Cardiac operations in patients with functioning renal allografts.
The Transplant Service at the University of Minnesota Hospitals has performed over 2,000 kidney transplants. Fourteen of these patients have developed cardiac conditions necessitating surgical intervention at intervals of 9 to 144 months (mean 67 months) following their transplantation. These individuals had a mean age of 42 years, and five (36%) were diabetic. All patients had functioning renal allografts with preoperative serum creatinine levels ranging from 1.0 to 1.8 mg/100 ml (mean 1.4 mg/100 ml). Ten patients underwent aorta-coronary saphenous vein bypass grafting. One patient underwent bypass grafting and concomitant left ventricular aneurysmectomy. Native valvular endocarditis developed in two patients. One had tricuspid valve debridement for fungal endocarditis and the other had aortic valve replacement for bacterial endocarditis. The final patient had calcific aortic stenosis and coronary artery disease necessitating aortic valve replacement and coronary bypass. Two patients (14%) died perioperatively. One was a young woman with juvenile-onset diabetes and preinfarction angina who died suddenly several days after the operation; at autopsy, she was found to have an occluded graft to the right coronary artery and extensive infarction. The other was a 54-year-old woman with calcific aortic stenosis, coronary artery disease, and unstable angina who died perioperatively of uncontrollable arrhythmias. Autopsy suggested that she may have had an unsuspected infarction 1 to 2 days before the operation. The remaining 12 patients had uneventful postoperative courses and returned to Class I functional status from a cardiac standpoint. There has been one late death (7%), 45 months after successful coronary artery bypass grafting, as a result of complications attendant to a perforated gastric ulcer. The remaining 11 patients are alive and well at intervals of 8 to 93 months (mean 31 months) after operation. Postoperative serum creatinine levels at hospital discharge averaged 1.6 mg/100 ml, not significantly changed from preoperative levels. Cardiac operations can be performed safely in patients with functioning renal allografts. Patient survival is acceptable and preservation of renal function has been uniformly successful in surviving patients.


Analyzing the Training Load Demands, and Influence of Sex and Body Mass, on the Tactical Task of a Casualty Drag via Surface Electromyography Wearable Technology.
This study measured the training load (TL) demands associated with a military-specific casualty drag measured via surface electromyography (sEMG) wearable technology, and the influence of sex and body mass on these measures. Thirty-six college-aged participants (males = 25; females = 11) performed two trials of a 123-kg (91-kg dummy with 32-kg load) backwards casualty drag over 15 m. Time was recorded to calculate drag velocity, with the fastest trial analyzed. Prior to testing, participants were fitted with compression garments embedded with sensors to measure the vastus lateralis and medialis (quadriceps; QUAD), biceps femoris (BF), and gluteus maximus (GM) of both legs. The sEMG signal for each muscle was measured as a percentage of maximal voluntary contraction to calculate TL. The variables included TL (total, QUAD, BF, GM), and between-muscle ratios. The sample was also ranked and median split via body mass into heavier and lighter groups. Independent samples t-tests calculated differences between drag velocity and TL for the sex and body mass groups. Pearson's correlations calculated relationships between body mass and velocity with the TL variables (combined, males, females). Females and lighter participants experienced greater TL compared to males and heavier participants, respectively (p < 0.01). A slower drag velocity correlated with a greater total and QUAD TL for all participants, males, and females (p ≤ 0.03, r = -0.65-0.80). Performing a slower casualty drag will increase TL demands, predominantly via QUAD stress. Training staff should develop the muscles important for the drag, especially for females and lighter males.


Inhibition of markers of hepatic stellate cell activation by the hormone relaxin.
Hepatic fibrosis results from excess extracellular matrix produced primarily by hepatic stellate cells (HSC). In response to injury, HSC differentiate to a myofibroblastic phenotype expressing smooth muscle actin and fibrillar collagens. Relaxin is a polypeptide hormone shown to have antifibrotic effects in fibrosis models. In this study, activated HSC from rat liver were treated with relaxin to determine if relaxin can reverse markers of HSC activation. Relaxin treatment resulted in a decrease in the expression of smooth muscle actin, but had no effect on cell proliferation rate. The levels of total collagen and type I collagen were reduced, while the synthesis of new collagen was inhibited. Furthermore, relaxin caused an increase in the expression and secretion of rodent interstitial collagenase (MMP-13), but there was no effect on the gelatinases MMP-2 or MMP-9. Relaxin also increased secretion of TIMP-1 and TIMP-2. The effective concentration of relaxin to induce these effects was consistent with action through the relaxin receptor. In conclusion, relaxin reversed markers of the activated phenotype of HSC including the production of fibrillar collagen. At the same time, the activity of a fibrillar collagenase was increased. These data suggest that relaxin not only inhibits HSC properties that contribute to the progression of hepatic fibrosis, but also promotes the clearance of fibrillar collagen. Therefore, relaxin may be a useful approach in the treatment of hepatic fibrosis.


Use of Cephalic Vein for Venous Anastomosis in Head and Neck Reconstruction: A Case Series.
Purpose: To describe the use of the cephalic vein as a recipient vessel for venous outflow in head and neck reconstruction. The cephalic vein is used as a vessel in cases where there is a paucity of veins in the neck. This may be due to previous surgery, previous radiation therapy, or advanced cancer. The cephalic vein may also be used to salvage a failing free flap. Methods: It is a retrospective review of 230 free flaps that had been used in head and neck reconstruction performed from July 2014 to July 2018 by a single surgeon. Results: There were 6 patients in whom the cephalic vein was used as a recipient vessel. The cephalic vein was used in 2 cases where a tumor was involved with the internal jugular vein, in 1 case where a previous neck dissection had been done, in 1 case where internal jugular vein had iatrogenic damage, and in 2 cases a salvage procedure was done. In all cases, the cephalic vein was rotated above the clavicle. The cephalic vein easily reached the free flap vein and had a good caliber. There were no failures in any of the patients. Conclusion: The cephalic vein is a good option for venous anastomoses in patients in whom there is a paucity of recipient vessels in the neck.


Genetic variation at the vlsE locus of Borrelia burgdorferi within ticks and mice over the course of a single transmission cycle.
The Lyme disease spirochete, Borrelia burgdorferi, causes a persistent infection in the vertebrate host even though infected animals mount an active immune response against the spirochete. One strategy used by the spirochete to evade vertebrate host immunity is to vary the structure and expression of outer membrane antigens. The vlsE locus represents the best-studied example of antigenic variation in B. burgdorferi. During vertebrate host infection, recombination between the active vlsE locus and silent, partial vlsE copies leads to gene conversion events and the generation of novel alleles at the expression site. In the present study, we followed a population of B. burgdorferi organisms moving through vertebrate host and tick stages to complete one transmission cycle. The major goal of the study was to determine if the vlsE locus was subject to different selective pressure and/or recombination frequency at different stages of the spirochete's life cycle. We report here that the vlsE genetic diversity generated within the rodent host was maintained through the larval and nymphal tick stages. Therefore, naturally infected ticks are likely to transmit spirochete populations with multiple vlsE alleles into naive vertebrate hosts. Although vlsE genetic diversity in mice was maintained through tick stages, the dominant vlsE alleles were different between tick stages as well as between individual ticks. We propose that population-level bottlenecks experienced by spirochetes, especially during the larval-to-nymphal molt, are responsible for individual infected ticks harboring different dominant vlsE alleles. Although vlsE genetic diversity is maintained through tick stages, the VlsE protein is unlikely to be of functional importance in the vector, because the protein was expressed by very few (<1%) bacteria in the vector.


Cutting edge: hierarchy of chemokine receptor and TCR signals regulating T cell migration and proliferation.
Chemokines play an important role in establishing the distribution of lymphocyte subpopulations in primary and secondary lymphoid tissues and in the recruitment of leukocytes to sites of inflammation. However, the potential of chemokines to down-regulate immune responses has not been demonstrated. We now show that certain chemokine gradients have the potential to suppress T cell activation by preventing formation of the immunological synapse, the specialized cell-cell junction that forms before a T cell can be fully activated. Our data reveals an immunosuppressive potential of chemokines engaging the CXCR3 and CCR7 receptors, but not the CXCR4, CCR2, CCR4, or CCR5 receptors. These results suggest a novel mechanism for T cell ignorance of agonist MHC-peptide complexes based on dominant chemokine gradients.


Structural behaviour and gene delivery in complexes formed between DNA and arginine-containing peptide amphiphiles.
We describe in depth the structure of complexes formed between DNA and two classes of arginine-containing peptide amphiphiles, namely, the lipopeptide PRW-C16 (P = proline, R = arginine, W = tryptophan, C16 = C16 : 0 alkyl chain) and the bolaamphiphile RFL4FR (R = arginine, F = phenylalanine, L = leucine). A combination of X-ray and neutron scattering provided unprecedented insights into the local structure of these complexes. Lipopeptide-based complexes self-assembled into layered structures with large-scale fractal features, hosting DNA in the interstices. Bola-amphiphile scaffolds were characterized by planar structures with DNA strands presumably sandwiched in-between peptide nanotapes. Importantly, complexation did not affect the structural integrity of DNA in either of the two complexes. The bolaamphiphile conjugates displayed high levels of molecular ordering in contrast to the liquid-crystalline features observed in lipopeptide assemblies. Peptide-DNA complexes were assessed for their potential as a means to deliver the reporter vector pEGFP-N1 into SW480 human colon carcinoma cells. Successfully transfected cells expressed green fluorescent protein. The potentiating effect of PRW-C16 on the cellular uptake of ectopic DNA was found to be much greater than that observed with RFL4FR. In contrast to the bolaamphiphile-based conjugate, the liquid-crystalline nature of the lipopeptide complex is likely to play a key role in DNA release and transfection efficiency since these weakly bound structures require lower energy expenditure during disassembly and load release.


Time-resolved synchrotron X-ray micro-tomography datasets of drainage and imbibition in carbonate rocks.
Multiphase flow in permeable media is a complex pore-scale phenomenon, which is important in many natural and industrial processes. To understand the pore-scale dynamics of multiphase flow, we acquired time-series synchrotron X-ray micro-tomographic data at a voxel-resolution of 3.28 μm and time-resolution of 38 s during drainage and imbibition in a carbonate rock, under a capillary-dominated flow regime at elevated pressure. The time-series data library contains 496 tomographic images (gray-scale and segmented) for the complete drainage process, and 416 tomographic images (gray-scale and segmented) for the complete imbibition process. These datasets have been uploaded on the publicly accessible British Geological Survey repository, with the objective that the time-series information can be used by other groups to validate pore-scale displacement models such as direct simulations, pore-network and neural network models, as well as to investigate flow mechanisms related to the displacement and trapping of the non-wetting phase in the pore space. These datasets can also be used for improving segmentation algorithms for tomographic data with limited projections.


A novel victorivirus from a phytopathogenic fungus, Rosellinia necatrix, is infectious as particles and targeted by RNA silencing.
A novel victorivirus, termed Rosellinia necatrix victorivirus 1 (RnVV1), was isolated from a plant pathogenic ascomycete, white root rot fungus Rosellinia necatrix, coinfected with a partitivirus. The virus was molecularly and biologically characterized using the natural and experimental hosts (chestnut blight fungus, Cryphonectria parasitica). RnVV1 was shown to have typical molecular victorivirus attributes, including a monopartite double-stranded RNA genome with two open reading frames (ORFs) encoding capsid protein (CP) and RNA-dependent RNA polymerase (RdRp), a UAAUG pentamer presumed to facilitate the coupled termination/reinitiation for translation of the two ORFs, a spherical particle structure ~40 nm in diameter, and moderate levels of CP and RdRp sequence identity (34 to 58%) to those of members of the genus Victorivirus within the family Totiviridae. A reproducible transfection system with purified RnVV1 virions was developed for the two distinct fungal hosts. Transfection assay with purified RnVV1 virions combined with virus elimination by hyphal tipping showed that the effects of RnVV1 on the phenotype of the natural host were negligible. Interestingly, comparison of the RNA silencing-competent (standard strain EP155) and -defective (Δdcl-2) strains of C. parasitica infected with RnVV1 showed that RNA silencing acted against the virus to repress its replication, which was restored by coinfection with hypovirus or transgenic expression of an RNA silencing suppressor, hypovirus p29. Phenotypic changes were observed in the Δdcl-2 strain but not in EP155. This is the first reported study on the host range expansion of a Totiviridae member that is targeted by RNA silencing.


Congenital segmental dilatation of the intestine in a neonate.
A woman in her 30s at 29 weeks of gestation was diagnosed with a fetal abdominal cyst and polyhydramnios. As the cyst gradually increased in size, an elective caesarean section was performed at 38 weeks of gestation. The neonate experienced respiratory distress due to tense abdominal distension shortly after birth. An emergency laparotomy was performed. The intestinal tract was markedly dilated and contiguous with the cyst. The small bowel distal to the dilated intestine had herniated through the defect. The dilated segment was resected, and an ileostomy was created. The operative and histopathological findings suggested segmental dilatation of the intestine (SDI). SDI is a rare gastrointestinal disorder presenting during the neonatal period. It can cause respiratory failure in newborns by compression owing to its large size. SDI should be considered in the differential diagnosis of relatively large abdominal cysts, and collaboration with paediatric surgeons and neonatologists is necessary for successful outcomes.


The effect of time constraints and running phases on combined event pistol shooting performance.
The combined event is a crucial aspect of the modern pentathlon competition, but little is known about how shooting performance changes through the event. This study aimed to identify (i) how performance-related variables changed within each shooting series and (ii) how performance-related variables changed between each shooting series. Seventeen modern pentathletes completed combined event trials. An optoelectronic shooting system recorded score and pistol movement, and force platforms recorded centre of pressure movement 1 s prior to every shot. Heart rate and blood lactate values were recorded throughout the event. Whilst heart rate and blood lactate significantly increased between series (P < 0.05), there were no accompanying changes in the time period that participants spent aiming at the target, shot score, pistol movement or centre of pressure movement (P > 0.05). Thus, combined event shooting performance following each running phase appears similar to shooting performance following only 20 m of running. This finding has potential implications for the way in which modern pentathletes train for combined event shooting, and highlights the need for modern pentathletes to establish new methods with which to enhance shooting accuracy.


Understanding the investigators: a qualitative study investigating the barriers and enablers to the implementation of local investigator-initiated clinical trials in Ethiopia.
Clinical trials provide 'gold standard' evidence for policy, but insufficient locally relevant trials are conducted in low-income and middle-income countries. Local investigator-initiated trials could generate highly relevant data for national governments, but information is lacking on how to facilitate them. We aimed to identify barriers and enablers to investigator-initiated trials in Ethiopia to inform and direct capacity strengthening initiatives. Exploratory, qualitative study comprising of in-depth interviews (n=7) and focus group discussions (n=3). Fieldwork took place in Ethiopia during March 2011. Local health researchers with previous experiences of clinical trials or stakeholders with an interest in trials were recruited through snowball sampling (n=20). Detailed discussion notes were analysed using thematic coding analysis and key themes were identified. All participants perceived investigator-initiated trials as important for generating local evidence. System and organisational barriers included: limited funding allocation, weak regulatory and administrative systems, few learning opportunities, limited human and material capacity and poor incentives for conducting research. Operational hurdles were symptomatic of these barriers. Lack of awareness, confidence and motivation to undertake trials were important individual barriers. Training, knowledge sharing and experience exchange were key enablers to trial conduct and collaboration was unanimously regarded as important for improving capacity. Barriers to trial conduct were found at individual, operational, organisational and system levels. These findings indicate that to increase locally led trial conduct in Ethiopia, system wide changes are needed to create a more receptive and enabling research environment. Crucially, the creation of research networks between potential trial groups could provide much needed practical collaborative support through sharing of financial and project management burdens, knowledge and resources. These findings could have important implications for capacity-strengthening initiatives but further research is needed before the results can be generalised more widely.


Early Detection of Pancreatic Cancer: Opportunities and Challenges.
Most patients with pancreatic ductal adenocarcinoma (PDAC) present with symptomatic, surgically unresectable disease. Although the goal of early detection of PDAC is laudable and likely to result in significant improvement in overall survival, the relatively low prevalence of PDAC renders general population screening infeasible. The challenges of early detection include identification of at-risk individuals in the general population who would benefit from longitudinal surveillance programs and appropriate biomarker and imaging-based modalities used for PDAC surveillance in such cohorts. In recent years, various subgroups at higher-than-average risk for PDAC have been identified, including those with familial risk due to germline mutations, a history of pancreatitis, patients with mucinous pancreatic cysts, and elderly patients with new-onset diabetes. The last 2 categories are discussed at length in terms of the opportunities and challenges they present for PDAC early detection. We also discuss current and emerging imaging modalities that are critical to identifying early, potentially curable PDAC in high-risk cohorts on surveillance.


Transcription of Simian Virus 40 chromosomes in an extract of HeLa cells.
Simian Virus 40 (SV40) chromosomes were incubated with a concentrated extract of HeLa cells containing RNA polymerase II and other factors involved in transcription. SV40-specific RNA was synthesized. In the absence of HeLa cell extract the synthesis of labeled RNA by endogenous RNA polymerase in the chromosome preparations amounted to less than one tenth of that when the HeLa cell extract was present. Incubation with the HeLa extract increased the amount of Sarkosyl-resistant (i.e., transcribing) RNA polymerase on the SV40 chromosomes. When restriction endonucleases able to cut SV40 DNA were added to transcription reactions containing SV40 chromosomes and the HeLa cell extract, RNAs of discrete length were produced. The RNAs were identified as correctly initiated run-off transcripts of the early and late genes. Most of the RNA synthesized by the HeLa extract from SV40 chromosomes was from the region of the late genes, whereas transcription of purified SV40 DNA was from both the early and the late regions, with the early transcripts predominating.


Risk pathways for suicide among Native American adolescents.
Native American (Native) adolescents have the highest suicide rates in the United States, yet no conceptual models describing risk factors specific to this population exist. We sought to further hone a Native-specific conceptual model developed from quantitative data with qualitative data collected from a longitudinal series of interviews with (N = 22) Native adolescents who had attempted suicide. Four levels of suicide risk emerged, detailing individual, family, community, and societal factors that affect youths' pathways to suicide, along with a variety of subthemes and constructs. Some themes parallel established models of suicide risk; however, others are unique to the experience of this sample, including the impact of overtaxed households and family composition, significant grief burden, contagion, and stigma surrounding treatment seeking. We suggest adaptations of existing themes and constructs in the model. We discuss practical implications for research and intervention development, along with strengths and limitations of the study.


Thermodynamics of the binding of Thermus aquaticus DNA polymerase to primed-template DNA.
DNA binding of the Type 1 DNA polymerase from Thermus aquaticus (Taq polymerase) and its Klentaq large fragment domain have been studied as a function of temperature. Equilibrium binding assays were performed from 5 to 70 degrees C using a fluorescence anisotropy assay and from 10 to 60 degrees C using isothermal titration calorimetry. In contrast to the usual behavior of thermophilic proteins at low temperatures, Taq and Klentaq bind DNA with high affinity at temperatures down to 5 degrees C. The affinity is maximal at 40-50 degrees C. The DeltaH and DeltaS of binding are highly temperature dependent, and the DeltaCp of binding is -0.7 to -0.8 kcal/mol K, for both Taq and Klentaq, with good agreement between van't Hoff and calorimetric values. Such a thermodynamic profile, however, is generally associated with sequence-specific DNA binding and not non- specific binding. Circular dichroism spectra show conformational rearrangements of both the DNA and the protein upon binding. The high DeltaCp of Taq/Klentaq DNA binding may be correlated with structure-specific binding in analogy to sequence- specific binding, or may be a general characteristic of proteins that primarily bind non-specifically to DNA. The low temperature DNA binding of Taq/Klentaq is suggested to be a general characteristic of thermophilic DNA binding proteins.


The management of acute hypertension in patients with renal dysfunction: labetalol or nicardipine?
To compare the safety and efficacy of U.S. Food and Drug Administration (FDA)-recommended doses of labetalol and nicardipine for hypertension (HTN) management in a subset of patients with renal dysfunction (RD). Randomized, open label, multicenter prospective clinical trial. Thirteen United States tertiary care emergency departments. Subgroup analysis of the Evaluation of IV Cardene (Nicardipine) and Labetalol Use in the Emergency Department (CLUE) clinical trial. The subjects were 104 patients with RD (i.e., creatinine clearance < 75 mL/min) who presented to the emergency department with a systolic blood pressure (SBP) ≥ 180 mmHg on 2 consecutive readings and for whom the emergency physician felt intravenous antihypertensive therapy was desirable. The FDA recommended doses of either labetalol or nicardipine for HTN management. The number of patients achieving the physician's predefined target SBP range within 30 minutes of treatment. Patients treated with nicardipine were within target range more often than those receiving labetalol (92% vs. 78%, P = 0.046). On 6 SBP measures, patients treated with nicardipine were more likely to achieve the target range on either 5 or all 6 readings than were patients treated with labetalol (46% vs. 25%, P = 0.024). Labetalol patients were more likely to require rescue medication (27% vs. 17%, P = 0.020). Adverse events thought to be related to either treatment group were not reported in the 30-minute active study period, and patients had slower heart rates at all time points after 5 minutes (P < 0.01). In severe HTN with RD, nicardipine-treated patients are more likely to reach a target blood pressure range within 30 minutes than are patients receiving labetalol. Within 30 minutes of administration, nicardipine is more efficacious than labetalol for acute blood pressure control in patients with RD.


Children, parents, and pets exercising together (CPET) randomised controlled trial: study rationale, design, and methods.
Objectively measured physical activity is low in British children, and declines as childhood progresses. Observational studies suggest that dog-walking might be a useful approach to physical activity promotion in children and adults, but there are no published public health interventions based on dog-walking with children. The Children, Parents, and Pets Exercising Together Study aims to develop and evaluate a theory driven, generalisable, family-based, dog walking intervention for 9-11 year olds. The Children, Parents, and Pets Exercising Together Study is an exploratory, assessor-blinded, randomised controlled trial as defined in the UK MRC Framework on the development and evaluation of complex interventions in public health. The trial will follow CONSORT guidance. Approximately 40 dog-owning families will be allocated randomly in a ratio of 1.5:1 to receive a simple behavioural intervention lasting for 10 weeks or to a 'waiting list' control group. The primary outcome is change in objectively measured child physical activity using Actigraph accelerometry. Secondary outcomes in the child, included in part to shape a future more definitive randomised controlled trial, are: total time spent sedentary and patterning of sedentary behaviour (Actigraph accelerometry); body composition and bone health from dual energy x-ray absorptiometry; body weight, height and BMI; and finally, health-related quality of life using the PedsQL. Secondary outcomes in parents and dogs are: changes in body weight; changes in Actigraph accelerometry measured physical activity and sedentary behaviour. Process evaluation will consist of assessment of simultaneous child, parent, and dog accelerometry data and brief interviews with participating families. The Children, Parents, and Pets Exercising Together trial should be the first randomised controlled study to establish and evaluate an intervention aimed at dog-based physical activity promotion in families. It should advance our understanding of whether and how to use pet dogs to promote physical activity and/or to reduce sedentary behaviour in children and adults. The trial is intended to lead to a subsequent more definitive randomised controlled trial, and the work should inform future dog-based public health interventions such as secondary prevention interventions in children or adults. ISRCTN85939423.


Expression of the central growth regulator BIG BROTHER is regulated by multiple cis-elements.
Much of the organismal variation we observe in nature is due to differences in organ size. The observation that even closely related species can show large, stably inherited differences in organ size indicates a strong genetic component to the control of organ size. Despite recent progress in identifying factors controlling organ growth in plants, our overall understanding of this process remains limited, partly because the individual factors have not yet been connected into larger regulatory pathways or networks. To begin addressing this aim, we have studied the upstream regulation of expression of BIG BROTHER (BB), a central growth-control gene in Arabidopsis thaliana that prevents overgrowth of organs. Final organ size and BB expression levels are tightly correlated, implying the need for precise control of its expression. BB expression mirrors proliferative activity, yet the gene functions to limit proliferation, suggesting that it acts in an incoherent feedforward loop downstream of growth activators to prevent over-proliferation. To investigate the upstream regulation of BB we combined a promoter deletion analysis with a phylogenetic footprinting approach. We were able to narrow down important, highly conserved, cis-regulatory elements within the BB promoter. Promoter sequences of other Brassicaceae species were able to partially complement the A. thaliana bb-1 mutant, suggesting that at least within the Brassicaceae family the regulatory pathways are conserved. This work underlines the complexity involved in precise quantitative control of gene expression and lays the foundation for identifying important upstream regulators that determine BB expression levels and thus final organ size.


Quantification of Hantaan virus with a SYBR green I-based one-step qRT-PCR assay.
Hantaan virus (HTNV) is a major zoonotic pathogen that causes hemorrhagic fever with renal syndrome (HFRS) in Asia, especially in China. Shaanxi province, which is located in northwest of China, is one of the areas in China most severely afflicted with HFRS epidemics annually. This study aims to establish a quantitative RT-PCR (qRT-PCR) assay to detect HTNV both in cell culture and clinical serum samples. We established a SYBR Green I-based one-step qRT-PCR assay that targets the S segment of the HTNV genome for rapid detection and quantification. The HTNV cRNA standards were constructed by in vitro transcription, and the copy numbers of the HTNV cRNA were quantified. Standard curve was generated by determining the mean cycle threshold (Ct) values versus 10-fold serial dilutions of the HTNV cRNA over a range of 1 × 10(8) to 1 × 10(3) copies/μl. The standard curve had a reaction efficiency of 102.1%, a correlation coefficient (R(2)) of 0.998, and a slope of -3.273. The coefficient of variation (CV) of the intra- and inter-assays ranged from 0.68% to 3.00% and from 0.86% to 3.21%, respectively. The cycle intervals of the qRT-PCR assay between each dilution ranged from 2.9 to 3.8 cycles, and the lowest detection limit of the qRT-PCR assay was 10 copies/μl. The assay exhibited high specificity that was confirmed by melting curve analysis, and no cross reaction with the Seoul virus (SEOV) and other viruses (HBV, HCV and HIV) was observed. HTNV RNA was also detected in the 27 serum samples of clinical HFRS patients using the assay, and the HTNV RNA viral load ranged from 2.06 × 10(1) to 1.95 × 10(5) copies/μl. The SYBR Green I-based one-step qRT-PCR assay is a sensitive, specific, reproducible, and simple method for detecting and quantifying HTNV in cell culture and clinical samples.


Neglect dyslexia as a word-centred impairment: A single case study.
Neglect Dyslexia is a neuropsychological syndrome in which patients commit consistently lateralised letter omission, addition, and substitution errors when reading individual words. Although neglect dyslexia frequently co-occurs with domain-general visuospatial neglect, some cases of neglect dyslexia may be best characterised as a dissociable impairment within a word-centred reference frame. This investigation employs data from a single case study of a patient who demonstrated word-centred neglect dyslexia to clarify neglect dyslexia's relationship with visuospatial neglect. AB completed the Oxford Cognitive Screen and an original reading assessment in which she read 302 words, pseudo-words, and numbers presented in normal, vertical, and mirror-reflected orientations. AB was found to commit consistently lateralised right neglect dyslexia errors (e.g., SHOWN misread as "show" or RELATED misread as "relate"). By contrast, AB did not exhibit object-centred or viewer-centred neglect. AB was also found to commit lateralised reading errors affecting the terminal portions of words when lateralised spatial bias was eliminated by presenting words vertically. Additionally, AB consistently misread terminal letters (originally right-lateralised) even when words were mirror-reflected so that these letters were presented in the left side of space. AB committed no neglect dyslexia errors when reading normally, vertically, or mirror-reflected numbers, and demonstrated a qualitatively different error pattern when reading pseudo-words. The results of this case study imply that neglect dyslexia can involve a content-specific, word-centred cognitive deficit and can be dissociated from egocentric and allocentric visuospatial neglect.


Factors affecting sentinel lymph node identification rate after neoadjuvant chemotherapy for breast cancer patients enrolled in ACOSOG Z1071 (Alliance).
To evaluate factors affecting sentinel lymph node (SLN) identification after neoadjuvant chemotherapy (NAC) in patients with initial node-positive breast cancer. SLN surgery is increasingly used for nodal staging after NAC and optimal technique for SLN identification is important. The American College of Surgeons Oncology Group Z1071 prospective trial enrolled clinical T0-4, N1-2, M0 breast cancer patients. After NAC, SLN surgery and axillary lymph node dissection (ALND) were planned. Multivariate logistic regression modeling assessing factors influencing SLN identification was performed. Of 756 patients enrolled, 34 women withdrew, 21 were ineligible, 12 underwent ALND only, and 689 had SLN surgery attempted. At least 1 SLN was identified in 639 patients (92.7%: 95% CI: 90.5%-94.6%). Among factors evaluated, mapping technique was the only factor found to impact SLN identification; with use of blue dye alone increasing the likelihood of failure to identify the SLN relative to using radiolabeled colloid +/- blue dye (P = 0.006; OR = 3.82; 95% CI: 1.47-9.92). The SLN identification rate was 78.6% with blue dye alone; 91.4% with radiolabeled colloid and 93.8% with dual mapping agents. Patient factors (age, body mass index), tumor factors (clinical T or N stage), pathologic nodal response to chemotherapy, site of tracer injection, and length of chemotherapy treatment did not significantly affect the SLN identification rate. The SLN identification rate after NAC was higher when mapping was performed using radiolabeled colloid alone or with blue dye compared with blue dye alone. Optimal tracer use is important to ensure successful identification of SLN(s) after NAC.


Adrenomedullin Function in Vascular Endothelial Cells: Insights from Genetic Mouse Models.
Adrenomedullin is a highly conserved peptide implicated in a variety of physiological processes ranging from pregnancy and embryonic development to tumor progression. This review highlights past and present studies that have contributed to our current appreciation of the important roles adrenomedullin plays in both normal and disease conditions. We provide a particular emphasis on the functions of adrenomedullin in vascular endothelial cells and how experimental approaches in genetic mouse models have helped to drive the field forward.


Heterogeneity of the bone marrow niche.
The bone marrow niche is increasingly recognized as heterogeneous with specific subtypes of mesenchymal niche cells governing the development or homeostasis of selective parenchymal hematopoietic subsets. The present review outlines recent efforts in dissecting these microniches regulated by unique cell pairings within the bone marrow and provides an overview of how the bone marrow orchestrates multiple facets of hematopoiesis. Recent advancement in technologies has significantly improved our understanding of the cellular and molecular constituents that contribute to regulation of hematopoiesis and to maintenance of the hematopoietic stem cells (HSCs). Transgenic mouse models that enable endogenous cell deletion or lineage tracing, coupled with advanced intravital microscopy has identified several mesenchymal cell types, including the osteolineage cells, megakaryocytes, macrophages, perivascular cells, and Schwann cells, to be indispensible regulators of hematopoiesis. These niche cells, when perturbed, each caused very specific hematopoietic consequences including impairment in B-cell maturation, T lineage development, erythropoiesis, and impact different aspects of HSC behavior such as quiescence, mobilization, and response to acute stress signals. The emerging concept is that the bone marrow environment is composed of multiple microniches, each consisting of unique pairing of distinct supportive stromal cells with distinct hematopoietic subtypes to regulate a particular branch of hematopoietic cell process. The bone marrow can be viewed as a carrier with subcompartments tailored to support different hematopoietic activities.


Risk factors for active trachoma in children and trichiasis in adults: a household survey in Amhara Regional State, Ethiopia.
Identification of risk factors is essential for planning and implementing effective trachoma control programmes. We aimed to investigate risk factors for active trachoma and trichiasis in Amhara Regional State, Ethiopia. A survey was undertaken and eligible participants (children aged 1-9 years and adults aged 15 years and above) examined for trachoma. Risk factors were assessed through interviews and observations. Using ordinal logistic regression, associations between signs of active trachoma in children and potential risk factors were explored. Associations between trichiasis in adults and potential risk factors were investigated using conventional logistic regression. A total of 5427 children from 2845 households and 9098 adults from 4039 households were included in the analysis. Ocular discharge [odds ratio (OR)=5.9; 95% CI 4.8-7.2], nasal discharge (OR=1.6; 95% CI 1.3-1.9), thatch roof in household (OR=1.3; 95% CI 1.0-1.5), no electricity in household (OR=2.4; 95% CI 1.3-4.3) and increasing altitude (Ptrend<0.001) were independently associated with severity of active trachoma. Trichiasis was associated with increasing age (ORper 5 year increase=1.5; 95% CI 1.4-1.7), female gender (OR=4.5; 95% CI 3.5-5.8), increasing prevalence of active trachoma in children (Ptrend=0.003) and increasing altitude (Ptrend=0.015).


Borrelia burgdorferi outer surface protein A (OspA) activates and primes human neutrophils.
Lyme disease is caused by infection with the spirochete Borrelia burgdorferi and is characterized by bacterial persistence and inflammation of many host tissues. B. burgdorferi express outer surface lipoproteins, including OspA, with inflammatory properties that could contribute to the localized tissue inflammation. Neutrophils are the predominant infiltrate into the inflamed arthritic joints, and are crucial for controlling the spirochete infection. They may also contribute to the joint pathology associated with Lyme arthritis. This study examines the effect of OspA on the activities of the neutrophil. Picomolar concentrations of OspA induce surface markers associated with neutrophil activation: increased CD10 and CD11b expression; decreased CD62-L expression; and an increased adherence to extracellular matrix. These events were similar in kinetics and magnitude to those induced by the strong activators LPS and FMLP. Like LPS, OspA could prime neutrophils for FMLP-induced release of lysosomal granules and production of superoxide. Thus, models of Lyme arthritis should include the possible contribution of direct activation of neutrophils to both defense and disease.


Wearability Testing of Ambulatory Vital Sign Monitoring Devices: Prospective Observational Cohort Study.
Timely recognition of patient deterioration remains challenging. Ambulatory monitoring systems (AMSs) may provide support to current monitoring practices; however, they need to be thoroughly tested before implementation in the clinical environment for early detection of deterioration. The objective of this study was to assess the wearability of a selection of commercially available AMSs to inform a future prospective study of ambulatory vital sign monitors in an acute hospital ward. Five pulse oximeters (4 with finger probes and 1 wrist-worn only, collecting pulse rates and oxygen saturation) and 2 chest patches (collecting heart rates and respiratory rates) were selected to be part of this study: The 2 chest-worn patches were VitalPatch (VitalConnect) and Peerbridge Cor (Peerbridge); the 4 wrist-worn devices with finger probe were Nonin WristOx2 3150 (Nonin), Checkme O2+ (Viatom Technology), PC-68B, and AP-20 (both from Creative Medical); and the 1 solely wrist-worn device was Wavelet (Wavelet Health). Adult participants wore each device for up to 72 hours while performing usual "activities of daily living" and were asked to score the perceived exertion and perception of pain or discomfort by using the Borg CR-10 scale; thoughts and feelings caused by the AMS using the Comfort Rating Scale (CRS); and to provide general free text feedback. Median and IQRs were reported and nonparametric tests were used to assess differences between the devices' CRS scores. Quantitative scores and feedback were collected in 70 completed questionnaires from 20 healthy volunteers, with each device tested approximately 10 times. The Wavelet seemed to be the most wearable device (P<.001) with an overall median (IQR) CRS score of 1.00 (0.88). There were no statistically significant differences in wearability between the chest patches in the CRS total score; however, the VitalPatch was superior in the Attachment section (P=.04) with a median (IQR) score of 3.00 (1.00). General pain and discomfort scores and total percentage of time worn are also reflective of this. Our results suggest that adult participants prefer to wear wrist-worn pulse oximeters without a probe compressing the fingertip and they prefer to wear a smaller chest patch. A compromise between wearability, reliability, and accuracy should be made for successful and practical integration of AMSs within the hospital environment.


External cephalic version for breech presentation before term.
External cephalic version (ECV) of the breech fetus at term (after 37 weeks) has been shown to be effective in reducing the number of breech presentations and caesarean sections, but the rates of success are relatively low. This review examines studies initiating ECV prior to term (before 37 weeks' gestation). To assess the effectiveness of a policy of beginning ECV before term (before 37 weeks' gestation) for breech presentation on fetal presentation at birth, method of delivery, and the rate of preterm birth, perinatal morbidity, stillbirth or neonatal mortality. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2015) and reference lists of retrieved studies. Randomised controlled trials (RCTs) of ECV attempted before term (37 weeks' gestation) or commenced before term, compared with a control group of women (in breech presentation) in which either no ECV attempted or ECV was attempted at term. Cluster-randomised trials were eligible for inclusion but none were identified. Quasi-RCTs or studies using a cross-over design were not eligible for inclusion. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked for accuracy. Studies were assessed for risk of bias and for important outcomes the overall quality of the evidence was assessed using the GRADE approach. Five studies are included (2187 women). It was not possible for the intervention to be blinded, and it is not clear what impact lack of blinding would have on the outcomes reported. For other 'Risk of bias' domains studies were either at low or unclear risk of bias.One study reported on ECV that was undertaken and completed before 37 weeks' gestation compared with no ECV. No difference was found in the rate of non-cephalic presentation at birth (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.64 to 1.69; participants = 102). One study reported on a policy of ECV that was initiated before term (33 weeks) and up until 40 weeks' gestation and which could be repeated up until delivery compared with no ECV. This study showed a decrease in the rate of non-cephalic presentation at birth (RR 0.59, 95% CI 0.45 to 0.77; participants = 179).Three studies reported on ECV started at between 34 to 35 weeks' gestation compared with beginning at 37 to 38 weeks' gestation. Pooled results suggested that early ECV reduced the risk of non-cephalic presentation at birth (RR 0.81, 95% CI 0.74 to 0.90; participants = 1906; studies = three; I² = 0%, evidence graded high quality), failure to achieve vaginal cephalic birth (RR 0.90, 95% CI 0.83 to 0.97; participants = 1888; studies = three; I² = 0%, evidence graded high quality), and vaginal breech delivery (RR 0.44, 95% CI 0.25 to 0.78; participants = 1888; studies = three; I² = 0%, evidence graded high quality). The difference between groups for risk of caesarean was not statistically significant (RR 0.92, 95% CI 0.85 to 1.00; participants = 1888; studies = three; I² = 0%, evidence graded high quality). There was evidence that risk of preterm labour was increased with early ECV compared with ECV after 37 weeks (6.6% in the ECV group and 4.3% for controls) (RR 1.51, 95% CI 1.03 to 2.21; participants = 1888; studies = three; I² = 0%, evidence graded high quality). There was no clear difference between groups for low infant Apgar score at five minutes or perinatal death (stillbirth plus neonatal mortality up to seven days) (evidence graded as low quality for both outcomes). Compared with no ECV attempt, ECV commenced before term reduces non-cephalic presentation at birth. Compared with ECV at term, beginning ECV at between 34 to 35 weeks may have some benefit in terms of decreasing the rate of non-cephalic presentation, and risk of vaginal breech birth. However, early ECV may increase risk of late preterm birth, and it is important that any future research reports infant morbidity outcomes. Results of the review suggest that there is a need for careful discussion with women about the timing of the ECV procedure so that they can make informed decisions.


Does "Individual Placement and Support" Satisfy the Users' Needs?
This study aims to investigate clients' satisfaction with individual placement and support (IPS) at the University Hospital for Psychiatry Zurich (PUK). Furthermore, this study aims to investigate if clients feel the approach of IPS as a useful approach to fulfill their needs. One hundred twenty-five people were recruited from one of the three IPS services of PUK and were asked to complete a structured questionnaire. The following IPS services were available: (i) randomized controlled trial (RCT) ZHEPP (www.zhepp.ch), (ii) RCT ZInEP (www.zinep.ch), and (iii) us clinical supported employment service of PUK (IPS-PUK). The clients mostly indicated that IPS was generally useful and fitted their needs. Overall satisfaction of the participants with the IPS services of the PUK was very high. Furthermore, client satisfaction and symptom severity are inversely associated. In conclusion, participants of the IPS services received the support they were looking for. This means that the approach of IPS fits the needs of different patient groups and can be used without any modifications. The most important limitation is the unequal group sizes. Therefore, the obtained results need to be strengthened by future research.


The prevalence of cardiovascular disease risk factors and the Framingham Risk Score in patients undergoing percutaneous intervention over the last 17 years by gender: time-trend analysis from the Mayo Clinic PCI Registry.
This study aims to investigate trends of cardiovascular disease (CVD) risk factor profiles over 17 years in percutaneous coronary intervention (PCI) patients at the Mayo Clinic. We performed a time-trend analysis within the Mayo Clinic PCI Registry from 1994 to 2010. Results were the incidence and prevalence of CVD risk factors as estimate by the Framingham risk score. Between 1994 and 2010, 25 519 patients underwent a PCI. During the time assessed, the mean age at PCI became older, but the gender distribution did not change. A significant trend towards higher body mass index and more prevalent hypercholesterolemia, hypertension, and diabetes was found over time. The prevalence of current smokers remained unchanged. The prevalence of ever-smokers decreased among males, but increased among females. However, overall CVD risk according to the Framingham risk score (FRS) and 10-year CVD risk significantly decreased. The use of most of medications elevated from 1994 to 2010, except for β-blockers and angiotensin converting enzyme inhibitors decreased after 2007 and 2006 in both baseline and discharge, respectively. Most of the major risk factors improved and the FRS and 10-year CVD risk declined in this population of PCI patients. However, obesity, history of hypercholesterolemia, hypertension, diabetes, and medication use increased substantially. Improvements to blood pressure and lipid profile management because of medication use may have influenced the positive trends. This study aims to investigate trends of cardiovascular disease (CVD) risk factor profiles over 17 years in percutaneous coronary intervention (PCI) patients at the Mayo Clinic. We performed a time-trend analysis within the Mayo Clinic PCI Registry from 1994 to 2010. Results were the incidence and prevalence of CVD risk factors as estimate by the Framingham risk score. Between 1994 and 2010, 25 519 patients underwent a PCI. During the time assessed, the mean age at PCI became older, but the gender distribution did not change. A significant trend towards higher body mass index and more prevalent hypercholesterolemia, hypertension, and diabetes was found over time. The prevalence of current smokers remained unchanged. The prevalence of ever-smokers decreased among males, but increased among females. However, overall CVD risk according to the Framingham risk score (FRS) and 10-year CVD risk significantly decreased. The use of most of medications elevated from 1994 to 2010, except for β-blockers and angiotensin converting enzyme inhibitors decreased after 2007 and 2006 in both baseline and discharge, respectively. Most of the major risk factors improved and the FRS and 10-year CVD risk declined in this population of PCI patients. However, obesity, history of hypercholesterolemia, hypertension, diabetes, and medication use increased substantially. Improvements to blood pressure and lipid profile management because of medication use may have influenced the positive trends.


New tools for the hydromorphological assessment and monitoring of European streams.
Hydromorphological stream assessment has significantly expanded over the last years, but a need has emerged from recent reviews for more comprehensive, process-based methods that consider the character and dynamics of the river with greater accuracy. With this as a focus, a series of hydromorphological tools have been developed and/or further extended in Europe within the context of the REFORM (REstoring rivers FOR effective catchment Management) project. The aim of this paper is to present the set of REFORM hydromorphological assessment methods and, based on some examples of their application, to illustrate and discuss their synergic use, specific features, limitations and strengths. This assessment and monitoring includes three tools: the Morphological Quality Index (MQI), the Morphological Quality Index for monitoring (MQIm), and the Geomorphic Units survey and classification System (GUS). These tools constitute the assessment phase of an overall multi-scale, process-based hydromorphological framework developed in REFORM. The MQI is aimed at an assessment, classification and monitoring of the current morphological state; the MQIm aims at monitoring the tendency of morphological conditions (enhancement or deterioration); the GUS provides a characterization, classification and monitoring of geomorphic units. A series of examples are used to illustrate the potential range of application, including: (i) an assessment of morphological conditions; (ii) an assessment of the morphological effects of restoration projects; (iii) an evaluation of the geomorphic impacts of interventions for risk mitigation; and (iv) an integrated use of MQI and GUS to assess and characterise morphological conditions. Finally, some of the main features, strengths and peculiarities of the three hydromorphological tools are discussed with the support of examples of their application.


Incidence and Risk Factors for Falls in Women With End-Stage Hip Osteoarthritis.
Fall-induced injuries and resulting deaths are a serious health problem among older adults. The most common risk factors for falls in older adults are muscle weakness, gait deficiencies, and balance deficits. Patients with end-stage hip osteoarthritis (OA) also have many hip dysfunctions, and these all have the potential to increase the risk of falls. However, the incidence and risk factors for falls in patients with end-stage hip OA remain unclear. The aim of this study was to determine the incidence of falls in women with end-stage hip OA and to identify risk factors for falls in this patient population. This study was a cross-sectional analysis. One hundred fifty-three women with end-stage hip OA (mean age = 64.0 years) and 112 age-matched healthy women (mean age = 64.1 years) were analyzed using available data. All participants were examined for the number and circumstances of falls in the past year. The circumstances of falls included the location, time, direction, cause, and injury. We examined the outcome of hip function, ambulatory ability, physical activity, and limping severity in women with end-stage hip OA. Multivariate logistic regression analysis was used to identify factors influencing falls in women with hip OA. The incidence of at least 1 fall in the past year was significantly higher in women with end-stage hip OA (30.1%) than in healthy women (12.5%) (P < .001). Falls in women with end-stage hip OA were most often caused by tripping and falling forward during the daytime. The majority of falls (65.2%) resulted in injuries and 13.0% resulted in fractures. The occurrence of a fall significantly correlated with limping (odds ratio = 3.26, 95% confidence interval = 1.49-7.14, P = .003) and knee extensor muscle strength (odds ratio = 0.22, 95% confidence interval = 0.05-0.85, P = .029). Women with end-stage hip OA have an increased risk of falls and fall-induced injuries. The prevention of falls in this vulnerable population should be a priority among health care practitioners. In particular, women who are limping and have reduced lower knee extensor strength should take care to avoid falls.


Optimization of the supercritical fluidized bed process for sirolimus coating and drug release.
Directly coating an active pharmaceutical ingredient (API) onto excipient granules has been a common approach to prepare solid dosage forms. The combination of supercritical anti-solvent (SAS) and fluidized bed (FB) coating technology (SAS-FB) has the advantages of preventing nanoparticles aggregation, oxidation and light exposure. However individual operating parameters and factors which contribute to the overall coating efficiency remain to be defined. Sirolimus is an immunosuppressive agent for preventing the rejection of organ transplants and this drug is sensitive to light exposure and high temperature. Our study used sirolimus as the model API to evaluate parameters including temperature, pressure, drug concentration, mass, material and diameter of carrier, CO2 flow rate and solvent in the SAS-FB process. By optimizing these parameters, we achieved a 3.5-fold enhancement of the coating efficiency over the standard condition. A series of characterizations of the sirolimus coated particles were performed from which scanning electron microscopy and Raman mapping confirmed that the sirolimus particles were uniformly coated on carriers as cuboid particles; X-ray powder diffraction showed that processed sirolimus is crystalline but has lower crystallinity than the API, and fourier transform infrared spectroscopy and differential scanning calorimeter confirmed that there is no chemical interaction between sirolimus and carriers after SAS-FB processing. Finally compared to sirolimus alone, sirolimus coated particles displayed a faster dissolution and higher bioavailability. Collectively, our optimized operation parameters for SAS-FB coating technique provide a useful guidance for achieving higher efficiency of drug coating and faster release rate of sirolimus pellets, which has the potential to apply to other APIs.


Crystal structure of the yeast eIF4A-eIF4G complex: an RNA-helicase controlled by protein-protein interactions.
Translation initiation factors eIF4A and eIF4G form, together with the cap-binding factor eIF4E, the eIF4F complex, which is crucial for recruiting the small ribosomal subunit to the mRNA 5' end and for subsequent scanning and searching for the start codon. eIF4A is an ATP-dependent RNA helicase whose activity is stimulated by binding to eIF4G. We report here the structure of the complex formed by yeast eIF4G's middle domain and full-length eIF4A at 2.6-A resolution. eIF4A shows an extended conformation where eIF4G holds its crucial DEAD-box sequence motifs in a productive conformation, thus explaining the stimulation of eIF4A's activity. A hitherto undescribed interaction involves the amino acid Trp-579 of eIF4G. Mutation to alanine results in decreased binding to eIF4A and a temperature-sensitive phenotype of yeast cells that carry a Trp579Ala mutation as its sole source for eIF4G. Conformational changes between eIF4A's closed and open state provide a model for its RNA-helicase activity.


Surficial deposits at Gusev Crater along Spirit Rover traverses.
The Mars Exploration Rover Spirit has traversed a fairly flat, rock-strewn terrain whose surface is shaped primarily by impact events, although some of the landscape has been altered by eolian processes. Impacts ejected basaltic rocks that probably were part of locally formed lava flows from at least 10 meters depth. Some rocks have been textured and/or partially buried by windblown sediments less than 2 millimeters in diameter that concentrate within shallow, partially filled, circular impact depressions referred to as hollows. The terrain traversed during the 90-sol (martian solar day) nominal mission shows no evidence for an ancient lake in Gusev crater.


Gamma rays and neutrinos as clues to the origin of high energy cosmic rays.
Compact regions in the Milky Way, such as accreting degenerate binary stars, may be sites of acceleration of particles with energies far greater than produced at any man-made accelerator, present or proposed. If so, they would emit characteristic neutral radiation of ultra-high energy, which might be strong enough to be detectable at Earth. The quest for these faint but energetic signals is the focus of more than 50 large, ground-based experiments that are looking for high energy photons or neutrinos from point sources in our galaxy and beyond. Several sources have been claimed, but the signals appear to have unexpected and puzzling features that must be clarified before the field can settle into a routine phase of systematic investigation. In the meantime, the potentially profound implications for particle physics, as well as astrophysics, make this field one of intense activity.


Laser capture microdissection and protein microarray analysis of human non-small cell lung cancer: differential epidermal growth factor receptor (EGPR) phosphorylation events associated with mutated EGFR compared with wild type.
Little is known about lung carcinoma epidermal growth factor (EGF) kinase pathway signaling within the context of the tissue microenvironment. We quantitatively profiled the phosphorylation and abundance of signal pathway proteins relevant to the EGF receptor within laser capture microdissected untreated, human non-small cell lung cancer (NSCLC) (n = 25) of known epidermal growth factor receptor (EGFR) tyrosine kinase domain mutation status. We measured six phosphorylation sites on EGFR to evaluate whether EGFR mutation status in vivo was associated with the coordinated phosphorylation of specific multiple phosphorylation sites on the EGFR and downstream proteins. Reverse phase protein array quantitation of NSCLC revealed simultaneous increased phosphorylation of EGFR residues Tyr-1148 (p < 0.044) and Tyr-1068 (p < 0.026) and decreased phosphorylation of EGFR Tyr-1045 (p < 0.002), HER2 Tyr-1248 (p < 0.015), IRS-1 Ser-612 (p < 0.001), and SMAD Ser-465/467 (p < 0.011) across all classes of mutated EGFR patient samples compared with wild type. To explore which subset of correlations was influenced by ligand induction versus an intrinsic phenotype of the EGFR mutants, we profiled the time course of 115 cellular signal proteins for EGF ligand-stimulated (three dosages) NSCLC mutant and wild type cultured cell lines. EGFR mutant cell lines (H1975 L858R) displayed a pattern of EGFR Tyr-1045 and HER2 Tyr-1248 phosphorylation similar to that found in tissue. Persistence of phosphorylation for AKT Ser-473 following ligand stimulation was found for the mutant. These data suggest that a higher proportion of the EGFR mutant carcinoma cells may exhibit activation of the phosphatidylinositol 3-kinase/protein kinase B (AKT)/mammalian target of rapamycin (MTOR) pathway through Tyr-1148 and Tyr-1068 and suppression of IRS-1 Ser-612, altered heterodimerization with ERBB2, reduced response to transforming growth factor beta suppression, and reduced ubiquitination/degradation of the EGFR through EGFR Tyr-1045, thus providing a survival advantage. This is the first comparison of multiple, site-specific phosphoproteins with the EGFR tyrosine kinase domain mutation status in vivo.


Disease prevention and preparedness for animal health emergencies in the Middle East.
The animal health situation in the Middle East is particularly unfavourable, as this area is exposed to many serious animal diseases. The Middle East is ill-prepared to institute disease prevention and control measures, due to deficiencies at both national and regional levels. Early detection, diagnosis and reporting of diseases must become a priority within these countries and effective communication should be maintained among them. Regional animal health programmes and the support of international institutions are essential to improve preparedness for natural or human-caused emergency situations, which can seriously affect animal health. Such emergencies can also have significant impacts on related public health issues.


NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer.
Alternative splicing is dysregulated in cancer and the reactivation of telomerase involves the splicing of TERT transcripts to produce full-length (FL) TERT. Knowledge about the splicing factors that enhance or silence FL hTERT is lacking. We identified splicing factors that reduced telomerase activity and shortened telomeres using a siRNA minigene reporter screen and a lung cancer cell bioinformatics approach. A lead candidate, NOVA1, when knocked down resulted in a shift in hTERT splicing to non-catalytic isoforms, reduced telomerase activity, and progressive telomere shortening. NOVA1 knockdown also significantly altered cancer cell growth in vitro and in xenografts. Genome engineering experiments reveal that NOVA1 promotes the inclusion of exons in the reverse transcriptase domain of hTERT resulting in the production of FL hTERT transcripts. Utilizing hTERT splicing as a model splicing event in cancer may provide new insights into potentially targetable dysregulated splicing factors in cancer.


Scatterometry-based metrology with feature region signatures matching.
Scatterometry takes advantage of the sensitivity exhibited by optical diffraction from periodic structures, and hence is an efficient technique for lithographic process monitoring. A feature region measurement algorithm has been developed to extract accurately and quickly the relevant constitutive parameters from diffraction data. It is a method for efficiently determining grating structure by seeking the reflectance at some angles contains more information about the structure of the surface relief profile than the reflectance at other angles in a library data match process. The number of measurements and size of signature matching library will be reduced in a great percentage by performing the feature region algorithm.


The European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP)--a sentinel approach in the European Union (EU)/European Economic Area (EEA).
Antimicrobial resistance in Neisseria gonorrhoeae is monitored in the European Union/European Economic Area through the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) coordinated by the European Centre for Disease Prevention and Control. Euro-GASP includes a sentinel surveillance programme which aims to detect in a timely manner changes in resistance patterns and inform treatment guidelines. The programme aims to test a representative number of isolates from each European Union/European Economic Area member state per year for a range of therapeutically relevant antimicrobials through a biannual hybrid centralised/decentralised system. Testing is supported by an External Quality Assurance programme and a laboratory training programme. Participation in the programme has increased to 21 countries in 2012. Euro-GASP has been able to detect the rapid spread of isolates with decreased susceptibility to cefixime across Europe in 2010 and 2011. Results from the programme have informed changes in European treatment guidelines for gonorrhoea and led to the development of the 'Response plan to control and manage the threat of multidrug resistant gonorrhoea in Europe'. Future challenges for Euro-GASP include supporting countries to participate in Euro-GASP through decentralised testing, improving timeliness and epidemiological data quality, and increasing participation from Eastern Europe.


Duplex Scorpion primers in SNP analysis and FRET applications.
Scorpions are fluorogenic PCR primers with a probe element attached at the 5'-end via a PCR stopper. They are used in real-time amplicon-specific detection of PCR products in homogeneous solution. Two different formats are possible, the 'stem-loop' format and the 'duplex' format. In both cases the probing mechanism is intramolecular. We have shown that duplex Scorpions are efficient probes in real-time PCR. They give a greater fluorescent signal than stem-loop Scorpions due to the vastly increased separation between fluorophore and quencher in the active form. We have demonstrated their use in allelic discrimination at the W1282X locus of the ABCC7 gene and shown that they can be used in assays where fluorescence resonance energy transfer is required.


Surveillance definitions of infections in long-term care facilities: revisiting the McGeer criteria.
(See the commentary by Moro, on pages 978-980 .) Infection surveillance definitions for long-term care facilities (ie, the McGeer Criteria) have not been updated since 1991. An expert consensus panel modified these definitions on the basis of a structured review of the literature. Significant changes were made to the criteria defining urinary tract and respiratory tract infections. New definitions were added for norovirus gastroenteritis and Clostridum difficile infections.


Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis.
Emerging data suggest that metastasis-associated protein 1 (MTA1) represses ligand-dependent transactivation functions of estrogen receptor-alpha in cultured breast cancer cells and that MTA1 is upregulated in human breast tumors. However, the role of MTA1 in tumorigenesis in a physiologically relevant animal system remains unknown. To reveal the role of MTA1 in mammary gland development, transgenic mice expressing MTA1 under the control of the mouse mammary tumor virus promoter long terminal repeat were generated. Unexpectedly, we found that mammary glands of these virgin transgenic mice exhibited extensive side branching and precocious differentiation because of increased proliferation of ductal and alveolar epithelial cells. Mammary glands of virgin transgenic mice resemble those from wild-type mice in mid-pregnancy and inappropriately express beta-casein, cyclin D1 and beta-catenin protein. Increased ductal growth was also observed in the glands of ovariectomized female mice, as well as of transgenic male mice. MTA1 dysregulation in mammary epithelium and cancer cells triggered downregulation of the progesterone receptor-B isoform and upregulation of the progesterone receptor-A isoform, resulting in an imbalance in the native ratio of progesterone receptor A and B isoforms. MTA1 transgene also increased the expression of progesterone receptor-A target genes Bcl-XL (Bcl2l1) and cyclin D1 in mammary gland of virgin mice, and, subsequently, produced a delayed involution. Remarkably, 30% of MTA1 transgenic females developed focal hyperplastic nodules, and about 7% exhibited mammary tumors within 18 months. These studies establish, for the first time, a potential role of MTA1 in mammary gland development and tumorigenesis. The underlying mechanism involves the upregulation of progesterone receptor A and its targets, Bcl-XL and cyclin D1.


Hepatitis A virus in stool during clinical relapse.
Among 256 patients with acute hepatitis A, 17 (6.6%) had a relapse of the disease between 30 and 90 days after the primary episode. We studied 7 of these patients. Serologic testing showed mean alanine aminotransferase levels of 1668 IU/L during the acute stage, 107 IU/L during the early convalescence, and 1027 IU/L during the relapse. Tests for IgM antibody against hepatitis A virus were positive in the 7 patients at the onset of disease, with decreasing levels in 3 of the 4 patients tested during the evolution of the illness. Stools collected during the relapse phase showed hepatitis A virus by immune electron microscopy, radioimmunoassay, and molecular hybridization using a 32P-labeled cDNA-hepatitis A virus probe. Stools collected from 4 of these patients 6 to 12 months after the onset of disease were negative for the virus. The finding of hepatitis A virus in the stool of these patients during the relapse phase strongly implicates hepatitis A virus as the causative agent of the clinical relapse.


Trypanosoma brucei BRCA2 acts in a life cycle-specific genome stability process and dictates BRC repeat number-dependent RAD51 subnuclear dynamics.
Trypanosoma brucei survives in mammals through antigenic variation, which is driven by RAD51-directed homologous recombination of Variant Surface Glycoproteins (VSG) genes, most of which reside in a subtelomeric repository of >1000 silent genes. A key regulator of RAD51 is BRCA2, which in T. brucei contains a dramatic expansion of a motif that mediates interaction with RAD51, termed the BRC repeats. BRCA2 mutants were made in both tsetse fly-derived and mammal-derived T. brucei, and we show that BRCA2 loss has less impact on the health of the former. In addition, we find that genome instability, a hallmark of BRCA2 loss in other organisms, is only seen in mammal-derived T. brucei. By generating cells expressing BRCA2 variants with altered BRC repeat numbers, we show that the BRC repeat expansion is crucial for RAD51 subnuclear dynamics after DNA damage. Finally, we document surprisingly limited co-localization of BRCA2 and RAD51 in the T. brucei nucleus, and we show that BRCA2 mutants display aberrant cell division, revealing a function distinct from BRC-mediated RAD51 interaction. We propose that BRCA2 acts to maintain the huge VSG repository of T. brucei, and this function has necessitated the evolution of extensive RAD51 interaction via the BRC repeats, allowing re-localization of the recombinase to general genome damage when needed.


Low back pain, sacroiliitis, and the relationship with HLA-B27 in Crohn's disease.
To determine the prevalence of sacroiliitis in patients who have back pain in Crohn's disease (CD) using computed tomography (CT); and to reassess the association of sacroiliitis in CD with HLA-B27. A total of 134 consecutive patients with CD completed a questionnaire about musculoskeletal symptoms. Those reporting low back pain were assessed, including plain radiographs and CT of the sacroiliac joints. HLA-B27 status was determined in patients with and without back pain. There were 70 (52%) patients with low back pain, of whom 31 (45%) had CT evidence of sacroiliitis. These were characterized by more frequent morning spinal stiffness and positive sacroiliac compression tests even when sacroiliitis was not suspected. Nine had previously recognized radiological and clinical ankylosing spondylitis (AS), and of these 78% were HLA-B27 positive. Of those with newly identified sacroiliitis, 14% were HLA-B27 positive. This frequency was not statistically dissimilar to the 9% HLA-B27 positivity of those without back pain. Sacroiliitis defined by CT is a common cause of low back pain in CD. A relationship of sacroiliitis and HLA-B27 could be confirmed only for those with classical AS. Our results accord with the possibility that sacroiliitis in CD is an isolated phenomenon, which is unrelated to HLA-B27 and which may evolve into classical spinal ankylosis in genetically susceptible subjects.


Factor VIII haplotypes frequencies in Tunisian hemophiliacs A.
The development of inhibitors against factor 8 (F8) is the most serious complication of replacement therapy with F8 in children with severe hemophilia. It was suggested that mismatched F8 replacement therapy may be a risk factor for the development of anti-factor F8 alloantibodies. Recently four single nucleotide polymorphisms (SNPs) encoding six distinct haplotypes, designated H1 through H6, were studied in different populations. Two SNPs are components of the A2 and C2 immunodominant-inhibitor epitopes.The aim of this study is to determine the different types of haplotypes in relation with inhibitors developments and their frequencies in our Tunisian hemophiliac population. 95/116 Tunisian patients with hemophilia A undergoing treatment at Hemophilia Treatment Center, Aziza Othmana hospital, participate in this study. Among them only six patients develop inhibitors. The four SNPs were amplified and sequenced. In a total of 77 patients, we identified the H1, H2, H3 and the infrequent H5 haplotypes. The H1 and H2 haplotypes, which have the same amino acid sequence in the recombinant F8 molecules used clinically, are the most represented with the frequency of 0.763 and 0.157 respectively. This distribution is almost similar to that of Caucasians in which the frequencies are respectively 0.926 and 0.074, whereas it is 0.354 and 0.374 among Subsaharians. Four patients with inhibitors studied here have the H1 haplotype. For one patient who has a large deletion including the exon 10 we can't identify his haplotype. Theses frequencies may explain partially the low level of inhibitors in our patients.


Immunonanoshells for targeted photothermal ablation of tumor cells.
Consisting of a silica core surrounded by a thin gold shell, nanoshells possess an optical tunability that spans the visible to the near infrared (NIR) region, a region where light penetrates tissues deeply. Conjugated with tumor-specific antibodies, NIR-absorbing immunonanoshells can preferentially bind to tumor cells. NIR light then heats the bound nanoshells, thus destroying the targeted cells. Antibodies can be consistently bound to the nanoshells via a bifunctional polyethylene glycol (PEG) linker at a density of approximately 150 antibodies per nanoshell. In vitro studies have confirmed the ability to selectively induce cell death with the photothermal interaction of immunonanoshells and NIR light. Prior to incubation with anti-human epidermal growth factor receptor (HER2) immunonanoshells, HER2-expressing SK-BR-3 breast carcinoma cells were seeded alone or adjacent to human dermal fibroblasts (HDFs). Anti-HER2 immunonanoshells bound to HER2-expressing cells resulted in the death of SK-BR-3 cells after NIR exposure only within the irradiated area, while HDFs remained viable after similar treatment since the immunonanoshells did not bind to these cells at high levels. Control nanoshells, conjugated with nonspecific anti-IgG or PEG, did not bind to either cell type, and cells continued to be viable after treatment with these control nanoshells and NIR irradiation.


Tea and other beverage consumption and prostate cancer risk: a Canadian retrospective cohort study.
Using participants in the 1970-1972 Nutrition Canada Survey (NCS), a retrospective cohort study was conducted to assess the relationship between tea, as well as coffee, cola and alcohol, and the risk of developing prostate cancer. The mortality and cancer experience of male NCS participants aged 50-84 years was determined up to 31 December 1993. Among the 3400 survey participants included in the study, 145 developed prostate cancer. No association was observed between tea (predominantly black tea) intake and prostate cancer. Subjects who drank more than 500 ml of tea per day experienced virtually the same risk as those who reported no tea consumption (rate ratio (RR) 1.02, 95% confidence interval (CI) 0.62-1.65). Compared to those who reported no coffee drinking, men who averaged more than 250-ml per day experienced a 40% increase in risk (95% CI 0.84-2.32). Cola consumption was not associated with an increased risk of prostate cancer. Total alcohol consumption was not related to subsequent development of prostate cancer, although very moderate consumption of wine (< 10 g per day), relative to no consumption, showed an RR of 1.48 (95% CI 1.05-2.09). These data do not support an association between consumption of tea and prostate cancer risk.


A method for defining a journal subset for a clinical discipline using the bibliographies of systematic reviews.
Searching for best evidence for clinical decisions in large biomedical databases is problematic because advances in health care practice that are ready for application are but a very dilute constituent in a much larger pool of biomedical literature. Sensitive search strategies have been developed to help alleviate this problem but search precision is still generally low. If "virtual journal subsets" that are likely to include all relevant articles can be defined for clinical discipline areas or disease content areas this will likely improve search precision. To determine whether studies cited in systematic literature reviews can define a journal subset for a given clinical discipline. Survey of the primary studies included in systematic reviews that are relevant to the clinical discipline of nephrology. Four data sources were searched to identify systematic reviews relevant to clinical nephrology: the Cochrane Database of Systematic Reviews, McMaster PLUS (Premium LiteratUre Service), MEDLINE, and the Renal Health Library. Three research assistants recorded data pertinent to each of the included primary studies. 195 systematic reviews relevant to nephrology were defined and the 2,779 unique original articles they cited were concentrated in 466 journals, with 90% of the articles in 217 titles. This journal subset can be stored online and used when searching the large biomedical data-bases such as MEDLINE. The bibliographies of systematic reviews can be used to define a journal subset for a clinical discipline area.


Calibration sample for arbitrary metrological characteristics of optical topography measuring instruments.
Areal optical surface topography measurement is an emerging technology for industrial quality control. However, neither calibration procedures nor the utilization of material measures are standardized. State of the art is the calibration of a set of metrological characteristics with multiple calibration samples (material measures). Here, we propose a new calibration sample (artefact) capable of providing the entire set of relevant metrological characteristics within only one single sample. Our calibration artefact features multiple material measures and is manufactured with two-photon laser lithography (direct laser writing, DLW). This enables a holistic calibration of areal topography measuring instruments with only one series of measurements and without changing the sample.


Isolates of Cryptococcus neoformans from infected animals reveal genetic exchange in unisexual, alpha mating type populations.
Sexual reproduction and genetic exchange are important for the evolution of fungal pathogens and for producing potentially infective spores. Studies to determine whether sex occurs in the pathogenic yeast Cryptococcus neoformans var. grubii have produced enigmatic results, however: basidiospores are the most likely infective propagules, and clinical isolates are fertile and genetically diverse, consistent with a sexual species, but almost all populations examined consist of a single mating type and have little evidence for genetic recombination. The choice of population is critical when looking for recombination, particularly when significant asexual propagation is likely and when latency may complicate assessing the origin of an isolate. We therefore selected isolates from infected animals living in the region of Sydney, Australia, with the assumption that the relatively short life spans and limited travels of the animal hosts would provide a very defined population. All isolates were mating type alpha and were of molecular genotype VNI or VNII. A lack of linkage disequilibrium among loci suggested that genetic exchange occurred within both genotype groups. Four diploid VNII isolates that produced filaments and basidium-like structures when cultured in proximity to an a mating type strain were found. Recent studies suggest that compatible alpha-alpha unions can occur in C. neoformans var. neoformans populations and in populations of the sibling species Cryptococcus gattii. As a mating type strains of C. neoformans var. grubii have never been found in Australia, or in the VNII molecular type globally, the potential for alpha-alpha unions is evidence that alpha-alpha unisexual mating maintains sexual recombination and diversity in this pathogen and may produce infectious propagules.


Activity-Based NIR Bioluminescence Probe Enables Discovery of Diet-Induced Modulation of the Tumor Microenvironment via Nitric Oxide.
Nitric oxide (NO) plays a critical role in acute and chronic inflammation. NO's contributions to cancer are of particular interest due to its context-dependent bioactivities. For example, immune cells initially produce cytotoxic quantities of NO in response to the nascent tumor. However, it is believed that this fades over time and reaches a concentration that supports the tumor microenvironment (TME). These complex dynamics are further complicated by other factors, such as diet and oxygenation, making it challenging to establish a complete picture of NO's impact on tumor progression. Although many activity-based sensing (ABS) probes for NO have been developed, only a small fraction have been employed in vivo, and fewer yet are practical in cancer models where the NO concentration is <200 nM. To overcome this outstanding challenge, we have developed BL660-NO, the first ABS probe for NIR bioluminescence imaging of NO in cancer. Owing to the low intrinsic background, high sensitivity, and deep tissue imaging capabilities of our design, BL660-NO was successfully employed to visualize endogenous NO in cellular systems, a human liver metastasis model, and a murine breast cancer model. Importantly, its exceptional performance facilitated two dietary studies which examine the impact of fat intake on NO and the TME. BL660-NO provides the first direct molecular evidence that intratumoral NO becomes elevated in mice fed a high-fat diet, which became obese with larger tumors, compared to control animals on a low-fat diet. These results indicate that an inflammatory diet can increase NO production via recruitment of macrophages and overexpression of inducible nitric oxide synthase which in turn can drive tumor progression.


Alkyl-Modified Oligonucleotides as Intercalating Vehicles for Doxorubicin Uptake via Albumin Binding.
DNA-based drug delivery vehicles have displayed promise for the delivery of intercalating drugs. Here, we demonstrate that oligonucleotides modified with an alkyl chain can bind to human serum albumin, mimicking the natural binding of fatty acids. These alkyl-DNA-albumin complexes display excellent serum stability and are capable of strongly binding doxorubicin. Complexes are internalized by cells in vitro, trafficking to the mitochondria, and are capable of delivering doxorubicin with excellent efficiency resulting in cell death. However, the cellular localization of the delivered doxorubicin, and ultimately the complex efficacy, is dependent on the nature of the linker between the alkyl group and the oligonucleotide.


Climatological determinants of woody cover in Africa.
Determining the factors that influence the distribution of woody vegetation cover and resolving the sensitivity of woody vegetation cover to shifts in environmental forcing are critical steps necessary to predict continental-scale responses of dryland ecosystems to climate change. We use a 6-year satellite data record of fractional woody vegetation cover and an 11-year daily precipitation record to investigate the climatological controls on woody vegetation cover across the African continent. We find that-as opposed to a relationship with only mean annual rainfall-the upper limit of fractional woody vegetation cover is strongly influenced by both the quantity and intensity of rainfall events. Using a set of statistics derived from the seasonal distribution of rainfall, we show that areas with similar seasonal rainfall totals have higher fractional woody cover if the local rainfall climatology consists of frequent, less intense precipitation events. Based on these observations, we develop a generalized response surface between rainfall climatology and maximum woody vegetation cover across the African continent. The normalized local gradient of this response surface is used as an estimator of ecosystem vegetation sensitivity to climatological variation. A comparison between predicted climate sensitivity patterns and observed shifts in both rainfall and vegetation during 2009 reveals both the importance of rainfall climatology in governing how ecosystems respond to interannual fluctuations in climate and the utility of our framework as a means to forecast continental-scale patterns of vegetation shifts in response to future climate change.


Lactation Leads to Modifications in Maternal Renin-Angiotensin System in Later Life.
The objective of this study was to evaluate whether the renin-angiotensin system (RAS) is associated with maternal cardioprotective phenotype observed in post-lactated mice later in life. Following the delivery, CD-1 female mice were randomized to one of the following groups: lactated (nursed pups for 3 weeks, n = 10) or non-lactated (pups were removed after birth, n = 10). The mice were sacrificed 6 months after the delivery, and tissues were collected. Protein levels of angiotensinogen, angiotensin type 1 and 2 receptors (AT1R, AT2R), angiotensin converting enzymes (ACE, ACE2), and MAS receptor were determined using Western blot. Results were analyzed using Student's t-test and Mann-Whitney test as appropriate (significance: P < 0.05). Angiotensinogen levels were significantly lower in the liver (P = 0.0002), and ACE was significantly decreased in the lungs (P = 0.04) and kidney (P = 0.001) from lactated mice as compared to non-lactated. The levels of AT2R in the kidney (P = 0.02) and visceral adipose tissue (VAT, P = 0.04), the ACE 2 in the VAT (P = 0.03) and heart (P = 0.04), and MAS receptor in VAT (P = 0.02) were significantly elevated in tissues from lactated mice. No other differences were found. Lactation led to the upregulation and downregulation of selected RAS components in lactated mice as compared to non-lactated group and may be a contributing factor to maternal cardioprotective phenotype later in life. Further studies are needed to dissect the mechanisms between lactation and the long-term maternal cardiometabolic benefits, which could lead to the therapies to prevent cardiovascular disease in women.


Protecting patients' privacy. Health information networks raise new questions.
Privacy is established as both a value and a right in our society, and as healthcare moves to improve quality and efficiency through the development of health information networks, which allow the electronic exchange of financial and clinical information, there will be a growing awareness of the necessity to protect patient privacy and confidentiality in these environments. Dealing with these concerns will require that healthcare providers take steps to ensure the security of patient information through technological and physical measures, programs of orientation and education, and the careful development and implementation of clear policies and procedures.


Cell death in age-related macular degeneration.
The cellular and molecular mechanisms underlying the death of photoreceptors and other retinal cells in age-related macular degeneration (AMD) remain poorly understood. Some of the questions for which answers need to be sought, and which are explicitly or implicitly addressed in this article include: (1) how do patterns of cell death in AMD compare, qualitatively and quantitatively, with "normal" cell death in aging retinas, and with cell death in retinitis pigmentosa (RP) and its animal models; (2) is apoptosis involved in AMD; (3) is there any evidence that rods are necessary for cone survival; (4) if the answer is yes, is there evidence that rods produce one or more survival-promoting factor(s) that act directly on cones; (5) are the effects of rods upon cones exclusively mediated by diffusible factors, or do they also involve contact-mediated interactions; (6) is there any evidence that photoreceptors regulate the survival and/or function of RPE and Müller cells, as well as the interactions between these cells and cones; (7) are trophic factors and their receptors in the macula different from those in other parts of the retina; and (8) are toxic mechanisms involved in the onset and progression of cell death in AMD? Clear cut answers to most of these (and related) questions about cell death in AMD are not yet available. The goal of this article is to summarize discussion that should help in the formulation of suitable hypotheses, amenable to experimental analysis. To provide a platform for such discussion, we present an overview of progress made in recent years in the analysis of other retinal degenerations and of neuronal degenerations in other regions of the CNS. We conclude with an overview of concepts and speculation derived from our current research.


Characterization of a cdc14 null allele in Drosophila melanogaster.
Cdc14 is an evolutionarily conserved serine/threonine phosphatase. Originally identified in Saccharomyces cerevisiae as a cell cycle regulator, its role in other eukaryotic organisms remains unclear. In Drosophila melanogaster, Cdc14 is encoded by a single gene, thus facilitating its study. We found that Cdc14 expression is highest in the testis of adult flies and that cdc14 null flies are viable. cdc14 null female and male flies do not display altered fertility. cdc14 null males, however, exhibit decreased sperm competitiveness. Previous studies have shown that Cdc14 plays a role in ciliogenesis during zebrafish development. In Drosophila, sensory neurons are ciliated. We found that the Drosophila cdc14 null mutants have defects in chemosensation and mechanosensation as indicated by decreased avoidance of repellant substances and decreased response to touch. In addition, we show that cdc14 null mutants have defects in lipid metabolism and resistance to starvation. These studies highlight the diversity of Cdc14 function in eukaryotes despite its structural conservation.


The value of 18F-FDG-PET/CT imaging for sinonasal malignant melanoma.
The aim this study was to evaluate imaging findings using position emission tomography (PET) in combination with computed tomography (CT) and 18F-fluorodeoxyglucose ((18)F-FDG) in sinonasal malignant melanoma (SNMM) of the head and neck in a retrospective analysis of a consecutive cohort of patients. (18)F-FDG-PET/CT examinations were performed for initial staging and compared with CT or magnetic resonance tomography (MRI), and (18)F-FDG-PET alone. Medical records were reviewed retrospectively with regard to the location and the size of the tumor. Furthermore, locoregional and distant metastases with a consecutive change in therapy detected by (18)F-FDG-PET/CT were assessed. Ten patients suffering from sinonasal malignant melanoma were staged and followed by (18)F-FDG-PET/CT imaging. A total of 34 examinations were obtained. (18)F-FDG-PET/CT depicted all primary tumors adequately. Aside from one cerebral metastasis all regional and distant metastases were truly identified by using this method. In summary, if available, (18)F-FDG-PET/CT is a valuable imaging modality for staging and re-staging sinonasal malignant melanoma to evaluate expansion of the primary tumor, locoregional disease, and distant metastases.


On-line social decision making and antisocial behavior: some essential but neglected issues.
The last quarter century has witnessed considerable progress in the scientific study of social information processing (SIP) and aggressive behavior in children. SIP research has shown that social decision making in youth is particularly predictive of antisocial behavior, especially as children enter and progress through adolescence. In furtherance of this research, more sophisticated, elaborate models of on-line social decision making have been developed, by which various domains of evaluative judgment are hypothesized to account for both responsive decision making and behavior, as well as self-initiated, instrumental functioning. However, discussions of these models have neglected a number of key issues. In particular, the roles of nonconscious cognitive factors, learning and development, impulsivity and behavioral disinhibition, emotion, and other internal and external factors (e.g., pharmacological influences and audience effects) have been largely absent from scholarly writings. In response, this article introduces discussion of these factors and reviews their possible roles in on-line social decision making and antisocial behavior in youth.


P. gingivalis lipopolysaccharide intensifies inflammation post-myocardial infarction through matrix metalloproteinase-9.
Periodontal disease (PD) strongly correlates with increased mortality post-myocardial infarction (MI); however, the underlying mechanisms are unknown. Matrix metalloproteinase (MMP)-9 levels directly correlate with dysfunction and remodeling of the left ventricle (LV) post-MI. Post-MI, MMP-9 is produced by leukocytes and modulates inflammation. We have shown that exposure to Porphyromonas gingivalis lipopolysaccharide (PgLPS), an immunomodulatory molecule identified in PD patients, increases LV MMP-9 levels in mice and leads to cardiac inflammation and dysfunction. The aim of the study was to determine if circulating PgLPS exacerbates the LV inflammatory response post-MI through MMP-9 dependent mechanisms. We exposed wild type C57BL/6J and MMP-9(-/-) mice to PgLPS (ATCC 33277) for a period of 28 days before performing MI, and continued to deliver PgLPS for up to 7 days post-MI. We found systemic levels of PgLPS 1) increased MMP-9 levels in both plasma and infarcted LV resulting in reduced wall thickness and increased incidence of LV rupture post-MI and 2) increased systemic and local macrophage chemotaxis leading to accelerated M1 macrophage infiltration post-MI and decreased LV function. MMP-9 deletion played a protective role by attenuating the inflammation induced by systemic delivery of PgLPS. In conclusion, MMP-9 deletion has a cardioprotective role against PgLPS exposure, by attenuating macrophage mediated inflammation.