientific discovery into effective and properly assessed orthopaedic treatments.


Genomic organisation of the human MDM2 oncogene and relationship to its alternatively spliced mRNAs.
The MDM2 proto-oncogene, which encodes a protein that binds to the p53 tumour suppressor, has been found amplified and overexpressed in a range of human tumours. Although the human MDM2 cDNA sequence has been reported, the genomic organisation of the human gene has not been documented. We have previously reported the detection of five alternative internally deleted MDM2 transcripts in human tumours and suggested these may represent alternatively spliced forms. Here we demonstrate two novel MDM2 transcripts with internal deletions, using RT-PCR followed by sequencing. To definitively ascribe these variant transcript forms to alternative splicing, and to explore associated mechanisms, we have determined the intron--exon organisation of the human genomic sequence. The human MDM2 gene spans approximately 33 kb and is divided into 12 exons. Exon sizes range from 50 to > or =1161 bp and intron sizes vary from 121 to approximately 7000 bp. The positions of intron--exon boundaries are compared with the deletion junctions of the multiple-sized transcripts and discussed in relation to alternative splicing mechanism.


Clinical significance of soluble hemoglobin scavenger receptor CD163 (sCD163) in sepsis, a prospective study.
We investigated serum soluble CD163 (sCD163) levels for use in the diagnosis, severity assessment, and prognosis of sepsis in the critical ill patients and compared sCD163 with other infection-related variables. During july 2010 and April 2011, serum was obtained from 102 sepsis patients (days 1, 3, 5, 7, and 10 after admission to an ICU) and 30 systemic inflammatory response syndrome (SIRS) patients with no sepsis diagnosed. Serum levels of sCD163, procalcitonon (PCT), and C reactive protein (CRP) were determined respectively. Sequential organ failure assessment (SOFA) scores for sepsis patients were also recorded. Then evaluated their roles in sepsis. The sCD163 levels were 0.88(0.78-1.00) ug/mL for SIRS patients, 1.50(0.92-2.00) ug/mL for moderate sepsis patients, and 2.95(2.18-5.57) ug/mL for severe sepsis patients on day 1. The areas under the ROC curves for sCD163, CRP, and PCT for the diagnosis of sepsis were, respectively, 0.856(95%CI: 0.791-0.921), 0.696(95%CI: 0.595-0.797), and 0.629(95%CI: 0.495-0.763), At the recommended cut-off 1.49 ug/mL for sCD163, the sensitivity is 74.0% with 93.3% specificity. Based on 28-day survivals, sCD163 levels in the surviving group stay constant, while they tended to gradually increase in the non-surviving group.The area under the ROC curve for sCD163 for sepsis prognosis was 0.706(95%CI 0.558-0.804). Levels of sCD163 with cut-off point >2.84 ug/mL have sensitivity of 55.8.0%, specificity 80.4%. Common risk factors for death and sCD163 were included in multivariate logistic regression analysis; the odds ratios (OR) for sCD163 and SOFA scores for sepsis prognosis were 1.173 and 1.396, respectively (P<0.05). Spearman rank correlation analysis showed that sCD163 was weakly, but positively correlated with CRP, PCT, and SOFA scores (0.2< r <0.4, P<0.0001), but not with leukocyte counts (r <0.2, P = 0.450). Serum sCD163 is superior to PCT and CRP for the diagnosis of sepsis and differentiate the severity of sepsis. sCD163 levels were more sensitive for dynamic evaluations of sepsis prognosis. Serum sCD163 and SOFA scores are prognostic factors for sepsis. www.chictr.orgChiCTR-ONC-10000812.


Dissociable roles for the basolateral amygdala and orbitofrontal cortex in decision-making under risk of punishment.
Several neuropsychiatric disorders are associated with abnormal decision-making involving risk of punishment, but the neural basis of this association remains poorly understood. Altered activity in brain systems including the basolateral amygdala (BLA) and orbitofrontal cortex (OFC) can accompany these same disorders, and these structures are implicated in some forms of decision-making. The current study investigated the role of the BLA and OFC in decision-making under risk of explicit punishment. Rats were trained in the risky decision-making task (RDT), in which they chose between two levers, one that delivered a small safe reward, and the other that delivered a large reward accompanied by varying risks of footshock punishment. Following training, they received sham or neurotoxic lesions of BLA or OFC, followed by RDT retesting. BLA lesions increased choice of the large risky reward (greater risk-taking) compared to both prelesion performance and sham controls. When reward magnitudes were equated, both BLA lesion and control groups shifted their choice to the safe (no shock) reward lever, indicating that the lesions did not impair punishment sensitivity. In contrast to BLA lesions, OFC lesions significantly decreased risk-taking compared with sham controls, but did not impair discrimination between different reward magnitudes or alter baseline levels of anxiety. Finally, neither lesion significantly affected food-motivated lever pressing under various fixed ratio schedules, indicating that lesion-induced alterations in risk-taking were not secondary to changes in appetitive motivation. Together, these findings indicate distinct roles for the BLA and OFC in decision-making under risk of explicit punishment.


Vaccinium macrocarpon: an interesting option for women with recurrent urinary tract infections and other health benefits.
To review the scientific publications concerning the clinical use and mechanism of action of the North American cranberry (Vaccinium macrocarpon) for women with recurrent urinary tract infections (UTI) and other health conditions. This is a retrospective study of published information concerning Vaccinium macrocarpon retrieved from a PubMed and individual searches. Urinary tract infections are very common in women, cause discomfort, and may aggravate other genitourinary conditions. The available scientific information supports a clinical benefit of Vaccinium macrocarpon in the prevention of recurrent UTI in women. There is a non-significant reduction of UTI associated with Vaccinium macrocarpon treatment during pregnancy. A group of proanthocyanidins (PAC) with A-type linkages have been isolated from Vaccinium macrocarpon which inhibit P-fimbriae synthesis and induce a bacterial deformation, on both antibiotic-susceptible and antibiotic-resistant uropathogenic Escherichia coli. It is plausible that cranberry PAC prevent bacteria from adhering to the uroepithelium of the bladder, thereby blocking the ability of E. coli to infect the urinary mucosa. Cranberry treatment is a safe, well-tolerated supplement that does not have significant drug interactions. Although investigations are in the early stages, experimental and preclinical studies suggest that cranberry components may have other potential benefits, including anti-infective, anticancer and antioxidant effects, which may be considered as positive for different age-related conditions. In addition, cranberry components may induce positive cardiovascular and metabolic changes, and may improve neuropsychological activity. These effects warrant further clinical research to better place the role of cranberry products for women.


Central nervous system chemoprophylaxis in non-Hodgkin lymphoma: current practice in the UK.
Central nervous system (CNS) involvement in non-Hodgkin lymphoma (NHL) is a well-recognised complication. There is no consensus regarding indications for prophylaxis or a standard CNS chemoprophylaxis regimen. Current UK practice was evaluated using a questionnaire. A total of 223 questionnaires were sent to clinicians who administered chemotherapy to patients with NHL; 158 (71%) evaluable questionnaires were returned. The overwhelming majority of respondents used prophylaxis in all cases of lymphoblastic lymphoma (97%) and Burkitt lymphoma (96%). Ninety-six per cent of respondents required risk factors to be present before prophylaxis was initiated in cases of diffuse large B-cell lymphoma. The commonest risk factor was site of involvement (paranasal sinus 88%, testicular 85%, orbital cavity 78%, bone marrow 65% and bone 28%). Other risk factors included stage IV, high International Prognostic Index score, >1 extranodal site and raised lactate dehydrogenase levels (34%, 21%, 16% and 10%). A total of 82% did not give prophylaxis in follicular lymphoma and 90% used intrathecal chemotherapy as their preferred method of prophylaxis. The most popular regimen was 12.5 mg methotrexate with each cycle of chemotherapy for six courses. Thirty-nine per cent used systemic chemotherapy for CNS prophylaxis either alone (4%) or as an adjunct to intrathecal prophylaxis (35%). These variations in the indications and methods of prophylaxis indicate that this subject deserves further review.


Effect of age, gender, and repeated measures on intraoral air pressure in normal adults.
The effect of age, gender, and repeated measures on intraoral air pressure (P0) was examined. Sixty adults comprised of 10 males and 10 females in each of three age groups (i.e., 20-39, 40-59, and 60-83 years) participated. P0 was assessed during voiceless stop plosive /p/ productions in repeated vowel/consonant syllables. The three medial plosives of a seven-syllable train were averaged to comprise a token. Five tokens were obtained and averaged for each of three trials. Thus each participant contributed 105 syllables and a subsequent three P0s for analyses. There was no statistically significant difference in P0 as a function of age or gender (P > 0.05). These findings support the conception that P0 remains stable throughout adulthood and is not dependent on gender. Differences in repeated measures of P0 attained statistical significance (P = 0.03), however the mean differences between trials (0.23 cm H20) were negligible and deemed to be clinically insignificant. Thus, across a short sampling session, P0 is a relatively stable measurement and does not change as a function of age or gender.


Modulation of the smooth-muscle L-type Ca2+ channel alpha1 subunit (alpha1C-b) by the beta2a subunit: a peptide which inhibits binding of beta to the I-II linker of alpha1 induces functional uncoupling.
Modulation of the smooth-muscle Ca(2+) channel alpha1C-b subunit by the auxiliary beta2a subunit was studied in the HEK 293 (cell line from human embryonic kidney cells) expression system. In addition, we tested whether the alpha1-beta interaction in functional channels is sensitive to an 18-amino-acid synthetic peptide that corresponds to the sequence of the defined major interaction domain in the cytoplasmic I-II linker of alpha1C (AID-peptide). Ca(2+) channels derived by co-expression of alpha1C-b and beta2a subunits exhibited an about 3-fold higher open probability (P(o)) than alpha1C-b channels. High-P(o) gating of alpha1C-b.beta2a channels was associated with the occurrence of long-lasting channel openings [mean open time (tau)>10 ms] which were rarely observed in alpha1C-b channels. Modulation of fast gating by the beta2a subunit persisted in the cell-free, inside-out recording configuration. Biochemical experiments showed that the AID-peptide binds with appreciable affinity to beta2 subunits of native Ca(2+) channels. Binding of the beta2 protein to immobilized AID-peptide was specifically inhibited (K(i) of 100 nM) by preincubation with free (uncoupled) AID-peptide, but not by a corresponding scrambled peptide. Administration of the AID-peptide (10 microM) to the cytoplasmic side of inside-out patches induced a substantial reduction of P(o) of alpha1C-b.beta2a channels. The scrambled control peptide failed to affect alpha1C-b. beta2a channels, and the AID-peptide (10 microM) did not modify alpha1C-b channel function in the absence of expressed beta2a subunit. Our results demonstrate that the beta2a subunit controls fast gating of alpha1C-b channels, and suggest the alpha1-beta interaction domain in the cytoplasmic I-II linker of alpha1C (AID) as a possible target of modulation of the channel. Moreover, our data are consistent with a model of alpha1-beta interaction that is based on multiple interaction sites, including AID as a determinant of the affinity of the alpha1-beta interaction.


Genome-wide analysis of the NAC transcription factor family and their expression during the development and ripening of the Fragaria × ananassa fruits.
NAC proteins are a family of transcription factors which have a variety of important regulatory roles in plants. They present a very well conserved group of NAC subdomains in the N-terminal region and a highly variable domain at the C-terminus. Currently, knowledge concerning NAC family in the strawberry plant remains very limited. In this work, we analyzed the NAC family of Fragaria vesca, and a total of 112 NAC proteins were identified after we curated the annotations from the version 4.0.a1 genome. They were placed into the ligation groups (pseudo-chromosomes) and described its physicochemical and genetic features. A microarray transcriptomic analysis showed six of them expressed during the development and ripening of the Fragaria x ananassa fruit. Their expression patterns were studied in fruit (receptacle and achenes) in different stages of development and in vegetative tissues. Also, the expression level under different hormonal treatments (auxins, ABA) and drought stress was investigated. In addition, they were clustered with other NAC transcription factor with known function related to growth and development, senescence, fruit ripening, stress response, and secondary cell wall and vascular development. Our results indicate that these six strawberry NAC proteins could play different important regulatory roles in the process of development and ripening of the fruit, providing the basis for further functional studies and the selection for NAC candidates suitable for biotechnological applications.


Exciton dynamics of C60-based single-photon emitters explored by Hanbury Brown-Twiss scanning tunnelling microscopy.
Exciton creation and annihilation by charges are crucial processes for technologies relying on charge-exciton-photon conversion. Improvement of organic light sources or dye-sensitized solar cells requires methods to address exciton dynamics at the molecular scale. Near-field techniques have been instrumental for this purpose; however, characterizing exciton recombination with molecular resolution remained a challenge. Here, we study exciton dynamics by using scanning tunnelling microscopy to inject current with sub-molecular precision and Hanbury Brown-Twiss interferometry to measure photon correlations in the far-field electroluminescence. Controlled injection allows us to generate excitons in solid C60 and let them interact with charges during their lifetime. We demonstrate electrically driven single-photon emission from localized structural defects and determine exciton lifetimes in the picosecond range. Monitoring lifetime shortening and luminescence saturation for increasing carrier injection rates provides access to charge-exciton annihilation dynamics. Our approach introduces a unique way to study single quasi-particle dynamics on the ultimate molecular scale.


Reducing the spread of antimicrobial-resistant microorganisms. Control of vancomycin-resistant enterococci.
Strategies to reduce the spread of hospital-acquired microorganisms resistant to multiple antimicrobial agents are discussed. Because hospitals have experienced a rapid increase in the incidence of infection and colonization with vancomycin-resistant enterococci (VRE) in the past 5 years, the Hospital Infection Control Practices Advisory Committee of the Centers for Disease Control and Prevention has issued recommendations for preventing the spread of vancomycin resistance. Controlling VRE dissemination in pediatric patients requires prompt detection of VRE by microbiology laboratories, education of staff and families about VRE, use of infection control measures to prevent person-to-person VRE transmission, and prudent vancomycin use.


Fractal dimension of the EEG for detection of behavioural microsleeps.
The fractal dimension (FD) of EEG has been shown to be of value in the detection of epileptic seizures. In this paper, we assess its usefulness in detecting behavioural microsleeps. Fifteen non-sleep-deprived normal subjects performed two 1-hour sessions of a continuous tracking task while EEG, EOG and facial video were recorded. Higuchi's algorithm was used to calculate the FD of the EEG. Video lapses were scored independently from tracking performance by a human rater. A subset of data was rated independently by three human raters observing both tracking performance and the video rating to identify behavioural microsleep events. The mean point-biserial correlation between FD and the mean human rating was -0.213 indicating modest agreement. Crossvalidated detection performance of the FD was poor with a mean correlation (.. = -0.099). This suggests that, on its own, FD of the EEG is unlikely to be useful for detecting microsleeps.


Correction of enhanced Na(+)-H+ exchange of rat small intestinal brush-border membranes in streptozotocin-induced diabetes by insulin or 1,25-dihydroxycholecalciferol.
Diabetes was induced in rats by administration of a single i.p. injection of streptozotocin (50 mg/kg body wt). After 7 d, diabetic rats were further treated with insulin or 1,25-dihydroxycholecalciferol [1,25(OH)2D3] for an additional 5-7 d. Control, diabetic, diabetic + insulin, and diabetic + 1,25(OH)2D3 rats were then killed, their proximal small intestines were removed, and villus-tip epithelial cells were isolated and used to prepare brush-border membrane vesicles. Preparations from each of these groups were then analyzed and compared with respect to their amiloride-sensitive, electroneutral Na(+)-H+ exchange activity, using 22Na uptake as well as acridine orange techniques. The results of these experiments demonstrated that (a) H+ gradient-dependent 22Na uptake as well as Na+ gradient-dependent transmembrane H+ fluxes were significantly increased in diabetic vesicles compared to their control counterparts, (b) kinetic studies demonstrated that this enhanced 22Na uptake in diabetes was a result of increased maximal velocity (Vmax) of this exchanger with no change in apparent affinity (Km) for Na+, (c) serum levels of 1,25(OH)2D3 were significantly lower in diabetic animals compared with their control counterparts; and (d) insulin or 1,25(OH)2D3 treatment restored the Vmax alterations to control values, without any significant changes in Km, concomitant with significantly increasing the serum levels of 1,25(OH)2D3 in diabetic animals. These results indicate that Na(+)-H+ activity is significantly increased in proximal small intestinal luminal membranes of streptozotocin-induced diabetic rats. Moreover, alterations in the serum levels of 1,25(OH)2D3 may, at least in part, explain this enhanced antiporter activity and its correction by insulin.


Real-world utilization of molecular diagnostic testing and matched drug therapies in the treatment of metastatic cancers.
To assess the frequency of biopsies and molecular diagnostic testing (human DNA/RNA analysis), anti-cancer drug use (genomically-matched targeted therapy [GMTT], unmatched targeted therapy [UTT], endocrine therapy [ET], and chemotherapy [CT]), and medical service costs among adults with metastatic cancer. Adults diagnosed with metastatic breast, non-small cell lung (NSCLC), colorectal, head and neck, ovarian, and uterine cancer (2010Q1-2015Q1) were identified in the OptumHealth Care Solutions claims database and followed from first metastatic diagnosis for ≥1 month and until the end of data availability. Utilization was assessed for each cancer cohort (all and patients aged ≥65 years); per-patient-per-month (PPPM) medical service costs were assessed for all patients. Testing frequency estimates were applied to Surveillance, Epidemiology, and End Results Program data to estimate the number of untested patients (2010-2014). Patients with metastatic cancer (n = 8,193; breast [n = 3,414], NSCLC [n = 2,231], colorectal [n = 1,611], head and neck [n = 511], ovarian [n = 275], and uterine [n = 151]) were 63 years old (mean), with 11.1-22.2 months of observation. Biopsy and molecular diagnostic testing frequencies ranged from 7% (uterine) to 73% (ovarian), and from 34% (head and neck) to 52% (breast), respectively. Few were treated with GMTT (breast, 11%; NSCLC, 9%; colorectal, 6%). Treatment with UTT ranged from 0.7% (uterine) to 21% (colorectal). Biopsy, diagnostic testing, and anti-cancer drug therapy were less frequent for those ≥65 years. Medical service costs (PPPM, mean) ranged from $6,618 (head and neck) to $9,940 (ovarian). The estimated number of untested new patients with metastatic cancer was 636,369 (all) and 341,397 (≥65). In addition to the limitations of claims analyses, diagnostic testing frequency may be under-estimated if patients underwent testing prior to study inclusion. The low frequency of molecular diagnostic testing suggests there are opportunities to better inform management of patients with advanced cancer, particularly decisions to treat with GMTT.


Purification of carbamoyl phosphate synthetase 1 (CPS1) from wood frog (Rana sylvatica) liver and its regulation in response to ice-nucleation and subsequent whole-body freezing.
Carbamoyl phosphate synthetase I (CPS1) represents an important regulatory enzyme of the urea cycle that mediates the ATP-driven reaction ligating ammonium, carbonate, and phosphate to form carbamoyl phosphate. The freeze-tolerant wood frog (Rana sylvatica or Lithobates sylvaticus) accumulates high concentrations of urea during bouts of freezing to detoxify any ammonia generated and to contribute as a cryoprotectant thereby helping to avoid freeze damage to cells. Purification of CPS1 to homogeneity from wood frog liver was performed in control and frozen wood frogs by a three-step chromatographic process. The affinity of CPS1 for its three substrates was tested in the purified control and freeze-exposed enzyme under a variety of conditions including the presence and absence of the natural cryoprotectants urea and glucose. The results demonstrated that affinity for ammonium was higher in the freeze-exposed CPS1 (1.26-fold) and that with the addition of 400 mM glucose it displayed higher affinity for ATP (1.30-fold) and the obligate activator N-acetylglutamate (1.24-fold). Denaturation studies demonstrated the freeze-exposed enzyme was less thermally stable than the control with an unfolding temperature approximately 1.5 °C lower (52.9 °C for frozen and 54.4 °C for control). The control form of CPS1 had a significantly higher degree of glutarylated lysine residues (1.42-fold increase) relative to the frozen. The results suggest that CPS1 activation and maintenance of urea cycle activity despite the hypometabolic conditions associated with freezing are important aspects in the metabolic survival strategies of the wood frog.


Mycotherapy of cancer: an update on cytotoxic and antitumor activities of mushrooms, bioactive principles and molecular mechanisms of their action.
Mycotherapy is defined as the study of the use of extracts and compounds obtained from mushrooms as medicines or health-promoting agents. The present review updates the recent findings on anticancer/antitumor agents derived from mushroom extracts and their metabolites. The increasing number of studies in the past few years revealed mushroom extracts as potent antitumor agents. Also, numerous studies were conducted on bioactive compounds isolated from mushrooms reporting the heteropolysaccharides, β-glucans, α-glucans, proteins, complexes of polysaccharides with proteins, fatty acids, nucleoside antagonists, terpenoids, sesquiterpenes, lanostanoids, sterols and phenolic acids as promising antitumor agents. Also, molecular mechanisms of cytotoxicity against different cancer cell lines are discussed in this review. Findings with Antrodia camphorata and Ganoderma lucidium extracts and isolated compounds are presented, as being the most deeply studied previously.


Synthesis of graphene nanoribbons with a defined mixed edge-site sequence by surface assisted polymerization of (1,6)-dibromopyrene on Ag(110).
By a combination of scanning tunneling microscopy, X-ray spectroscopic techniques and density functional theory calculations, we prove the formation of extended patterns of parallel, graphene nanoribbons with alternate zig-zag and armchair edges and selected width by surface-assisted Ullmann coupling polymerization and dehydrogenation of 1,6-dibromopyrene (C16H8Br2). Besides the relevance of these nanostructures for their possible application in nanodevices, we demonstrate the peculiarity of halogenated pyrene derivatives for the formation of nanoribbons, in particular on Ag(110). These results open the possibility of tuning the shape and dimension of nanoribbons (and hence the correlated electronic properties) by choosing suitably tailored or on-purpose designed molecular precursors.


Genetically modified dendritic cells prime autoreactive T cells through a pathway independent of CD40L and interleukin 12: implications for cancer vaccines.
Genetic immunization through ex vivo transduction of dendritic cells has been suggested as an effective approach to enhance antitumor immunity by activating both CD4+ and CD8+ T cells. Immunizing mice with dendritic cells transduced with an adenovirus expressing the human melanoma antigen glycoprotein 100 (DCAdhgp100) as a cancer vaccine, we demonstrated complete protective immunity and a potent CTL response against melanomas expressing murine glycoprotein 100 in a CD4+ cell-dependent manner. Surprisingly, however, effective tumor rejection was not the result of cooperation between CD4+ and CD8+ T cells. Protective immunity was completely lost when CD4+ cells were depleted immediately before tumor challenge, whereas it was unaffected by removal of CD8+ cells, establishing a principal role for CD4+ cells in the effector phase of tumor rejection. Neither protective immunity nor CTL generation in this model required interleukin 12, in spite of high levels of IFN-gamma secretion by tumor-reactive T cells. Most notably, the DCAdhgp100 vaccine could elicit protective antitumor CD4+ cells in the absence of CD40 ligand, although it does not bypass the need for CD40-mediated signals to generate melanoma-reactive CTLs. Thus, in contrast to the current thinking that the optimal cancer vaccine should include determinants for both CD4+ and CD8+ cells, the potency of the DCAdhgp100 vaccine appears to be a result of its ability to directly prime autoreactive CD4+ cells through a process that does not require interleukin 12 and CD40 signals.


Colonic lesions in patients undergoing small bowel capsule endoscopy: incidence, diagnostic and therapeutic impact.
Nowadays, capsule endoscopy is the first-line procedure to assess the small bowel. During small bowel procedures, other segments of the gastrointestinal tract may be visualized. The aim of the current study was to evaluate the incidence of colonic abnormalities in patients undergoing small bowel capsule and its impact on patient management. This study is a retrospective analysis of data from 526 consecutive capsule endoscopy procedures performed at a single tertiary-care centre between 2008 and 2011. Patients with incomplete procedures were excluded from the analysis. Patient baseline characteristics, colonic lesions, diagnosis and management before and after capsule endoscopy were recorded and a descriptive analysis was performed. Four hundred and sixty four patients were finally included in the analysis. Two hundred and ninety three patients were male (57.3%) and the mean age was 61.3 ± 20.03 years (18-86). Obscure gastrointestinal bleeding (59%) and inflammatory bowel disease (19%) were the main indications for the procedure. Colonic abnormalities were detected by capsule endoscopy in 47 (9%) of 464 patients. The most common types of missed lesions were vascular lesions (34%) and colonic ulcers (32%). This information had a clinical or diagnostic impact of 7.55% and a therapeutic impact of 6.03%. All images of the colon should be evaluated during small bowel capsule endoscopy as they may provide relevant information that may result in changes in patient management.


Elongation factor-2 kinase: its role in protein synthesis and autophagy.
Elongation factor-2 kinase (eEF-2 kinase; Ca(2+)/calmodulin-dependent kinase III) controls the rate of peptide chain elongation. The activity of eEF-2 kinase is increased in many malignancies, yet its precise function in carcinogenesis remains unknown. Autophagy, a well-defined survival pathway in yeast, may also play an important role in oncogenesis. Furthermore, the autophagic response to nutrient deprivation is regulated by the mammalian target of rapamycin (mTOR). eEF-2 kinase lies downstream of mTOR and is regulated by several kinases in this pathway. Therefore, we studied the role of eEF-2 kinase in autophagy. Knockdown of eEF-2 kinase by RNA interference inhibited autophagy in several cell types as measured by light chain 3 (LC3)-II formation, acidic vesicular organelle staining, and electron microscopy. In contrast, overexpression of eEF-2 kinase increased autophagy. Furthermore, inhibition of autophagy markedly decreased the viability of glioblastoma cells grown under conditions of nutrient depletion. These results suggest that eEF-2 kinase plays a regulatory role in the autophagic process in tumor cells and may promote cancer cell survival under conditions of nutrient deprivation. Therefore, eEF-2 kinase activation may be a part of a survival mechanism in glioblastoma, and targeting this kinase may represent a novel approach to cancer treatment.


Distress in individuals facing predictive DNA testing for autosomal dominant late-onset disorders: comparing questionnaire results with in-depth interviews. Rotterdam/Leiden Genetics Workgroup.
In 50% risk carriers for Huntington disease (n = 41), hereditary cerebral hemorrhage with amyloidosis Dutch-type (n = 9) familial adenomatous polyposis coli (n = 45) and hereditary breast and ovarian cancer (n = 24), pretest intrusion and avoidance (Impact of Event Scale), anxiety and depression (Hospital Anxiety and Depression Scale), feelings of hopelessness (Beck Hopelessness Scale), and psychological complaints (Symptom Checklist) were assessed to determine their psychological well-being. The manner of discussing the genetic disorder, the test, and its implications during a semistructured interview (reflecting on one's emotions without getting carried away or dismissing or minimizing the subject) was judged in terms of coherence. Participants at risk for neurodegenerative disorders had higher anxiety and depression scores and more psychological complaints than did those at risk for cancer syndromes. Those reporting high intrusion/high avoidance had higher anxiety and depression scores and more psychological complaints than did those reporting low intrusion/low avoidance. However, the scoring of the interview showed that participants reporting high intrusion/high avoidance were more reflective about their emotions without getting carried away or dismissing the subject (e.g., more coherent) than those reporting low intrusion/low avoidance. This result suggests that participants with higher stress scores may be actively dealing with the emotional implications of the test, whereas those with low stress scores may (as yet) be unable to face these implications. It is important to identify the strategy of coping with threat to provide suitable counseling and necessary guidance. However, long-term follow-up is needed to learn the consequences of a denial coping strategy for those participating in a genetic testing program.


I'm better off than most other people: the role of social comparisons for coping with regret in young adulthood and old age.
This longitudinal study was designed to examine the importance of social comparisons for coping with regret among young and older adults. It was expected that making downward social comparisons would be associated with a greater reduction in regret intensity over time among older, compared with young, adults. A total of 104 participants took part in this 4-month longitudinal study. The findings suggest that across different comparison targets, making downward (relative to upward) social comparisons was consistently related to reduced regret intensity over time among older adults. Among young adults, making downward social comparisons with personally known others, as opposed to age peers, was associated with lower regret intensity. In addition, older adults increased their reliance on downward social comparisons over time. This age-differential shift toward downward social comparisons further explained age differences in changes of regret intensity over time. Finally, differences in opportunities to undo regrets explained some of the age differences in the use and adaptive value of downward social comparisons. The implications of the findings for understanding and examining pathways to successful development are discussed.


Community interventions for preventing smoking in young people.
Cigarette smoking is one of the leading causes of preventable death in the world. Decisions to smoke are often made within a broad social context and therefore community interventions using coordinated, multi-component programmes may be effective in influencing the smoking behaviour of young people. To determine the effectiveness of multi-component community based interventions in influencing smoking behaviour, which includes preventing the uptake of smoking in young people. The Tobacco Addiction group's specialised register, Medline and other health, psychology and public policy electronic databases were searched, the bibliographies of identified studies were checked and raw data was requested from study authors. Searches were updated in August 2010. Randomized and non randomized controlled trials that assessed the effectiveness of multi-component community interventions compared to no intervention or to single component or school-based programmes only. Reported outcomes had to include smoking behaviour in young people under the age of 25 years. Information relating to the characteristics and the content of community interventions, participants, outcomes and methods of the study was extracted by one reviewer and checked by a second. Studies were combined in a meta-analysis where possible and reported in narrative synthesis in text and table. Twenty-five studies were included in the review and sixty-eight studies did not meet all of the inclusion criteria. All studies used a controlled trial design, with fifteen using random allocation of schools or communities. One study reported a reduction in short-term smoking prevalence (twelve months or less), while nine studies detected significant long-term effects. Two studies reported significantly lower smoking rates in the control population while the remaining thirteen studies showed no significant difference between groups. Improvements were seen in secondary outcomes for intentions to smoke in six out of eight studies, attitudes in five out of nine studies, perceptions in two out of six studies and knowledge in three out of six studies, while significant differences in favour of the control were seen in one of the nine studies assessing attitudes and one of six studies assessing perceptions. There is some evidence to support the effectiveness of community interventions in reducing the uptake of smoking in young people, but the evidence is not strong and contains a number of methodological flaws.


Quantification of urinary AICAR concentrations as a matter of doping controls.
Influencing the endurance in elite sports is one of the key points in modern sports science. Recently, a new class of prohibited substances reached in the focus of doping control laboratories and their misuse was classified as gene doping. The adenosine monophosphate activated protein kinase activator 5-amino-4-imidazolecarboxyamide ribonucleoside (AICAR) was found to significantly enhance the endurance even in sedentary mice after treatment. Due to endogenous production of AICAR in healthy humans, considerable amounts were present in the circulation and, thus, were excreted into urine. Considering these facts, the present study was initiated to fix reference values of renally cleared AICAR in elite athletes. Therefore a quantitative analytical method by means of isotope-dilution liquid chromatography (analytical column: C6-phenyl) coupled to tandem mass spectrometry, after a sample preparation consisting of a gentle dilution of native urine, was developed. Doping control samples of 499 athletes were analysed, and AICAR concentrations in urine were determined. The mean AICAR value for all samples was 2,186 ng/mL with a standard deviation of 1,655 ng/mL. Concentrations were found to differ depending on gender, type of sport and type of sample collection (in competition/out of competition). The method was fully validated for quantitative purposes considering the parameters linearity, inter- (12%, 7% and 10%) and intraday precision (14%, 9% and 12%) at low, mid and high concentration, robustness, accuracy (approx. 100%), limit of quantification (100 ng/mL), stability and ion suppression effects, employing an in-house synthesised (13)C(5)-labelled AICAR as internal standard.


Evolution on a local scale: developmental, functional, and genetic bases of divergence in bill form and associated changes in song structure between adjacent habitats.
Divergent selection on traits involved in both local adaptation and the production of mating signals can strongly facilitate population differentiation. Because of its links to foraging morphologies and cultural inheritance song of birds can contribute particularly strongly to maintenance of local adaptations. In two adjacent habitats--native Sonoran desert and urban areas--house finches (Carpodacus mexicanus) forage on seeds that are highly distinct in size and shell hardness and require different bite forces and bill morphologies. Here, we first document strong and habitat-specific natural selection on bill traits linked to bite force and find adaptive modifications of bite force and bill morphology and associated divergence in courtship song between the two habitats. Second, we investigate the developmental basis of this divergence and find that early ontogenetic tissue transformation in bill, but not skeletal traits, is accelerated in the urban population and that the mandibular primordia of the large-beaked urban finches express bone morphogenetic proteins (BMP) earlier and at higher level than those of the desert finches. Further, we show that despite being geographically adjacent, urban and desert populations are nevertheless genetically distinct corroborating findings of early developmental divergence between them. Taken together, these results suggest that divergent selection on function and development of traits involved in production of mating signals, in combination with localized learning of such signals, can be very effective at maintaining local adaptations, even at small spatial scales and in highly mobile animals.


More invaders do not result in heavier impacts: The effects of non-native bullfrogs on native anurans are mitigated by high densities of non-native crayfish.
With accelerating species introductions in an era of globalization, co-occurring alien species have become increasingly common. Understanding the combined ecological impacts of multiple invaders is not only crucial for wildlife managers attempting to ameliorate biodiversity loss, but also provides key insights into invasion success and species coexistence mechanisms in natural ecosystems. Compared with much attentions given to single-invader impacts, little is known about the impacts of multiple co-occurring invaders. The American bullfrog (Lithobates catesbeianus = Rana catesbeiana) and the red swamp crayfish (Procambarus clarkii) are two aquatic invasive species in many different areas of the globe. They coexist with native anurans in a variety of permanent lentic waters, which provide an ideal model system to explore the combined effects of multiple invaders from different trophic levels on native species. Based on a global diet analysis covering 34 native and invasive bullfrog populations, and data from 10-year field surveys across 157 water bodies in the Zhoushan Archipelago, China, we observed a reduced impact of bullfrogs on native anurans at high crayfish densities when the two invaders co-occurred. The global diet analysis showed that crayfish occurrence reduced the number of native anuran prey consumed by bullfrogs in both native and invasive populations. After accounting for pseudoreplication of different observations among water bodies, islands, and survey time, model averaging analyses based on GLMMs showed a negative relationship between bullfrog density and native anuran densities for field observations of invasive bullfrogs alone and co-invaded observations with low crayfish density. However, this negative relationship disappeared when the two invaders co-occurred with high crayfish density. Structural equation modelling (SEM) analyses further validated that the impacts of bullfrogs on native frogs were mitigated by the negative interactions between crayfish and bullfrogs. Our results provide novel evidence of a density-dependent antagonistic effect of two sympatric invaders from different trophic levels on native species. This study highlights the importance of considering complex interactions among co-invaders and native species when prioritizing conservation and management actions and will facilitate the development of a more precise framework to predict invasion impacts.


Unprecedented Melioidosis Cases in Northern Australia Caused by an Asian Burkholderia pseudomallei Strain Identified by Using Large-Scale Comparative Genomics.
Melioidosis is a disease of humans and animals that is caused by the saprophytic bacterium Burkholderia pseudomallei. Once thought to be confined to certain locations, the known presence of B. pseudomallei is expanding as more regions of endemicity are uncovered. There is no vaccine for melioidosis, and even with antibiotic administration, the mortality rate is as high as 40% in some regions that are endemic for the infection. Despite high levels of recombination, phylogenetic reconstruction of B. pseudomallei populations using whole-genome sequencing (WGS) has revealed surprisingly robust biogeographic separation between isolates from Australia and Asia. To date, there have been no confirmed autochthonous melioidosis cases in Australia caused by an Asian isolate; likewise, no autochthonous cases in Asia have been identified as Australian in origin. Here, we used comparative genomic analysis of 455 B. pseudomallei genomes to confirm the unprecedented presence of an Asian clone, sequence type 562 (ST-562), in Darwin, northern Australia. First observed in Darwin in 2005, the incidence of melioidosis cases attributable to ST-562 infection has steadily risen, and it is now a common strain in Darwin. Intriguingly, the Australian ST-562 appears to be geographically restricted to a single locale and is genetically less diverse than other common STs from this region, indicating a recent introduction of this clone into northern Australia. Detailed genomic and epidemiological investigations of new clinical and environmental B. pseudomallei isolates in the Darwin region and ST-562 isolates from Asia will be critical for understanding the origin, distribution, and dissemination of this emerging clone in northern Australia.


Introduction of plant and fungal genes into pea (Pisum sativum L.) hairy roots reduces their ability to produce pisatin and affects their response to a fungal pathogen.
Pisatin is an isoflavonoid phytoalexin synthesized by pea (Pisum sativum L.). Previous studies have identified two enzymes apparently involved in the synthesis of this phytoalexin, isoflavone reductase (IFR), which catalyzes an intermediate step in pisatin biosynthesis, and (+)6a-hydroxymaackiain 3-O-methyltransferase (HMM), an enzyme catalyzing the terminal step. To further evaluate the involvement of these enzymes in pisatin biosynthesis, sense- and antisense-oriented cDNAs of Ifr and Hmm fused to the 35s CaMV promoter, and Agrobacterium rhizogenes, were used to produce transgenic pea hairy root cultures. PDA, a gene encoding pisatin demethylating activity (pda) in the pea-pathogenic fungus Nectria haematococca, also was used in an attempt to reduce pisatin levels. Although hairy root tissue with either sense or antisense Ifr cDNA produced less pisatin, the greatest reduction occurred with sense or antisense Hmm cDNA. The reduced pisatin production in these lines was associated with reduced amounts of Hmm transcripts, HMM protein, and HMM enzyme activity. Hairy roots containing the PDA gene also produced less pisatin. To evaluate the role of pisatin in disease resistance, the virulence of N. haematococca on the transgenic roots that produced the lowest levels of pisatin was tested. Hairy roots expressing antisense Hmm were more susceptible than the control hairy roots to isolates of N. haematococca that are either virulent or nonvirulent on wild-type pea plants. This appears to be the first case of producing transgenic plant tissue with a reduced ability to produce a phytoalexin and demonstrating that such tissue is less resistant to fungal infection: these results support the hypothesis that phytoalexin production is a disease resistance mechanism.


Transcripts of the malaria vector Anopheles gambiae that are differentially regulated in the midgut upon exposure to invasive stages of Plasmodium falciparum.
Understanding the interactions between the most deadly malaria parasite, Plasmodium falciparum, and its main vector, Anopheles gambiae, would be of great help in developing new malaria control strategies. The malaria parasite undergoes several developmental transitions in the mosquito midgut and suffers population losses to which mosquito factors presumably contribute. To identify such factors, we analysed An. gambiae midgut transcripts whose expression is regulated upon ingestion of invasive or non-invasive forms of P. falciparum using a differential display approach. Sixteen cDNA were studied in detail; 12 represent novel genes of An. gambiae including a gene encoding profilin. Four transcripts were specifically regulated by P. falciparum gametocytes (invasive forms), whereas the others were regulated by either non-invasive or both non-invasive and invasive forms of the parasite. This differential regulation of some genes may reflect the adaptation of P. falciparum to its natural vector. These genes may be involved in the development of P. falciparum in An. gambiae or in the defence reaction of the mosquito midgut towards the parasite.


The neuropsychological correlates of cannabis use in schizophrenia: lifetime abuse/dependence, frequency of use, and recency of use.
This study examined the relationship between neuropsychological performance and three different indices of cannabis use in schizophrenia. These indices were DSM-IV lifetime abuse/dependence, frequency of use, and recency of use. Sixty males with schizophrenia/schizoaffective disorder and 17 healthy males were recruited. The two groups were matched for age, years of education, and premorbid IQ. Medical history, substance use, and psychiatric symptoms were assessed. A neuropsychological battery was also administered to assess attention/processing speed, executive functions, memory, and perceptual organisation. Substance use within 24 hours of cognitive assessment was screened by urine analysis, and a range of confounds were controlled. In the schizophrenia group, 44 participants met DSM-IV criteria for lifetime cannabis abuse/dependence. In addition, there were three mutually exclusive frequency-of-cannabis-use subgroups comprising "high" frequency users (n=11), "medium" frequency users (n=7), and "low" frequency users (n=34) over the preceding year. There were also four mutually exclusive recency-of-cannabis-use categories comprising "cannabis abuse/dependence in the past week" (n=11 users), "non-dependent cannabis use in the past week" (n=7 users), "non-dependent cannabis use in the past month, but prior to the past week" (n=7 users), and "non-dependent cannabis use prior to the past month" (n=9 users). The control group performed better than the schizophrenia group in all cognitive domains. Within the schizophrenia group, a larger proportion of participants with lifetime cannabis abuse/dependence demonstrated better performance than those without lifetime abuse/dependence on a component of psychomotor speed. Frequency and recency of cannabis use were also associated with better neuropsychological performance, predominantly in the domains of attention/processing speed and executive functions. In conclusion, cannabis use is associated with enhanced cognitive functioning in schizophrenia. Implications of the results, limitations of the study, and directions for future research are discussed.


Increased β-cyanoalanine nitrilase activity improves cyanide tolerance and assimilation in Arabidopsis.
Plants naturally produce cyanide (CN) which is maintained at low levels in their cells by a process of rapid assimilation. However, high concentrations of environmental CN associated with activities such as industrial pollution are toxic to plants. There is thus an interest in increasing the CN detoxification capacity of plants as a potential route to phytoremediation. Here, Arabidopsis seedlings overexpressing the Pseudomonas fluorescens β-cyanoalanine nitrilase pinA were compared with wild-type and a β-cyanoalanine nitrilase knockout line (ΔAtnit4) for growth in the presence of exogenous CN. After incubation with CN, +PfpinA seedlings had increased root length, increased fresh weight, and decreased leaf bleaching compared with wild-type, indicating increased CN tolerance. The increased tolerance was achieved without an increase in β-cyanoalanine synthase activity, the other enzyme in the cyanide assimilation pathway, suggesting that nitrilase activity is the limiting factor for cyanide detoxification. Labeling experiments with [¹³C]KCN demonstrated that the altered CN tolerance could be explained by differences in flux from CN to Asn caused by altered β-cyanoalanine nitrilase activity. Metabolite profiling after CN treatment provided new insight into downstream metabolism, revealing onward metabolism of Asn by the photorespiratory nitrogen cycle and accumulation of aromatic amino acids.


Topical pine tar: History, properties and use as a treatment for common skin conditions.
Pine tar is the end product of pine wood carbonisation following distillation using extreme heat. An extensive literature search was conducted back to the 1950s for this review. Pine tar has been used in medicine for more than 2000 years to treat a range of skin conditions because of its soothing and antiseptic properties. Pine tar should not be confused with coal tar, which has been produced from coal for approximately a hundred years. Pine tar is thought to exert its effect by reducing DNA synthesis and mitotic activity, which promotes a return to normal keratinisation. In addition, pine tar has been shown to be antipruritic, anti-inflammatory, antibacterial and antifungal. These properties make pine tar suitable for the topical treatment of eczema, psoriasis, seborrhoeic dermatitis and other dry, itchy, flaky or inflamed skin conditions. Topical products available over-the-counter in Australia today contain up to 2.3% pine tar, and come in several different formulations that can be used on the entire body, including the face. Modern day pine tar is manufactured with increased purity to eliminate toxic phenol and carcinogenic components, which have been of concern in the past. Primary irritation is uncommon. In conclusion, the long experience with topical pine tar therapy and its worldwide usage, together with the evidence presented in this review, suggests that pine tar is an effective treatment with minimal safety risk.


Genetic and Molecular Mapping of Stripe Rust Resistance Gene in Wheat-Psathyrostachys huashanica Translocation Line H9020-1-6-8-3.
Stripe rust, caused by Puccinia striiformis f. sp. tritici, is one of the most important diseases of wheat worldwide. The best strategy to control stripe rust is to grow resistant cultivars, but only a few effective genes are available. The wheat accession H9020-1-6-8-3 is a translocation line previously developed from interspecific hybridization between wheat genotype 7182 and Psathyrostachys huashanica, and is resistant to most Chinese Puccinia striiformis f. sp. tritici races. To identify the resistance genes in the translocation line, H9020-1-6-8-3 was crossed with susceptible genotype Mingxian 169, and seedlings of parents and F1, F2, and F3 progenies were tested with prevalent Chinese P. striiformis f. sp. tritici races CYR32 and CYR33 under controlled greenhouse conditions. The genetic results indicated that two single dominant genes in H9020-1-6-8-3 confer resistance to CYR32 and CYR33, respectively. The gene for resistance to CYR33 was temporarily designated as YrH9020. Six simple-sequence repeat markers were used to map the resistance gene to the short arm of wheat chromosome 2D, using 329 F2 plants tested with CYR33 in the greenhouse. The genetic distances of the two closest flanking markers, Xgwm261 and Xgwm455, were 4.4 and 5.8 centimorgans, respectively. Disease assessments and polymorphic tests of the flanking markers among the Psathyrostachys huashanica line and wheat lines 7182, H9020-1-6-8-3, and Mingxian169 suggested that the resistance gene YrH9020 in H9020-1-6-8-3 was originally from P. huashanica. The exotic stripe rust resistance gene and linked molecular markers should be useful for pyramiding with other genes to develop wheat cultivars with high-level and durable resistance to stripe rust.


Origins of hydration differences in homochiral and racemic crystals of aspartic acid.
The propensity for crystalline hydrates of organic molecules to form is related to the strength of the interactions between molecules, including the chiral composition of the molecular solids. Specifically, homochiral versus racemic crystalline samples can exhibit distinct differences in their ability to form energetically stable hydrates. The focus of the current study is a comparison of the crystal structures and intermolecular forces found in solid-state L-aspartic acid, DL-aspartic acid, and L-aspartic acid monohydrate. The absence of experimental evidence for the DL-aspartic acid monohydrate is considered here in terms of the enhanced thermodynamic stability of the DL-aspartic acid anhydrate crystal as compared to the L-aspartic acid anhydrate as revealed through solid-state density functional theory calculations and terahertz spectroscopic measurements. The results indicate that anhydrous DL-aspartic acid is the more stable solid, not due to intermolecular forces alone but also due to the improved conformations of the molecules within the racemic solid. Hemihydrated and monohydrated forms of DL-aspartic acid have been computationally evaluated, and in each case, the hydrates produce destabilized aspartic acid conformations that prevent DL-aspartic acid hydrate formation from occurring.


Coupling of boswellic acid-induced Ca2+ mobilisation and MAPK activation to lipid metabolism and peroxide formation in human leucocytes.
1. We have previously shown that 11-keto boswellic acids (11-keto-BAs), the active principles of Boswellia serrata gum resins, activate p38 MAPK and p42/44(MAPK) and stimulate Ca(2+) mobilisation in human polymorphonuclear leucocytes (PMNL). 2. In this study, we attempted to connect the activation of MAPK and mobilisation of Ca(2+) to functional responses of PMNL, including the formation of reactive oxygen species (ROS), release of arachidonic acid (AA), and leukotriene (LT) biosynthesis. 3. We found that, in PMNL, 11-keto-BAs stimulate the formation of ROS and cause release of AA as well as its transformation to LTs via 5-lipoxygenase. 4. Based on inhibitor studies, 11-keto-BA-induced ROS formation is Ca(2+)-dependent and is mediated by NADPH oxidase involving PI 3-K and p42/44(MAPK) signalling pathways. Also, the release of AA depends on Ca(2+) and p42/44(MAPK), whereas the pathways stimulating 5-LO are not readily apparent. 5. Pertussis toxin, which inactivates G(i/0) protein subunits, prevents MAPK activation and Ca(2+) mobilisation induced by 11-keto-BAs, implying the involvement of a G(i/0) protein in BA signalling. 6. Expanding studies on differentiated haematopoietic cell lines (HL60, Mono Mac 6, BL41-E-95-A) demonstrate that the ability of BAs to activate MAPK and to mobilise Ca(2+) may depend on the cell type or the differentiation status. 7. In summary, we conclude that BAs act via G(i/0) protein(s) stimulating signalling pathways that control functional leucocyte responses, in a similar way as chemoattractants, that is, N-formyl-methionyl-leucyl-phenylalanine or platelet-activating factor.


Designing, implementing and evaluating the overdose response with take-home naloxone model of care: An evaluation of client outcomes and perspectives.
Take-home naloxone (THN) interventions are an effective response to preventing overdose deaths, however uptake across Australia remains limited. This project designed, implemented and evaluated a model of care targeting opioid users attending alcohol and other drug (AOD) treatment, needle and syringe programs (NSP) and related health services targeting people who inject drugs. Service providers, consumers and regulators collaboratively designed a THN brief intervention (ORTHN, Overdose Response with Take-Home Naloxone) involving client education and supply of naloxone in pre-filled syringes, delivered by nursing, allied health and NSP workers. ORTHN interventions were implemented in over 15 services across New South Wales, Australia. The evaluation included client knowledge, attitudes, substance use and overdose experiences immediately before and 3 months after ORTHN intervention in a subsample of participants. Six hundred and sixteen interventions were delivered, with 145 participants recruited to the research subsample, of whom 95 completed the three-month follow up. Overdose-related attitudes amongst participants improved following ORTHN, with no evidence of increased substance use or failure to implement other 'first responses' (e.g. calling an ambulance). Nine participants (10%) reversed an overdose using THN in the follow-up period. Participants identified a willingness to access THN from a range of services. While a minority (16%) indicated they were unwilling to pay for THN, the median price that participants were willing to pay was $AUD20 (IQR $10.40). The ORTHN model of care for THN appears an effective way to disseminate THN to people who use opioids attending AOD, NSP and related health-care settings.


Endovascular repair reduces early and late morbidity compared to open surgery for abdominal aortic aneurysm.
To compare systemic complications between standard surgery and endovascular repair of abdominal aortic aneurysms (AAA) for both primary and late secondary procedures. At a single center between July 1993 and May 2000, 297 patients (255 men; mean age 73.4 +/- 8.1 years, range 50-93) were treated with open surgical repair; beginning in 1996, 200 (166 men; mean age 73.6 +/- 8.0 years, range 45-96) patients were treated with the AneuRx stent-graft. In a comparison of the cohorts, which were similar in terms of age, gender, and aneurysm diameter, the main outcomes were early major systemic morbidity following the primary procedure to treat the aneurysm and late (>30 days) organ system morbidity for any secondary procedures. Mean length of follow-up for open patients was 20.1 +/- 17.1 months (range 1-150) compared to 12.4 +/- 9.6 months (range 1-60) after endovascular repair (p<0.05). There were 36 (12.1%) systemic complications after the primary open surgery and 15 (7.5%) after endovascular repair (p=NS). There were 43 (14.5%) combined primary and secondary morbidities in the open surgery group versus 15 (7.5%) for patients undergoing endovascular repair (p<0.01). The need for invasive procedures to treat these primary and secondary systemic complications was 4 times greater in the open group (17, 5.7%) than in endograft patients (3, 1.5%) (p<0.05). After secondary procedures (32 in the open group and 30 in the endovascular patients) for graft-related complications, there were 7 (21.9%) adverse events in the open group versus none (0%) for endograft patients (p<0.01). Hospital lengths of stay following both primary and secondary procedures were lower for the endograft patients (p<0.01 and p<0.001, respectively). Endovascular stent-graft repair compared to open surgery has reduced the early and late morbidity by half. Complications that require invasive or secondary surgical procedures and hospitalization are reduced with endovascular repair.


Melatonin overcomes gemcitabine resistance in pancreatic ductal adenocarcinoma by abrogating nuclear factor-κB activation.
Constitutive activation and gemcitabine induction of nuclear factor-κB (NF-κB) contribute to the aggressive behavior and chemotherapeutic resistance of pancreatic ductal adenocarcinoma (PDAC). Thus, targeting the NF-κB pathway has proven an insurmountable challenge for PDAC therapy. In this study, we investigated whether the inhibition of NF-κB signaling pathway by melatonin might lead to tumor suppression and overcome gemcitabine resistance in pancreatic tumors. Our results showed that melatonin inhibited activities of NF-κB by suppressing IκBα phosphorylation and decreased the expression of NF-κB response genes in MiaPaCa-2, AsPc-1, Panc-28 cells and gemcitabine resistance MiaPaCa-2/GR cells. Moreover, melatonin not only inhibited cell proliferation and invasion in a receptor-independent manner, but also enhanced gemcitabine cytotoxicity at pharmacologic concentrations in these PDAC cells. In vivo, the mice treated with both agents experienced a larger reduction in tumor burden than the single drug-treated groups in an orthotopic xenograft mouse model. Taken together, these results indicate that melatonin inhibits proliferation and invasion of PDAC cells and overcomes gemcitabine resistance of pancreatic tumors through NF-κB inhibition. Our findings therefore provide novel preclinical knowledge about melatonin inhibition of NF-κB in PDAC and suggest that melatonin should be investigated clinically, alone or in combination with gemcitabine for PDAC treatment.


Flavonoid intake is inversely associated with obesity and C-reactive protein, a marker for inflammation, in US adults.
Recent studies have demonstrated the importance of flavonoid intake and disease risk, however the association between flavonoid intake and obesity has not been evaluated in a nationally representative sample of US adults. The objective of the study was to evaluate the association between flavonoid consumption and established risk factors for obesity and obesity-related inflammation. Data from a nationally representative sample of 9551 adults who participated in the 2005-2008 National Health and Nutrition Examination Survey (NHANES) were analyzed. Flavonoid consumption was inversely associated with obesity in both men and women in multivariate models. Adults in the highest quartile of flavonoid intake had significantly lower body mass index and waist circumference than those in the lowest quartile of flavonoid intake (P<0.03 and P<0.04, respectively), and flavonoid intake was inversely related to C-reactive protein levels in women (p-trend, 0.01). These findings support a growing body of laboratory evidence that flavonoid consumption may be beneficial for disease prevention.


PedHunter 2.0 and its usage to characterize the founder structure of the Old Order Amish of Lancaster County.
Because they are a closed founder population, the Old Order Amish (OOA) of Lancaster County have been the subject of many medical genetics studies. We constructed four versions of Anabaptist Genealogy Database (AGDB) using three sources of genealogies and multiple updates. In addition, we developed PedHunter, a suite of query software that can solve pedigree-related problems automatically and systematically. We report on how we have used new features in PedHunter to quantify the number and expected genetic contribution of founders to the OOA. The queries and utility of PedHunter programs are illustrated by examples using AGDB in this paper. For example, we calculated the number of founders expected to be contributing genetic material to the present-day living OOA and estimated the mean relative founder representation for each founder. New features in PedHunter also include pedigree trimming and pedigree renumbering, which should prove useful for studying large pedigrees. With PedHunter version 2.0 querying AGDB version 4.0, we identified 34,160 presumed living OOA individuals and connected them into a 14-generation pedigree descending from 554 founders (332 females and 222 males) after trimming. From the analysis of cumulative mean relative founder representation, 128 founders (78 females and 50 males) accounted for over 95% of the mean relative founder contribution among living OOA descendants. The OOA are a closed founder population in which a modest number of founders account for the genetic variation present in the current OOA population. Improvements to the PedHunter software will be useful in future studies of both the OOA and other populations with large and computerized genealogies.


Validation of a Clinical Instrument for Measuring the Severity of Acute Bronchitis in Children - The BSS-ped.
There are no validated standardised clinical procedures for severity measurement of acute bronchitis in children. The "BSS-ped", a short version of the physician-rated assessment scale BSS (Bronchitis Severity Scale), can fill this gap, if it is valid. To examine the scale´s validity. Investigations were planned according to classical clinical-psychometric validity criteria including a formal competence evaluation of the scale´s authors and statistical analyses of data from 78 patients aged 1-6 and diagnosed with "acute bronchitis". Cross-validation was provided by analysis of data from 70 children with matching age, sex and diagnosis. All children were examined three times (day 0, 3-5 and 7) using the BSS-ped in addition to other clinical and psychometric monitoring procedures. The evidently high level of expertise of the scale's authors substantiates pronounced content validity and relevance of the BSS-ped and its items. The validity criterion, i.e. to reflect the unidimensional severity of acute bronchitis and its change using the BSS-ped score, was fulfilled. There were substantial correlations with other scales measuring the current health-related quality of life, as well as satisfaction and success of treatment. Severity change prognoses for acute bronchitis under placebo and an active substance were correct. The BSS-ped was found to be a feasible instrument because it can be repeated at short intervals (minute range) without any special technical aids or extended training. The BSS-ped is a valid procedure for measuring the severity of acute bronchitis in children.


Modulation of human mesenchymal stem cell behavior on ordered tantalum nanotopographies fabricated using colloidal lithography and glancing angle deposition.
Ordered surface nanostructures have attracted much attention in biotechnology and biomedical engineering because of their potential to modulate cell-surface interactions in a controllable manner. However, the ability to fabricate large area ordered nanostructures is limited because of high costs and low speed of fabrication. Here, we have fabricated ordered nanostructures with large surface areas (1.5 × 1.5 cm(2)) using a combination of facile techniques including colloidal self-assembly, colloidal lithography and glancing angle deposition (GLAD). Polystyrene (722 nm) colloids were self-assembled into a hexagonally close-packed (hcp) crystal array at the water-air interface, transferred on a biocompatible tantalum (Ta) surface and used as a mask to generate an ordered Ta pattern. The Ta was deposited by sputter coating through the crystal mask creating approximately 60-nm-high feature sizes. The feature size was further increased by approximately 200-nm-height respectively using GLAD, resulting in the fabrication of four different surfaces (FLAT, Ta60, GLAD100, and GLAD200). Cell adhesion, proliferation, and osteogenic differentiation of primary human adipose-derived stem cells (hADSCs) were studied on these ordered nanostructures for up to 2 weeks. Our results suggested that cell spreading, focal adhesion formation, and filopodia extension of hADSCs were inhibited on the GLAD surfaces, while the growth rate was similar between each surface. Immunostaining for type I collagen (COL1) and osteocalcin (OC) showed that there was higher osteogenic components deposited on the GLAD surfaces compared to the Ta60 and FLAT surfaces after 1 week of osteogenic culture. After 2 weeks of osteogenic culture, alkaline phosphatase (ALP) activity and the amount of calcium was higher on the GLAD surfaces. In addition, osteoblast-like cells were confluent on Ta60 and FLAT surfaces, whereas the GLAD surfaces were not fully covered suggesting that the cell-cell interactions are stronger than cell-substrate interactions on GLAD surfaces. Visible extracellular matrix deposits decorated the porous surface can be found on the GLAD surfaces. Depth profiling of surface components using a new Ar cluster source and X-ray photoelectron spectroscopy (XPS) showed that deposited extracellular matrix on GLAD surfaces is rich in nitrogen. The fabricated ordered surface nanotopographies have potential to be applied in diverse fields, and demonstrate that the behavior of human stem cells can be directed on these ordered nanotopographies, providing new knowledge for applications in biomaterials and tissue engineering.


Parathyroid disorders.
Disorders of the parathyroid glands most commonly present with abnormalities of serum calcium. Patients with primary hyperparathyroidism, the most common cause of hypercalcemia in outpatients, are often asymptomatic or may have bone disease, nephrolithiasis, or neuromuscular symptoms. Patients with chronic kidney disease may develop secondary hyperparathyroidism with resultant chronic kidney disease-mineral and bone disorder. Hypoparathyroidism most often occurs after neck surgery; it can also be caused by autoimmune destruction of the glands and other less common problems. Evaluation of patients with abnormal serum calcium levels includes a history and physical examination; repeat measurement of serum calcium level; and measurement of creatinine, magnesium, vitamin D, and parathyroid hormone levels. The treatment for symptomatic primary hyperparathyroidism is parathyroidectomy. Management of asymptomatic primary hyperparathyroidism includes monitoring symptoms; serum calcium and creatinine levels; and bone mineral density. Patients with hypoparathyroidism require close monitoring and vitamin D (e.g., calcitriol) replacement.


The intuitive use of laryngeal airway tools by first year medical students.
Providing a secured airway is of paramount importance in cardiopulmonary resuscitation. Although intubating the trachea is yet seen as gold standard, this technique is still reserved to experienced healthcare professionals. Compared to bag-valve facemask ventilation, however, the insertion of a laryngeal mask airway offers the opportunity to ventilate the patient effectively and can also be placed easily by lay responders. Obviously, it might be inserted without detailed background knowledge.The purpose of the study was to investigate the intuitive use of airway devices by first-year medical students as well as the effect of a simple, but well-directed training programme. Retention of skills was re-evaluated six months thereafter. The insertion of a LMA-Classic and a LMA-Fastrach performed by inexperienced medical students was compared in an airway model. The improvement on their performance after a training programme of overall two hours was examined afterwards. Prior to any instruction, mean time to correct placement was 55.5 +/- 29.6 s for the LMA-Classic and 38.1 +/- 24.9 s for the LMA-Fastrach. Following training, time to correct placement decreased significantly with 22.9 +/- 13.5 s for the LMA-Classic and 22.9 +/- 19.0 s for the LMA-Fastrach, respectively (p < 0.05). After six months, the results are comparable prior (55.6 +/- 29.9 vs 43.1 +/- 34.7 s) and after a further training period (23.5 +/- 13.2 vs 26.6 +/- 21.6, p < 0.05). Untrained laypersons are able to use different airway devices in a manikin and may therefore provide a secured airway even without having any detailed background knowledge about the tool. Minimal theoretical instruction and practical skill training can improve their performance significantly. However, refreshment of knowledge seems justified after six months.


Molecular characterization of Treponema pallidum subsp. pallidum in Switzerland and France with a new multilocus sequence typing scheme.
Syphilis is an important public health problem and an increasing incidence has been noted in recent years. Characterization of strain diversity through molecular data plays a critical role in the epidemiological understanding of this re-emergence. We here propose a new high-resolution multilocus sequence typing (MLST) scheme for Treponema pallidum subsp. pallidum (TPA). We analyzed 30 complete and draft TPA genomes obtained directly from clinical samples or from rabbit propagated strains to identify suitable typing loci and tested the new scheme on 120 clinical samples collected in Switzerland and France. Our analyses yielded three loci with high discriminatory power: TP0136, TP0548, and TP0705. Together with analysis of the 23S rRNA gene mutations for macrolide resistance, we propose these loci as MLST for TPA. Among clinical samples, 23 allelic profiles as well as a high percentage (80% samples) of macrolide resistance were revealed. The new MLST has higher discriminatory power compared to previous typing schemes, enabling distinction of TPA from other treponemal bacteria, distinction between the two main TPA clades (Nichols and SS14), and differentiation of strains within these clades.


Test-retest reliability of two instruments for measuring public attitudes towards persons with mental illness.
Research has identified stigmatization as a major threat to successful treatment of individuals with mental illness. As a consequence several anti-stigma campaigns have been carried out. The results have been discouraging and the field suffers from lack of evidence about interventions that work. There are few reports on psychometric data for instruments used to assess stigma, which thus complicates research efforts. The aim of the present study was to investigate test-retest reliability of the Swedish versions of the questionnaires: FABI and "Changing Minds" and to examine the internal consistency of the two instruments. Two instruments, fear and behavioural intentions (FABI) and "Changing Minds", used in earlier studies on public attitudes towards persons with mental illness were translated into Swedish and completed by 51 nursing students on two occasions, with an interval of three weeks. Test-retest reliability was calculated by using weighted kappa coefficient and internal consistency using the Cronbach's alpha coefficient. Both instruments attain at best moderate test-retest reliability. For the Changing Minds questionnaire almost one fifth (17.9%) of the items present poor test-retest reliability and the alpha coefficient for the subscales ranges between 0.19 - 0.46. All of the items in the FABI reach a fair or a moderate agreement between the test and retest, and the questionnaire displays a high internal consistency, alpha 0.80. There is a need for development of psychometrically tested instruments within this field of research.


Methyl-Guanine-Methyl-Transferase Transgenic Bone Marrow Transplantation Allows N,N-bis(2-chloroethyl)-Nitrosourea Driven Donor Mixed-Chimerism Without Graft-Versus-Host Disease, and With Donor-Specific Allograft Tolerance.
Transplant tolerance has been achieved by mixed chimerism in animal models and in a limited number of kidney transplant patients. However, these mixed-chimerism strategies were limited either by loss of long-term mixed chimerism or risk of graft-versus-host disease (GVHD). Selective bone marrow (BM) engraftment using marrow protective strategies are currently reaching clinical use. In this study, we tested the utility of methyl-guanine-methyl-transferase (MGMT)-transgenic-C57BL/6 BM into a major histocompatibility complex mismatched-BALB/c model followed by N,N-bis(2-chloroethyl)-nitrosourea (BCNU) treatment to enhance donor-cell engraftment and then evaluated transplant tolerance induction. A single-dose of anti-CD8 antibody and busulfan was administered into BALB/c-host-mice at day 1. The BALB/c-mice also received costimulatory blockade through multiple-doses of anti-CD40L antibody. 10 × 10(6) BM-cells from MGMT-transgenic-mice were transplanted into host BALB/c mice at day 0. The BCNU was administered at 4 time points after BM transplantation (BMT). Heterotopic donor C57BL/6 cardiac allografts were performed at day 243 after BMT. Skin transplantation with third-party CBA, host BALB/c and donor C57BL/6 grafts was performed at day 358 after BMT. The BALB/c-mice showed long-term stable and high-level donor-cell engraftment with MGMT transgenic C57BL/6 BMT after BCNU treatment, demonstrating full reconstitution and donor cardiac-allograft tolerance and no GVHD with expanded donor and host Foxp3 T regulatory cells. Further, skin grafts from donor, host, and third party showed good immune function with rejection of third-party grafts from all mice and benefit from enhanced chimerism after BCNU with less cell infiltrate and no chronic rejection in the donor skin grafts of BCNU treated mice compared no BCNU treated mice. High-level mixed chimerism without GVHD can be achieved using MGMT transgenic BM in a mixed-chimerism model receiving BCNU across a major histocompatibility complex mismatch. Enhanced mixed chimerism leads to long-term donor-specific allograft tolerance.


An efficient hybrid method for scattering from arbitrary dielectric objects buried under a rough surface: TM case.
A hybrid method combining the finite element method (FEM) with the boundary integral equation (BIE) is presented in this paper to investigate two-dimensional (2D) electromagnetic scattering properties of multiple dielectric objects buried beneath a dielectric rough ground for TM case. In traditional FEM simulation, the artificial boundaries, such as perfectly matched layer (PML) and the absorbing boundary conditions (ABC), are usually adopted as truncated boundaries to enclose the whole model. However, the enclosed computational domain increases quickly in size for a rough surface with a large scale, especially for the scattering model of objects away from the rough surface. In the hybrid FEM-BIE method, one boundary integral equation is adopt to depict the scattering above the rough surface based on Green's function. Based on the domain decomposition technique, the computational region below the rough ground is divided into multiple isolated interior regions containing each object and the exterior region. Finite element formulations are only applied inside interior regions to derive a set of linear systems, and another boundary integral formula is developed below the rough surface which also acts as the boundary constraint of the FEM region. Compared with traditional FEM, the hybrid technique presented here is highly efficient in terms of computational memory, time, and versatility. Numerical simulations are carried out based on hybrid FEM-BIE to study the scattering from multiple dielectric objects buried beneath a rough ground.