Adhesive elastocapillary force on a cantilever beam.
This paper reports an experimental and theoretical investigation of a cantilever beam in contact with an underlying substrate, in the presence of an intervening liquid bridge. The beam is deflected in response to the adhesive capillary forces generated by the liquid. Three main regimes of contact are observed, similarly to other elastocapillary systems already reported in the literature. We measured both the position of the liquid meniscus and the force at the beam clamp in the direction normal to the substrate, as functions of the distance between the beam clamp and the substrate. The resulting force-displacement curve is not monotonic and it exhibits hysteresis in the second regime that we could attribute to solid-solid friction at the beam tip. In the third regime, the adhesive force measured at the clamp strongly increases as the beam approaches the substrate. A 2-dimensional beam model is proposed to rationalize these measurements. This model involves several non-linearities due to geometrical constraints, and its solution with a minimum of iterations is not trivial. The model correctly reproduces the force-displacement curve under two conditions: friction is considered in the second regime, and the reaction force applied by the substrate on the beam is distributed in the third regime. These results are discussed in the context of the adhesion of setal tips involved in the terrestrial locomotion of beetles.


Characterization of the sesame (Sesamum indicum L.) global transcriptome using Illumina paired-end sequencing and development of EST-SSR markers.
Sesame is an important oil crop, but limited transcriptomic and genomic data are currently available. This information is essential to clarify the fatty acid and lignan biosynthesis molecular mechanism. In addition, a shortage of sesame molecular markers limits the efficiency and accuracy of genetic breeding. High-throughput transcriptomic sequencing is essential to generate a large transcriptome sequence dataset for gene discovery and molecular marker development. Sesame transcriptomes from five tissues were sequenced using Illumina paired-end sequencing technology. The cleaned raw reads were assembled into a total of 86,222 unigenes with an average length of 629 bp. Of the unigenes, 46,584 (54.03%) had significant similarity with proteins in the NCBI nonredundant protein database and Swiss-Prot database (E-value < 10-5). Of these annotated unigenes, 10,805 and 27,588 unigenes were assigned to gene ontology categories and clusters of orthologous groups, respectively. In total, 22,003 (25.52%) unigenes were mapped onto 119 pathways using the Kyoto Encyclopedia of Genes and Genomes Pathway database (KEGG). Furthermore, 44,750 unigenes showed homology to 15,460 Arabidopsis genes based on BLASTx analysis against The Arabidopsis Information Resource (TAIR, Version 10) and revealed relatively high gene coverage. In total, 7,702 unigenes were converted into SSR markers (EST-SSR). Dinucleotide SSRs were the dominant repeat motif (67.07%, 5,166), followed by trinucleotide (24.89%, 1,917), tetranucleotide (4.31%, 332), hexanucleotide (2.62%, 202), and pentanucleotide (1.10%, 85) SSRs. AG/CT (46.29%) was the dominant repeat motif, followed by AC/GT (16.07%), AT/AT (10.53%), AAG/CTT (6.23%), and AGG/CCT (3.39%). Fifty EST-SSRs were randomly selected to validate amplification and to determine the degree of polymorphism in the genomic DNA pools. Forty primer pairs successfully amplified DNA fragments and detected significant amounts of polymorphism among 24 sesame accessions. This study demonstrates that Illumina paired-end sequencing is a fast and cost-effective approach to gene discovery and molecular marker development in non-model organisms. Our results provide a comprehensive sequence resource for sesame research.


Blocking HIV-1 Infection by Chromosomal Integrative Expression of Human CD4 on the Surface of Lactobacillus acidophilus ATCC 4356.
Lactobacillus bacteria are potential delivery vehicles for biopharmaceutical molecules because they are well-recognized as safe microorganisms that naturally inhabit the human body. The goal of this study was to employ these lactobacilli to combat human immunodeficiency virus type 1 (HIV-1) infection and transmission. By using a chromosomal integration method, we engineered Lactobacillus acidophilus ATCC 4356 to display human CD4, the HIV-1 receptor, on the cell surface. Since human CD4 can bind to any infectious HIV-1 particles, the engineered lactobacilli can potentially capture HIV-1 of different subtypes and prevent infection. Our data demonstrate that the CD4-carrying bacteria are able to adsorb HIV-1 particles and reduce infection significantly in vitro and also block intrarectal HIV-1 infection in a humanized mouse model in preliminary tests in vivo Our results support the potential of this approach to decrease the efficiency of HIV-1 sexual transmission.IMPORTANCE In the absence of an effective vaccine, alternative approaches to block HIV-1 infection and transmission with commensal bacteria expressing antiviral proteins are being considered. This report provides a proof-of-concept by using Lactobacillus bacteria stably expressing the HIV-1 receptor CD4 to capture and neutralize HIV-1 in vitro and in a humanized mouse model. The stable expression of antiviral proteins, such as CD4, following genomic integration of the corresponding genes into this Lactobacillus strain may contribute to the prevention of HIV-1 sexual transmission.


Surgeon leadership in the coding, billing, and contractual negotiations for fenestrated endovascular aortic aneurysm repair increases medical center contribution margin and physician reimbursement.
Fenestrated endovascular aneurysm repair (FEVAR) allows endovascular treatment of thoracoabdominal and juxtarenal aneurysms previously outside the indications of use for standard devices. However, because of considerable device costs and increased procedure time, FEVAR is thought to result in financial losses for medical centers and physicians. We hypothesized that surgeon leadership in the coding, billing, and contractual negotiations for FEVAR procedures will increase medical center contribution margin (CM) and physician reimbursement. At the UMass Memorial Center for Complex Aortic Disease, a vascular surgeon with experience in medical finances is supported to manage the billing and coding of FEVAR procedures for medical center and physician reimbursement. A comprehensive financial analysis was performed for all FEVAR procedures (2011-2015), independent of insurance status, patient presentation, or type of device used. Medical center CM (actual reimbursement minus direct costs) was determined for each index FEVAR procedure and for all related subsequent procedures, inpatient or outpatient, 3 months before and 1 year subsequent to the index FEVAR procedure. Medical center CM for outpatient clinic visits, radiology examinations, vascular laboratory studies, and cardiology and pulmonary evaluations related to FEVAR were also determined. Surgeon reimbursement for index FEVAR procedure, related adjunct procedures, and assistant surgeon reimbursement were also calculated. All financial analyses were performed and adjudicated by the UMass Department of Finance. The index hospitalization for 63 FEVAR procedures incurred $2,776,726 of direct costs and generated $3,027,887 in reimbursement, resulting in a positive CM of $251,160. Subsequent related hospital procedures (n = 26) generated a CM of $144,473. Outpatient clinic visits, radiologic examinations, and vascular laboratory studies generated an additional CM of $96,888. Direct cost analysis revealed that grafts accounted for the largest proportion of costs (55%), followed by supplies (12%), bed (12%), and operating room (10%). Total medical center CM for all FEVAR services was $492,521. Average surgeon reimbursements per FEVAR from 2011 to 2015 increased from $1601 to $2480 while the surgeon payment denial rate declined from 50% to 0%. Surgeon-led negotiations with the Centers for Medicare & Medicaid Services during 2015 resulted in a 27% increase in physician reimbursement for the remainder of 2015 ($2480 vs $3068/case) and a 91% increase in reimbursement from 2011 ($1601 vs $3068). Assistant surgeon reimbursement also increased ($266 vs $764). Concomitant FEVAR-related procedures generated an additional $27,347 in surgeon reimbursement. Physician leadership in the coding, billing, and contractual negotiations for FEVAR results in a positive medical center CM and increased physician reimbursement.


Efficient table-top dual-wavelength beamline for ultrafast transient absorption spectroscopy in the soft X-ray region.
We present a table-top beamline providing a soft X-ray supercontinuum extending up to 370 eV from high-order harmonic generation with sub-13 fs 1300 nm driving pulses and simultaneous production of sub-5 fs pulses centered at 800 nm. Optimization of high harmonic generation in a long and dense gas medium yields a photon flux of ~ 1.4 × 106 photons/s/1% bandwidth at 300 eV. The temporal resolution of X-ray transient absorption experiments with this beamline is measured to be 11 fs for 800 nm excitation. This dual-wavelength approach, combined with high flux and high spectral and temporal resolution soft X-ray absorption spectroscopy, is a new route to the study of ultrafast electronic dynamics in carbon-containing molecules and materials at the carbon K-edge.


Development of Thyroid-Associated Ophthalmopathy in Patients Who Underwent Total Thyroidectomy.
To report clinical characteristics of thyroid-associated ophthalmopathy (TAO) in patients who previously underwent total thyroidectomy for thyroid cancer or a benign mass of the thyroid. Of the patients who were diagnosed with TAO from March 2008 to March 2012, we performed a retrospective chart review on those who had undergone total thyroidectomy for thyroid cancer or a benign mass of the thyroid before the occurrence of ophthalmopathy. Of the 206 patients diagnosed with TAO, seven (3.4%) met the inclusion criteria. The mean age of the subjects was 47.4 years, and all were female. Six patients were diagnosed with papillary thyroid cancer, and one was diagnosed with a benign mass. The duration between total thyroidectomy and onset of TAO ranged from 3-120 months (median 48 months). Ophthalmic manifestations varied among cases. Except for the patient who was diagnosed with a benign mass, all patients showed hyperthyroid status and were under Synthroid hormone treatment at the time of TAO development. Five of these six patients had positive levels of thyroid-stimulating hormone (TSH) receptor autoantibodies. TAO rarely develops after total thyroidectomy, and the mechanism of TAO occurrence is unclear. However, most patients showed abnormalities in thyroid function and TSH receptor autoantibodies.


A robust quantitative solid phase immunoassay for the acute phase protein C-reactive protein (CRP) based on cytidine 5'-diphosphocholine coupled dendrimers.
C-reactive protein (CRP) is an important acute phase protein, being used as a sensitive indicator of inflammation and infection and is also associated with the risk of cardiovascular problems. The present paper describes a robust and sensitive ELISA for CRP, based on the affinity of CRP for phosphocholine. In this design synthetic globular polymers (dendrimers) are used as scaffolds for the multivalent display of phosphocholine molecules. CRP present in a sample binds to the phosphocholine moiety presented at high density in the coating layer and is detectable by specific antibodies. The ELISA was applied to determination of pig and human CRP using commercially available antibodies against human CRP. The assay was shown to be more sensitive than previously published immunoassays employing albumin-coupled cytidine diphosphocholine. The coating was stable for at least 30 days at room temperature and the assay showed high intra- and interassay reproducibility. Results were compared with an immunoturbidimetric method and with a commercial ELISA kit and there was very good agreement with the immunoturbidimetric method, however not with the commercial assay, probably due to a calibration discrepancy. The assay is applicable to other species by providing an adequate detection antibody having the desired species specificity.


The management of infections in children in general practice in Sweden: a repeated 1-week diagnosis-prescribing study in 5 counties in 2000 and 2002.
A diagnosis-prescribing study was performed in 5 Swedish counties during 1 week in November in 2000 and repeated in 2002. The aim of the present study was to analyse data for children 0-15y of age who consulted a general practitioner with symptoms of an infection. During the 2 weeks studied, 4049 children were consulted. Respiratory tract infections (RTI) were the predominant diagnoses, above all among the youngest children, while the proportion of urinary tract infections and skin infections increased with increasing age. Between the y 2000 and 2002, the proportion of children allocated the diagnosis streptococcal tonsillitis and pneumonia decreased (p<0.01 and p<0.001, respectively) while the proportion of common cold increased (p<0.001). Antibiotic prescribing decreased from 55% to 48% (p<0.001) for respiratory infections between the years studied. The only significant changes in type of antibiotics prescribed were the increase of isoxazolylpenicillins (p<0.001) used for skin infection and the decrease of macrolides (p=0.001). A diagnostic test was used in more than half of the consultations. Of children allocated a RTI diagnosis, 36% were prescribed antibiotics when a C-reactive protein test was performed compared to 58% in those not tested. Further studies are needed in general practice to determine the optimal use of near-patient tests in children with RTI.


The establishment of an intracranial tumour registry at the University Hospital of the West Indies.
In March 2010, the first intracranial tumour registry (ITR) in the English-speaking Caribbean was started at the University Hospital of the West Indies (UHWI). This was deemed necessary as the already established Jamaica Cancer Registry only reports on malignant brain tumours. The ITR will collect data on all prospective intracranial tumours, benign and malignant, which are diagnosed histologically at the UHWI. Retrospective information dating back five years was also collected. Data collected so far reveal that between the years 2006 to 2010, a total of 317 cases were entered into the database. Of these, only 45 cases were considered eligible. The issues surrounding this discrepancy are discussed in this paper along with the many challenges experienced in the establishment of the ITR. From these experiences, the authors have also put forward several recommendations that may be useful to other researchers who wish to implement similar systems.


Only adding stationary storage to vaccine supply chains may create and worsen transport bottlenecks.
Although vaccine supply chains in many countries require additional stationary storage and transport capacity to meet current and future needs, international donors tend to donate stationary storage devices far more often than transport equipment. To investigate the impact of only adding stationary storage equipment on the capacity requirements of transport devices and vehicles, we used HERMES (Highly Extensible Resource for Modeling Supply Chains) to construct a discrete event simulation model of the Niger vaccine supply chain. We measured the transport capacity requirement for each mode of transport used in the Niger vaccine cold chain, both before and after adding cold rooms and refrigerators to relieve all stationary storage constraints in the system. With the addition of necessary stationary storage, the average transport capacity requirement increased from 88% to 144% for cold trucks, from 101% to 197% for pickup trucks, and from 366% to 420% for vaccine carriers. Therefore, adding stationary storage alone may worsen or create new transport bottlenecks as more vaccines flow through the system, preventing many vaccines from reaching their target populations. Dynamic modeling can reveal such relationships between stationary storage capacity and transport constraints.


The mechanism of DNA repair by uracil-DNA glycosylase: studies using nucleotide analogues.
2',4'-Dideoxy-4'-methyleneuridine incorporated into oligodeoxynucleotides forms regular B-DNA duplexes as shown by Tm and CD measurements. Such oligomers are not cleaved by the DNA repair enzyme, UDG, which cleaves the glycosylic bond in dU but not in dT nor in dC nucleosides in single stranded and double stranded DNA. Differential binding of oligomers containing carbadU, 4'-thiodU, and dU residues to wild type and mutant UDG proteins identify an essential role for the furanose 4'-oxygen in recognition and cleavage of dU residues in DNA.


Avemar and Echinacea extracts enhance mobilization and homing of CD34(+) stem cells in rats with acute myocardial infarction.
Activation of endogenous stem cell mobilization can contribute to myocardial regeneration after ischemic injury. This study aimed to evaluate the possible role of Avemar or Echinacea extracts in inducing mobilization and homing of CD34(+) stem cells in relation to the inflammatory and hematopoietic cytokines in rats suffering from acute myocardial infarction (AMI). AMI was developed by two consecutive subcutaneous injections of isoprenaline (85 mg/kg). AMI rats were either post-treated or pre- and post-treated daily with oral doses of Avemar (121 mg/kg) or Echinacea (130 mg/kg). In whole blood, the number of CD34(+) cells was measured by flow cytometry and their homing to the myocardium was immunohistochemically assessed. Serum creatine kinase, vascular endothelial growth factor, interleukin-8 and granulocyte macrophage colony stimulating factor were determined on days 1, 7 and 14 after AMI. Sections of the myocardium were histopathologically assessed. Rats pre- and post-treated with Avemar or Echinacea exhibited substantial increases in the number of circulating CD34(+) cells, peaking on the first day after AMI to approximately 13-fold and 15-fold, respectively, with a decline in their level on day 7 followed by a significant increase on day 14 compared to their corresponding AMI levels. Only post-treatment with Echinacea caused a time-dependent increase in circulating CD34(+) cells on days 7 and 14. Such increases in circulating CD34(+) cells were accompanied by increased homing to myocardial tissue 14 days after AMI. Interestingly, pre- and post-treatment with Avemar or Echinacea substantially increased serum creatine kinase on day 1, normalized its activity on day 7 and, on continued treatment, only Echinacea markedly increased its activity on day 14 compared to the corresponding AMI values. Moreover, both treatments modified differently the elevated serum vascular endothelial growth factor and the lowered granulocyte macrophage colony stimulating factor levels of the AMI group but did not affect the level of interleukin-8. These results were supported histopathologically by reduced inflammatory reactions and enhanced neovascularization. Avemar and Echinacea extracts can effectively induce mobilization and homing of CD34(+) stem cells to the myocardial tissue and thus may help in stem cell-based regeneration of the infarcted myocardium.


Detection and quantification of new psychoactive substances (NPSs) within the evolved "legal high" product, NRG-2, using high performance liquid chromatography-amperometric detection (HPLC-AD).
The global increase in the production and abuse of cathinone-derived New Psychoactive Substances (NPSs) has developed the requirement for rapid, selective and sensitive protocols for their separation and detection. Electrochemical sensing of these compounds has been demonstrated to be an effective method for the in-field detection of these substances, either in their pure form or in the presence of common adulterants, however, the technique is limited in its ability to discriminate between structurally related cathinone-derivatives (for example: (±)-4′-methylmethcathinone (4-MMC, 2a) and (±)-4′-methyl-N-ethylmethcathinone (4-MEC, 2b) when they are both present in a mixture. In this paper we demonstrate, for the first time, the combination of HPLC-UV with amperometric detection (HPLC-AD) for the qualitative and quantitative analysis of 4-MMC and 4-MEC using either a commercially available impinging jet (LC-FC-A) or custom-made iCell channel (LC-FC-B) flow-cell system incorporating embedded graphite screen-printed macroelectrodes. The protocol offers a cost-effective, reproducible and reliable sensor platform for the simultaneous HPLC-UV and amperometric detection of the target analytes. The two systems have similar limits of detection, in terms of amperometric detection [LC-FC-A: 14.66 μg mL(-1) (2a) and 9.35 μg mL(-1) (2b); LC-FC-B: 57.92 μg mL(-1) (2a) and 26.91 μg mL(-1) (2b)], to the previously reported oxidative electrochemical protocol [39.8 μg mL(-1) (2a) and 84.2 μg mL(-1) (2b)], for two synthetic cathinones, prevalent on the recreational drugs market. Though not as sensitive as standard HPLC-UV detection, both flow cells show a good agreement, between the quantitative electroanalytical data, thereby making them suitable for the detection and quantification of 4-MMC and 4-MEC, either in their pure form or within complex mixtures. Additionally, the simultaneous HPLC-UV and amperometric detection protocol detailed herein shows a marked improvement and advantage over previously reported electroanalytical methods, which were either unable to selectively discriminate between structurally related synthetic cathinones (e.g. 4-MMC and 4-MEC) or utilised harmful and restrictive materials in their design.


Earthworm-Driven Changes in Soil Chemico-Physical Properties, Soil Bacterial Microbiota, Tree/Tea Litter Decomposition, and Plant Growth in a Mesocosm Experiment with Two Plant Species.
Earthworms and soil microorganisms contribute to soil health, quality, and fertility, but their importance in agricultural soils is often underestimated. This study aims at examining whether and to what extent the presence of earthworms (Eisenia sp.) affected the (a) soil bacterial community composition, (b) litter decomposition, and (c) plant growth (Brassica oleracea L., broccoli; Vicia faba L., faba bean). We performed a mesocosm experiment in which plants were grown outdoors for four months with or without earthworms. Soil bacterial community structure was evaluated by a 16S rRNA-based metabarcoding approach. Litter decomposition rates were determined by using the tea bag index (TBI) and litter bags (olive residues). Earthworm numbers almost doubled throughout the experimental period. Independently of the plant species, earthworm presence had a significant impact on the structure of soil bacterial community, in terms of enhanced α- and β-diversity (especially that of Proteobacteria, Bacteroidota, Myxococcota, and Verrucomicrobia) and increased 16S rRNA gene abundance (+89% in broccoli and +223% in faba bean). Microbial decomposition (TBI) was enhanced in the treatments with earthworms, and showed a significantly higher decomposition rate constant (kTBI) and a lower stabilization factor (STBI), whereas decomposition in the litter bags (dlitter) increased by about 6% in broccoli and 5% in faba bean. Earthworms significantly enhanced root growth (in terms of total length and fresh weight) of both plant species. Our results show the strong influence of earthworms and crop identity in shaping soil chemico-physical properties, soil bacterial community, litter decomposition and plant growth. These findings could be used for developing nature-based solutions that ensure the long-term biological sustainability of soil agro- and natural ecosystems.


Long-term patient reported outcomes following acetabular fracture fixation.
Patient reported outcome scores may be the preferred method to assess clinical results following acetabular fracture fixation. However, in current acetabular fracture research, there is a scarcity of studies using these scores and long-term follow-up is lacking. The aim of this study is to describe long-term patient reported outcomes following acetabular fracture surgery and to evaluate the association between reduction quality and these outcome measures. Patients who received operative fixation for acetabular fractures (1992-2012) were sent questionnaires (short musculoskeletal functional assessment (SMFA) function index and short form (SF)-12), which was returned by 106 patients (22%) (mean age 51 years, 74% male). Mean follow-up was 11.3 years and hip survivorship 78%. Reduction quality was assessed on postoperative CT or plain pelvic radiography (PXR) (3 patients). Reductions were graded as adequate (CT: <1 mm step and <5 mm gap/PXR: ≤3 mm displacement) or inadequate (CT: ≥1 mm step and/or ≥5 mm gap/PXR: >3 mm displacement). Outcome scores between native hip versus total hip arthroplasty (THA) and adequate versus inadequate reduction groups were compared and association between reduction quality and hip survivorship was determined. Subgroup analysis was performed in older patients (≥50 years). Patients with native hips reported overall superior relevant outcome scores (SMFA function index (p = 0.047), mobility (p = 0.048) and SF-12 physical component (p = 0.008)) compared to THA patients. Hip survivorship was associated with adequate reductions (p = 0.019). In the native hip group, an adequate reduction was also associated with lower (better) clinical scores (exceeding the minimal clinical important difference) (MCID) specifically for SMFA function index (p = 0.117) and mobility (p = 0.022). In elderly patients, the native hip versus THA group had similar outcomes, and adequate reductions were associated with hip survivorship as well as superior clinical scores (at least exceeding the MCID) in those who retained their native hip. At long-term follow-up, acetabular fracture surgery is associated with excellent patient reported outcomes. Patients who retain their native hip have overall superior relevant (SMFA and SF-12) function scores compared to those who convert to THA. Adequate reductions (on CT) were associated with both hip survivorship and superior outcome scores in patients who retain their hip.


SOD mimetic improves the function, growth, and survival of small-size liver grafts after transplantation in rats.
Small-for-size syndrome (SFSS) may occur when graft volume is less than 45% of the standard liver volume, and it manifests as retarded growth and failure of the grafts and more mortality. However, its pathogenesis is poorly understood, and few effective interventions have been attempted. The present study aimed to delineate the critical role of oxidant stress in SFSS and protective effects of a superoxide dismutase mimetic, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), on graft function, growth, and survival in the recipient rats. Small size graft liver transplantation (SSGLT) was performed to determine the survival, graft injury, and growth. MnTBAP was administered in SSGLT recipients (SSGLT+MnTBAP). Serum alanine aminotransferase levels were sustained higher in SSGLT recipients, which were correlated with an increased apoptotic cell count and hepatocellular necrosis in liver sections. Malondialdehyde content, gene expression of tumor necrosis factor α and interleukin 1β, and DNA binding activity of nuclear factor-κB in the grafts were increased significantly in SSGLT recipients compared with sham-operated controls. Both phosphorylated p38 mitogen-activated protein kinase and nuclear c-Jun were increased in SSGLT. All these changes were strikingly reversed by the administration of MnTBAP, with an increase in serum superoxide dismutase activity. Moreover, in situ bromodeoxyuridine incorporation demonstrated that graft regeneration was much more profound in the SSGLT+MnTBAP group than in the SSGLT group. Finally, the survival of recipients with MnTBAP treatments was significantly improved. Enhanced oxidant stress with activation of the p38/c-Jun/nuclear factor-κB signaling pathway contributes to SFSS-associated graft failure, retarded graft growth, and poor survival. MnTBAP effectively reversed the pathologic changes in SFSS-associated graft failure.


An Autopsy Case of Rupture of Infectious Thoracic Aortitis Induced by Methicillin-Resistant Staphylococcus Aureus.
BACKGROUND Infectious aortitis has a poor prognosis and high mortality rate if untreated. Here, we report a case of rupture of infectious aortitis induced by methicillin-resistant staphylococcus aureus (MRSA). CASE REPORT An 83-year-old female patient was hospitalized due to continuous fever and diarrhea, which was diagnosed as colitis. The colitis was determined to have been induced by small vessel vasculitis upon histological examination. Fasting and central venous hyperalimentation using a peripherally inserted central catheter (PICC) were carried out for rest of the intestine. Swelling and pus were observed at the insertion site of the PICC. Since methicillin resistant staphylococcus aureus (MRSA) was detected in the culture of the pus and the blood, the patient was treated with vancomycin. After confirming that the blood culture became negative, prednisolone (PDL) was started as therapy for the colitis. Her diarrhea and fever improved. After vancomycin was stopped, MRSA-arthritis appeared. She suddenly died due to acute massive hemorrhage into the mediastinum and left thoracic cavity from the atherosclerotic ulcer of the thoracic aorta. It took 98 days from the first detection of MRSA in her blood to her death. We found gram-positive coccus in the ruptured aortic ulcer and we also detected MRSA gene by polymerase chain reaction in the ulcer. These results suggest that MRSA could colonize in the aortic ulcer during the MRSA-bacteremia and the MRSA could contribute to the vulnerability of the aortic wall. CONCLUSIONS After septicemia occurrs in an elderly person, the patient should be followed up by considering infectious aortitis, especially when the patient has several risk factors.


An Office-Initiated Multilevel Intervention for Tobacco Smoke Exposure: A Randomized Trial.
Provider adherence to best practice guidelines (ask, advise, refer [AAR]) for addressing child tobacco smoke exposure (TSE) motivates parents to reduce TSE. However, high-risk, vulnerable populations of smokers may require more intensive treatment. We hypothesized that a pragmatic, multilevel treatment model including AAR coupled with individualized, telephone-based behavioral counseling promoting child TSE reduction would demonstrate greater child TSE reduction than would standard AAR. In this 2-arm randomized controlled trial, we trained pediatric providers in systems serving low-income communities to improve AAR adherence by using decision aid prompts embedded in routine electronic health record assessments. Providers faxed referrals to the study and received ongoing AAR adherence feedback. Referred participants were eligible if they were daily smokers, >17 years old, and spoke English. Participants were randomly assigned to telephone-based behavioral counseling (AAR and counseling) or nutrition education (AAR and attention control). Participants completed prerandomization and 3-month follow-up assessments. Of providers, >80% (n = 334) adhered to AAR procedures and faxed 2949 referrals. Participants (n = 327) were 83% women, 83% African American, and 79% low income (below poverty level). Intention-to-treat logistic regression showed robust, positive treatment effects: more parents in AAR and counseling than in AAR and attention control eliminated all sources of TSE (45.8% vs 29.9%; odds ratio 1.99 [95% confidence interval 1.44-2.74]) and quit smoking (28.2% vs 8.2%; odds ratio 3.78 [95% confidence interval 1.51-9.52]). The results indicate that the integration of clinic- and individual-level smoking interventions produces improved TSE and cessation outcomes relative to standalone clinic AAR intervention. Moreover, this study was among the first in which researchers demonstrated success in embedding AAR decision aids into electronic health records and seamlessly facilitated TSE intervention into routine clinic practice.


Drivers of workplace discrimination against people with disabilities: the utility of Attribution Theory.
The purpose of this paper was to determine what drives workplace discrimination against people with disabilities. These findings are then compared to available literature on attribution theory, which concerns itself with public perceptions of the controllability and stability of various impairments. The sample included 35,763 allegations of discriminations filed by people with disabilities under the employment provisions of the Americans with Disabilities Act. Group A included impairments deemed by Corrigan et al. [1988] to be uncontrollable but stable: visual impairment (representing 13% of the total allegations in this study), cancer (12%), cardiovascular disease (19%), and spinal cord injuries (5%). The controllable but unstable impairments in group B included depression (38%), schizophrenia (2%), alcohol and other drug abuse (4%), and HIV/AIDS (7%). The Equal Employment Opportunity Commission had resolved all allegations in terms of merit Resolutions (a positive finding of discrimination) and Resolutions without merit. Allegations of workplace discrimination were found to center mainly on hiring, discharge, harassment, and reasonable accommodation issues. Perceived workplace discrimination (as measured by allegations filed with EEOC) does occur at higher levels in Group B, especially when serious issues involving discharge and disability harassment are involved. With the glaring exception of HIV/AIDS, however, actual discrimination (as measured by EEOC merit Resolutions) occurs at higher levels for Group A.


Computed tomography angiography of coarctation of the aorta in a dog.
Coarctation of the aorta has been described previously as either a post-mortem or angiographic finding in three dogs with clinical signs related to the aortic coarctation. A 10-year-old dog was presented for evaluation of suspected laryngeal paralysis. On physical examination, femoral pulses were absent bilaterally, with an indirect systolic blood pressure difference of 60 mmHg between the ipsilateral thoracic and pelvic limbs. Coarctation of the aorta was detected on a thoracic computed tomographic angiography study. The coarctation was pre-ductal in position, with extensive dilation of the descending thoracic aorta. Characteristic rib changes that are seen in humans with coarctation were not apparent in this dog. 3D reconstructions of the thorax provided high vascular definition with exact localization of the aortic narrowing.


Clinical Characteristics and Prognosis of Pregnancy-Associated Breast Cancer: Poor Survival of Luminal B Subtype.
Pregnancy-associated breast cancer (PABC) is rare and is generally defined as breast cancer diagnosed during pregnancy or within 1 year of delivery. The average ages of marriage and childbearing are increasing, and PABC is expected to also increase. This study is intended to increase understanding of the characteristics of PABC. A database of 2,810 patients with breast cancer diagnosed when they were less than 40 years of age was reviewed. The clinicopathological factors and survival of PABC (40 patients) were compared to those of patients with young breast cancer (YBC, non-pregnant or over 12 months after delivery; 2,770 patients). PABC had significantly lower estrogen receptor (ER) and progesterone receptor (PR) expression (ER-positive 50.0%, PR-positive 45.0%) and higher HER2 overexpression (38.5%) than YBC. The most common subtype of PABC was triple-negative breast cancer (TNBC; 35.9%), and luminal A subtype represented only 7.7% of cases. In univariate analysis, PABC had significantly worse disease-free survival (DFS) and breast cancer-specific survival (BCSS) compared to YBC. In multivariate analysis, PABC was associated with worse BCSS (HR 4.0, 95% CI 1.2-12.9, p = 0.019) and survival, but there was no difference in DFS between PABC and YBC. In subgroup analysis by subtype, luminal B subtype of PABC showed worse DFS (HR 3.5; 95% CI 1.1-11.2, p = 0.039) and BCSS (HR 10.2, 95% CI 1.2-87.1, p = 0.035), especially with high Ki67. However, no differences were demonstrated in other subtypes. In this study, PABC showed lower expression of ER/PR, higher overexpression of HER2, fewer luminal A subtype, and more TNBC subtype compared to YBC. PABC had worse BCSS, especially luminal B subtype, compared to YBC.


Site-directed MT1-MMP trafficking and surface insertion regulate AChR clustering and remodeling at developing NMJs.
At vertebrate neuromuscular junctions (NMJs), the synaptic basal lamina contains different extracellular matrix (ECM) proteins and synaptogenic factors that induce and maintain synaptic specializations. Here, we report that podosome-like structures (PLSs) induced by ubiquitous ECM proteins regulate the formation and remodeling of acetylcholine receptor (AChR) clusters via focal ECM degradation. Mechanistically, ECM degradation is mediated by PLS-directed trafficking and surface insertion of membrane-type 1 matrix metalloproteinase (MT1-MMP) to AChR clusters through microtubule-capturing mechanisms. Upon synaptic induction, MT1-MMP plays a crucial role in the recruitment of aneural AChR clusters for the assembly of postsynaptic specializations. Lastly, the structural defects of NMJs in embryonic MT1-MMP-/- mice further demonstrate the physiological role of MT1-MMP in normal NMJ development. Collectively, this study suggests that postsynaptic MT1-MMP serves as a molecular switch to synaptogenesis by modulating local ECM environment for the deposition of synaptogenic signals that regulate postsynaptic differentiation at developing NMJs.


Evidence for greater burden of peripheral arterial disease in lower extremity arteries of spinal cord-injured individuals.
Spinal cord injury leads to increased risk for cardiovascular disease and results in greater risk of death. Subclinical markers of atherosclerosis have been reported in carotid arteries of spinal cord-injured individuals (SCI), but the development of lower extremity peripheral arterial disease (PAD) has not been investigated in this population. The purpose of this study was to determine the effect of spinal cord injury on ankle-brachial index (ABI) and intima-media thickness (IMT) of upper-body and lower-extremity arteries. We hypothesized that the aforementioned measures of lower-extremity PAD would be worsened in SCI compared with controls and that regular participation in endurance exercise would improve these in both groups. To test these hypotheses, ABI and IMT were determined in 105 SCI and compared with 156 able-bodied controls with groups further subdivided into physically active and sedentary. ABIs were significantly lower in SCI versus controls (0.96 ± 0.12 vs. 1.06 ± 0.07, P < 0.001), indicating a greater burden of lower-extremity PAD. Upper-body IMTs were similar for brachial and carotid arteries in controls versus SCI. Lower extremity IMTs revealed similar thicknesses for both superficial femoral and popliteal arteries, but when normalized for artery diameter, individuals with SCI had greater IMT than controls in the superficial femoral (0.094 ± 0.03 vs. 0.073 ± 0.02 mm/mm lumen diameter, P < 0.01) and popliteal (0.117 ± 0.04 vs. 0.091 ± 0.02 mm/mm lumen diameter, P < 0.01) arteries. The ABI and normalized IMT of SCI compared with controls indicate that subclinical measures of lower-extremity PAD are worsened in individuals with SCI. These findings should prompt physicians to consider using the ABI as a screening method to detect lower-extremity PAD in SCI.


On the evolutionary ecology of host-parasite interactions: addressing the question with regard to bumblebees and their parasites.
Over the last decade, there has been a major shift in the study of adaptive patterns and processes towards including the role of host-parasite interactions, informed by concepts from evolutionary ecology. As a consequence, a number of major questions have emerged. For example, how genetics affects host-parasite interactions, whether parasitism selects for offspring diversification, whether parasite virulence is an adaptive trait, and what constrains the use of the host's immune defences. Using bumblebees, Bombus spp, and their parasites as a model system, answers to some of these questions have been found, while at the same time the complexity of the interaction has led expectations away from simple theoretical models. In addition, the results have also led to the unexpected discovery of novel phenomena concerning, for instance, female mating strategies.


The effect of time between handling and photoactivation on self-adhesive resin cement properties.
To evaluate the degree of conversion, absorption, and solubility in water of self-adhesive resin cements subjected to different time intervals between material preparation and the photoactivation procedure. Two dual self-adhesive resin cements were tested: RelyX Unicem and SmartCem2. The degree of conversion as a function of time was evaluated by Fourier-transformed infrared spectroscopy using the attenuated total reflectance technique. Three time intervals between handling and photoactivation were applied: Group 1 = immediately; Group 2 = a 1-minute interval; Group 3 = a 4-minute interval. All specimens were irradiated with a light-emitting diode source for 40 seconds. Thirty discs of each cement (1 mm thick × 6 mm diameter, n = 10) were prepared for the absorption and solubility tests. These specimens were stored in distilled water at 37°C for 90 days. The results were subjected to ANOVA with two factors (material and activation time intervals) and Tukey's test (95% significance). The 4-minute interval significantly reduced the degree of conversion of SmartCem2 (30.6% ± 8.3%). No other significant changes were observed for the degree of conversion; however, the time intervals before photoactivation interfered significantly in the water absorption of the RelyX Unicem specimens but not the SmartCem2 specimens. The time intervals did not affect the solubility of either cement. In all cases, SmartCem2 had higher solubility than RelyX Unicem. The time interval between handling and photoactivation significantly influenced the degree of conversion and water sorption of the resin-based cements. In general, one can say that the self-adhesive resin cements should be photoactivated as soon as possible after the material handling process.


Molecular profiling of the Clostridium leptum subgroup in human fecal microflora by PCR-denaturing gradient gel electrophoresis and clone library analysis.
A group-specific PCR-based denaturing gradient gel electrophoresis (DGGE) method was developed and combined with group-specific clone library analysis to investigate the diversity of the Clostridium leptum subgroup in human feces. PCR products (length, 239 bp) were amplified using C. leptum cluster-specific primers and were well separated by DGGE. The DGGE patterns of fecal amplicons from 11 human individuals revealed host-specific profiles; the patterns for fecal samples collected from a child for 3 years demonstrated the structural succession of the population in the first 2 years and its stability in the third year. A clone library was constructed with 100 clones consisting of 1,143-bp inserts of 16S rRNA gene fragments that were amplified from one adult fecal DNA with one forward universal bacterial primer and one reverse group-specific primer. Eighty-six of the clones produced the 239-bp C. leptum cluster-specific amplicons, and the remaining 14 clones did not produce these amplicons but still phylogenetically belong to the subgroup. Sixty-four percent of the clones were related to Faecalibacterium prausnitzii (similarity, 97 to 99%), 6% were related to Subdoligranulum variabile (similarity, approximately 99%), 2% were related to butyrate-producing bacterium A2-207 (similarity, 99%), and 28% were not identified at the species level. The identities of most bands in the DGGE profiles for the same adult were determined by comigration analysis with the 86 clones that harbored the 239-bp group-specific fragments. Our results suggest that DGGE combined with clone library analysis is an effective technique for monitoring and analyzing the composition of this important population in the human gut flora.


Functional selectivity and classical concepts of quantitative pharmacology.
The concept of intrinsic efficacy has been enshrined in pharmacology for half of a century, yet recent data have revealed that many ligands can differentially activate signaling pathways mediated via a single G protein-coupled receptor in a manner that challenges the traditional definition of intrinsic efficacy. Some terms for this phenomenon include functional selectivity, agonist-directed trafficking, and biased agonism. At the extreme, functionally selective ligands may be both agonists and antagonists at different functions mediated by the same receptor. Data illustrating this phenomenon are presented from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems. A variety of mechanisms may influence this apparently ubiquitous phenomenon. It may be initiated by differences in ligand-induced intermediate conformational states, as shown for the beta(2)-adrenergic receptor. Subsequent mechanisms that may play a role include diversity of G proteins, scaffolding and signaling partners, and receptor oligomers. Clearly, expanded research is needed to elucidate the proximal (e.g., how functionally selective ligands cause conformational changes that initiate differential signaling), intermediate (mechanisms that translate conformation changes into differential signaling), and distal mechanisms (differential effects on target tissue or organism). Besides the heuristically interesting nature of functional selectivity, there is a clear impact on drug discovery, because this mechanism raises the possibility of selecting or designing novel ligands that differentially activate only a subset of functions of a single receptor, thereby optimizing therapeutic action. It also may be timely to revise classic concepts in quantitative pharmacology and relevant pharmacological conventions to incorporate these new concepts.


Acidemia at birth in the vigorous infant as a trigger incident to assess intrapartum care with regard to CTG patterns.
To evaluate if acidemia in vigorous infants is a useful variable in the assessment of intrapartum care with regard to cardiotocographic (CTG) patterns during the second stage. Cases (n = 241) were infants with an umbilical artery pH < 7.05, controls (n = 482) were infants with pH ≥ 7.05. Apgar score was ≥ 7 at 5 min in both groups. CTGs during the last two hours of labor were assessed and neonatal outcomes compared. A sub-analysis of cases with metabolic acidemia: pH < 7.00 and base deficit ≥ 12 mmol/L and acidemia: 7.00 < pH < 7.05 was performed. 63% of cases had a pathological CTG versus 26% of controls (p < 0.001). Patterns with severe variable decelerations had a significantly longer duration in cases. Metabolic acidemia was significantly associated with severe variable decelerations and decreased variability. Infants to cases were admitted to neonatal care in 19% versus 2% of controls (p < 0.001). With metabolic acidemia, 32% were admitted. An umbilical artery pH < 7.05 at birth of vigorous infants may be a useful variable for quality control of intrapartum management with regard to the assessment of second-stage CTGs. Differences in duration of pathological patterns indicate passiveness in academic cases.


mTORC1 controls fasting-induced ketogenesis and its modulation by ageing.
The multi-component mechanistic target of rapamycin complex 1 (mTORC1) kinase is the central node of a mammalian pathway that coordinates cell growth with the availability of nutrients, energy and growth factors. Progress has been made in the identification of mTORC1 pathway components and in understanding their functions in cells, but there is relatively little known about the role of the pathway in vivo. Specifically, we have little knowledge regarding the role mTOCR1 has in liver physiology. In fasted animals, the liver performs numerous functions that maintain whole-body homeostasis, including the production of ketone bodies for peripheral tissues to use as energy sources. Here we show that mTORC1 controls ketogenesis in mice in response to fasting. We find that liver-specific loss of TSC1 (tuberous sclerosis 1), an mTORC1 inhibitor, leads to a fasting-resistant increase in liver size, and to a pronounced defect in ketone body production and ketogenic gene expression on fasting. The loss of raptor (regulatory associated protein of mTOR, complex 1) an essential mTORC1 component, has the opposite effects. In addition, we find that the inhibition of mTORC1 is required for the fasting-induced activation of PPARα (peroxisome proliferator activated receptor α), the master transcriptional activator of ketogenic genes, and that suppression of NCoR1 (nuclear receptor co-repressor 1), a co-repressor of PPARα, reactivates ketogenesis in cells and livers with hyperactive mTORC1 signalling. Like livers with activated mTORC1, livers from aged mice have a defect in ketogenesis, which correlates with an increase in mTORC1 signalling. Moreover, we show that the suppressive effects of mTORC1 activation and ageing on PPARα activity and ketone production are not additive, and that mTORC1 inhibition is sufficient to prevent the ageing-induced defect in ketogenesis. Thus, our findings reveal that mTORC1 is a key regulator of PPARα function and hepatic ketogenesis and suggest a role for mTORC1 activity in promoting the ageing of the liver.


Chlorhexidine-Loaded Amorphous Calcium Phosphate Nanoparticles for Inhibiting Degradation and Inducing Mineralization of Type I Collagen.
A major shortcoming of contemporary dentin adhesives is their limited durability. Exposed collagen fibrils within the bonding interface are degraded by matrix metalloproteinases (MMPs), resulting in aging of the resin-dentin bond. In this study, chlorhexidine-loaded amorphous calcium phosphate (ACP) nanoparticles were synthesized to induce the mineralization of collagen fibrils. The nanoparticles sustainably released chlorhexidine to inhibit MMPs during mineralization. Three types of ACP nanoparticles were prepared: N-ACP containing no chlorhexidine, C-ACP containing chlorhexidine acetate, and G-ACP containing chlorhexidine gluconate, which had a higher drug-loading than C-ACP. Scanning and transmission electron microscopy indicated that the synthesized nanoparticles had diameters of less than 100 nm. Some had diameters of less than 40 nm, which was smaller than the width of gap zones in the collagen fibrils. Energy dispersive X-ray spectroscopy, Fourier-transform infrared spectroscopy, and high performance liquid chromatography confirmed the presence of chlorhexidine in the nanoparticles. X-ray diffraction confirmed that the nanoparticles were amorphous. The drug loading was 0.11% for C-ACP and 0.53% for G-ACP. In vitro release profiles indicated that chlorhexidine was released sustainably via first-order kinetics. Released chlorhexidine inhibited the degradation of collagen in human dentine powder, and its effect lasted longer than that of pure chlorhexidine of the same concentration. The ACP could induce the mineralization of self-assembled type I collagen fibrils. The chlorhexidine-loaded ACP nanoparticles sustainably released chlorhexidine and ACP under appropriate conditions. This is useful for inhibiting degradation and inducing the mineralization of dentine collagen fibrils.


Short-term High-fat Overfeeding Does Not Induce NF-κB Inflammatory Signaling in Subcutaneous White Adipose Tissue.
It is unclear how white adipose tissue (WAT) inflammatory signaling proteins respond during the early stages of overnutrition. To investigate the effect of short-term, high-fat overfeeding on fasting abdominal subcutaneous WAT total content and phosphorylation of proteins involved in nuclear factor-κB (NF-κB) inflammatory signaling, systemic metabolic and inflammatory biomarkers. Individuals consumed a high-fat (65% total energy from total fat), high-energy (50% above estimated energy requirements) diet for 7 days. Fifteen participants (aged 27 ± 1 years; body mass index 24.4 ± 0.6 kg/m2) completed the study. Body mass increased following high-fat overfeeding (+1.2 ± 0.2 kg; P < 0.0001). However, total content and phosphorylation of proteins involved in NF-κB inflammatory signaling were unchanged following the intervention. Fasting serum glucose (+0.2 ± 0.0 mmol/L), total cholesterol (+0.4 ± 0.1 mmol/L), low-density lipoprotein cholesterol (+0.3 ± 0.1 mmol/L), high-density lipoprotein cholesterol (+0.2 ± 0.0 mmol/L), and lipopolysaccharide-binding protein (LBP; +4.7 ± 2.1 µg/mL) increased, whereas triacylglycerol concentrations (-0.2 ± 0.1 mmol/L) decreased following overfeeding (all P < 0.05). Systemic biomarkers (insulin, soluble cluster of differentiation 14 [CD14], C-reactive protein, interleukin-6, tumor necrosis factor-α and monocyte chemoattractant protein-1) and the proportion and concentration of circulating CD14+ monocytes were unaffected by overfeeding. Acute lipid oversupply did not impact on total content or phosphorylation of proteins involved in WAT NF-κB inflammatory signaling, despite modest weight gain and metabolic alterations. Systemic LBP, which is implicated in the progression of low-grade inflammation during the development of obesity, increased in response to a 7-day high-fat overfeeding period.


A national survey into desirable personality traits in anaesthesia trainees in a developing country.
To explore personality traits considered to be important in selection of trainees by consultant anaesthetists in a developing country. A questionnaire listing 28 traits was sent to 125 consultant anaesthetists. The raters were asked to mark each trait on a scale of 1 to 10, with one being least desirable and 10 as most desirable. Listing of five most desirable and one least desirable trait was also required. The response rate was 79%. The most desirable trait was identified as reliability by 40%, followed by honesty 17%, functionality under stress 9%, punctuality 7%, and discipline 4%. The least desirable trait was considered as resourcefulness (21%), sense of humour (20%), unassuming mannerism (15%), high self esteem (11%), inquisitive (5%) and expedious (5%). Some traits have been identified as more desirable than others for trainees in our country. We plan to assess these in structured behavioural interviews in our residency programme.


Alcohol drinking behaviors among Turkish high school students.
The aim of this study was to evaluate the prevalence, behavioral patterns and correlates of regular alcohol drinking in high school students. This cross-sectional study involved the completion of a modified version of "Health Behavior in School Age Children" (HBSC 1997/1998) questionnaire by 4,153 grade 9-11 students from 26 randomly selected high schools in Istanbul. Chi-square test, Spearman correlation test and forward stepwise multiple logistic regression model were used for statistical analyses as appropriate. Overall, 61% of students were experimental drinkers, and 46% of the students were current drinkers. There was a significant difference between female and male students with respect to reporting current alcohol drinking at grade 9 and 11 (p > 0.05 for each comparison). Regular drinking was reported by 6% of students. Male students were more likely than female students to report regular drinking at each grade (p < 0.01 for each comparison). Nineteen percent of the students reported that they had been really drunk at least once during their lifetime. Malestudents were more likely than female students to report an occasion of drunkenness at each grade (p < 0.05 for each comparison). All types of drinking behavior rates tended to increase across grades for both genders (p < 0.05 for each comparison). In logistic regression analysis the following were all independently associated with regular drinking: being in grade 11, smoking cigarettes currently, lifetime drug use, bullying others, being sexually active, playing computer games > or = 4 h/week, exercising < or = 1 h/week, spending > or = four evenings with friends, at ease in talking to same gender friends, tiredness in the morning, perceived as good-looking/beautiful, higher educational level of the mother and perceived poor academic achievement. The results of this study showed that alcohol consumption is prevalent among high school students. There is therefore a need for school-based alcohol prevention programs which also deal with family and peer influences on drinking.


Change in Blood Pressure Variability Among Treated Elderly Hypertensive Patients and Its Association With Mortality.
Background Information is scarce regarding effects of antihypertensive medication on blood pressure variability (BPV) and associated clinical outcomes. We examined whether antihypertensive treatment changes BPV over time and whether such change (decline or increase) has any association with long-term mortality in an elderly hypertensive population. Methods and Results We used data from a subset of participants in the Second Australian National Blood Pressure study (n=496) aged ≥65 years who had 24-hour ambulatory blood pressure recordings at study entry (baseline) and then after a median of 2 years while on treatment (follow-up). Weighted day-night systolic BPV was calculated for both baseline and follow-up as a weighted mean of daytime and nighttime blood pressure standard deviations. The annual rate of change in BPV over time was calculated from these BPV estimates. Furthermore, we classified both BPV estimates as high and low based on the baseline median BPV value and then classified BPV changes into stable: low BPV, stable: high BPV, decline: high to low, and increase: low to high. We observed an annual decline (mean±SD: -0.37±1.95; 95% CI, -0.54 to -0.19; P<0.001) in weighted day-night systolic BPV between baseline and follow-up. Having constant stable: high BPV was associated with an increase in all-cause mortality (hazard ratio: 3.03; 95% CI, 1.67-5.52) and cardiovascular mortality (hazard ratio: 3.70; 95% CI, 1.62-8.47) in relation to the stable: low BPV group over a median 8.6 years after the follow-up ambulatory blood pressure monitoring. Similarly, higher risk was observed in the decline: high to low group. Conclusions Our results demonstrate that in elderly hypertensive patients, average BPV declined over 2 years of follow-up after initiation of antihypertensive therapy, and having higher BPV (regardless of any change) was associated with increased long-term mortality.


West Nile virus serosurveillance in Iowa white-tailed deer (1999-2003).
Sera from white-tailed deer (Odocoileus virginianus) were collected in Iowa during the winter months (1999-2003), 2 years before and after West Nile virus (WNV) was first reported in Iowa (2001), and were analyzed for antibodies to WNV. Samples from 1999 to 2001 were antibody negative by blocking enzyme-linked immunosorbent assay (bELISA) and plaque reduction neutralization test (PRNT(90)). Prevalence derived from bELISA (2002, 12.7%; 2003, 11.2%) and WNV PRNT(90) (2002, 7.9%; 2003, 8.5%) assays were similar. All samples were negative for antibodies against St. Louis encephalitis virus as determined by PRNT(90). Antibodies to flaviviruses were detected by indirect enzyme-linked immunosorbent assay (iELISA) prior to the first WNV cases reported in Iowa (1999-2001) with prevalence ranging from 2.2% to 3.2%, suggesting the circulation of an additional undescribed flavivirus prior to the introduction of WNV into the area. Flavivirus prevalence as determined by iELISA increased in 2002 and 2003 (23.3% and 31.9%, respectively). The increase in prevalence exceeded estimates of WNV prevalence, suggesting that conditions favored general flavivirus transmission (including WNV) during the 2002-2003 epizootic. These data indicate that serologic analysis of deer sera collected from hunter harvests may prove useful for surveillance and evidence of local transmission of WNV and other pathogens and identify white-tailed deer as a species for further studies for host competency.


A note on the power to detect transmission distortion in parent-child trios via the transmission disequilibrium test.
Transmission distortion refers to deviation from the normal 50:50 transmission of alleles from parents to offspring. Identification of genomic regions which undergo distortion is necessary for the correct interpretation of linkage and association studies, since tests of linkage using affected relative pairs and family based tests of association will yield spurious results in the presence of transmission distortion. With the increasing availability of genome-wide high density SNP data (e.g. from the International HapMap project), identification of these loci is now a real possibility. Here we present an analytical formula which demonstrates that the power to detect transmission distortion is a simple function of the number of heterozygous parents in the sample and the level of distortion at the locus. Our results indicate that whilst it will be possible to identify loci undergoing major levels of distortion using tens or hundreds of trios, large sample sizes in the order of tens of thousands of trios will be necessary to detect minor levels of distortion with appreciable power. The corollary is that genome-wide searches are unlikely to identify loci where the level of distortion is small, although they may serve to identify interesting regions worthy of follow up.


Import of rat ornithine transcarbamylase precursor into mitochondria: two-step processing of the leader peptide.
The mitochondrial matrix enzyme ornithine transcarbamylase (OTC) is synthesized on cytoplasmic polyribosomes as a precursor (pOTC) with an NH2-terminal extension of 32 amino acids. We report here that rat pOTC synthesized in vitro is internalized and cleaved by isolated rat liver mitochondria in two, temporally separate steps. In the first step, which is dependent upon an intact mitochondrial membrane potential, pOTC is translocated into mitochondria and cleaved by a matrix protease to a product designated iOTC, intermediate in size between pOTC and mature OTC. This product is in a trypsin-protected mitochondrial location. The same intermediate-sized OTC is produced in vivo in frog oocytes injected with in vitro-synthesized pOTC. The proteolytic processing of pOTC to iOTC involves the removal of 24 amino acids from the NH2 terminus of the precursor and utilizes a cleavage site two residues away from a critical arginine residue at position 23. In a second cleavage step, also catalyzed by a matrix protease, iOTC is converted to mature OTC by removal of the remaining eight residues of leader sequence. To define the critical regions in the OTC leader peptide required for these events, we have synthesized OTC precursors with alterations in the leader. Substitution of either an acidic (aspartate) or a "helix-breaking" (glycine) amino acid residue for arginine 23 of the leader inhibits formation of both iOTC and OTC, without affecting translocation. These mutant precursors are cleaved at an otherwise cryptic cleavage site between residues 16 and 17 of the leader. Interestingly, this cleavage occurs at a site two residues away from an arginine at position 15. The data indicate that conversion of pOTC to mature OTC proceeds via the formation of a third discrete species: an intermediate-sized OTC. The data suggest further that, in the rat pOTC leader, the essential elements required for translocation differ from those necessary for correct cleavage to either iOTC or mature OTC.


Values and Preferences on the Use of Oral Pre-exposure Prophylaxis (PrEP) for HIV Prevention Among Multiple Populations: A Systematic Review of the Literature.
Daily oral pre-exposure prophylaxis (PrEP) is the use of antiretroviral drugs by HIV-negative people to prevent HIV infection. WHO released new guidelines in 2015 recommending PrEP for all populations at substantial risk of HIV infection. To prepare these guidelines, we conducted a systematic review of values and preferences among populations that might benefit from PrEP, women, heterosexual men, young women and adolescent girls, female sex workers, serodiscordant couples, transgender people and people who inject drugs, and among healthcare providers who may prescribe PrEP. A comprehensive search strategy reviewed three electronic databases of articles and HIV-related conference abstracts (January 1990-April 2015). Data abstraction used standardised forms to categorise by population groups and relevant themes. Of 3068 citations screened, 76 peer-reviewed articles and 28 conference abstracts were included. Geographic coverage was global. Most studies (N = 78) evaluated hypothetical use of PrEP, while 26 studies included individuals who actually took PrEP or placebo. Awareness of PrEP was low, but once participants were presented with information about PrEP, the majority said they would consider using it. Concerns about safety, side effects, cost and effectiveness were the most frequently cited barriers to use. There was little indication of risk compensation. Healthcare providers would consider prescribing PrEP, but need more information before doing so. Findings from a rapidly expanding evidence base suggest that the majority of populations most likely to benefit from PrEP feel positively towards it. These same populations would benefit from overcoming current implementation challenges with the shortest possible delay.


Importance of the collagen adhesin ace in pathogenesis and protection against Enterococcus faecalis experimental endocarditis.
Ace is an adhesin to collagen from Enterococcus faecalis expressed conditionally after growth in serum or in the presence of collagen. Here, we generated an ace deletion mutant and showed that it was significantly attenuated versus wild-type OG1RF in a mixed infection rat endocarditis model (P<0.0001), while no differences were observed in a peritonitis model. Complemented OG1RFDeltaace (pAT392::ace) enhanced early (4 h) heart valve colonization versus OG1RFDeltaace (pAT392) (P = 0.0418), suggesting that Ace expression is important for early attachment. By flow cytometry using specific anti-recombinant Ace (rAce) immunoglobulins (Igs), we showed in vivo expression of Ace by OG1RF cells obtained directly from infected vegetations, consistent with our previous finding of anti-Ace antibodies in E. faecalis endocarditis patient sera. Finally, rats actively immunized against rAce were less susceptible to infection by OG1RF than non-immunized (P = 0.0004) or sham-immunized (P = 0.0475) by CFU counts. Similarly, animals given specific anti-rAce Igs were less likely to develop E. faecalis endocarditis (P = 0.0001) and showed fewer CFU in vegetations (P = 0.0146). In conclusion, we have shown for the first time that Ace is involved in pathogenesis of, and is useful for protection against, E. faecalis experimental endocarditis.


Carbon dioxide laser fiber for laryngeal cancer surgery.
The carbon dioxide laser has evolved to be the premier dissecting instrument for hemostatic cutting during endolaryngeal cancer resection. However, dissection is limited to mirror-reflected line-of-sight delivery of the laser. A recently developed flexible, hollow photonic bandgap fiber (PBF) appears to offer advantages in endolaryngeal dissection. The suitability of the PBF for human application was evaluated in a canine experiment in which human surgical procedures for microlaryngoscopic en bloc partial laryngectomy were simulated. The specimens that were resected endoscopically and the completion laryngectomy specimen were evaluated histologically. Observations from this experiment revealed that en bloc partial laryngectomy procedures were substantially easier to achieve as compared with prior experience in humans. This improvement resulted from three factors: 1) enhanced tangential dissection due to increased angulation of the laser energy, 2) enhanced procedural orientation due to proprioception of the tissues in contact mode, and 3) improved hemostasis. Histopathologic analysis of the resection margins revealed minimal thermal trauma. The PBF shows substantial promise for human application in endoscopic partial laryngectomy. It will likely enhance the ability of any surgeon to extend his or her indications for performing endoscopic laryngeal cancer resections regardless of philosophy (en bloc resection or piecemeal).


The influence of psychological factors on the opiate withdrawal syndrome.
Psychological and drug-related variables and their effect on the severity of withdrawal symptoms were examined in a group of addicts being withdrawn from opiates on an in-patient drug dependence unit. Two psychological factors--neuroticism and the degree of distress expected by the patient--were related to subsequent severity of symptoms. Both are anxiety-related, and may serve to amplify withdrawal symptoms. Surprisingly, drug dose was unrelated to symptom severity.


Human breast milk contains bovine IgG. Relationship to infant colic?
Previous studies have suggested that an unidentified cow's milk protein, other than beta-lactoglobulin and casein, might play a pathogenetic role in infant colic. Therefore, a radioimmunoassay was used to analyze human breast milk and infant formula samples for the presence of bovine IgG. Milk samples from 88 of the 97 mothers tested contained greater than 0.1 micrograms/mL of bovine IgG. In a study group of 59 mothers with infants in the colic-prone 2- to 17-week age group, the 29 mothers of colicky infants had higher levels of bovine IgG in their breast milk (median 0.42 micrograms/mL) than the 30 mothers of noncolicky infants (median 0.32 micrograms/mL) (P less than .02). The highest concentrations of bovine IgG observed in human milk were 8.5 and 8.2 micrograms/mL. Most cow's milk-based infant formulas contained 0.6 to 6.4 micrograms/mL of bovine IgG, a concentration comparable with levels found in many human milk samples. The results suggest that appreciable quantities of bovine IgG are commonly present in human milk, that significantly higher levels are present in milk from mothers of colicky infants, and that bovine IgG may possibly be involved in the pathogenesis of infant colic.


A study on nm23-H1 expression in diffuse large B-cell lymphoma that was treated with CyclOBEAP plus rituximab therapy.
In our previous study on nm23-H1 expression with diffuse large B-cell lymphoma (DLBCL), we found that patients with positive nm23-H1 had significantly poorer prognosis than patients with negative nm23-H1. We examined whether nm23-H1 is a prognostic factor of DLBCL in the rituximab era. The subjects were 101 DLBCL patients who underwent R-CyclOBEAP (rituximab, cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, and prednisolone) therapy and in whom markers could be analyzed. We evaluated CD5, CD10, BCL2, BCL6, MUM1, and nm23-H1 expression by immunohistochemistry. Ninety-four DLBCL patients who underwent CyclOBEAP therapy were assumed as historical controls. Among DLBCL patients who underwent CyclOBEAP therapy, BCL2 positivity, MUM1 positivity, non-germinal center B-cell (non-GCB), and nm23-H1 positivity were associated with significantly shorter overall survival (OS) and progression-free survival (PFS). On the other hand, among DLBCL patients who underwent R-CyclOBEAP therapy, the 5-year OS rates of the nm23-H1-positive DLBCL (n = 32) and nm23-H1-negative DLBCL groups (n = 69) were 65% and 97%, respectively (p = 0.001), with 5-year PFS rates of 51% and 89%, respectively (p = 0.001). In the rituximab era, BCL2, MUM1, and non-GCB were not prognostic factors. We demonstrated that among patients with DLBCL who underwent R-CyclOBEAP therapy, patients with nm23-H1 expression had a significantly poorer prognosis than patients without nm23-H1 expression. These results suggest an important role for nm23-H1 in malignant progression and a potential therapeutic target for DLBCL.


Exogenous tumour necrosis factor alpha induces suppression of autoimmune arthritis.
Our previous studies showed that arthritic Lewis (LEW) rats produced the highest levels of tumour necrosis factor (TNF)alpha in the recovery phase of adjuvant arthritis (AA), suggesting a correlation between high TNFalpha levels and reduced severity of arthritis. To further explore this correlation, we compared the TNFalpha secretion profile of the AA-resistant Wistar Kyoto (WKY) rats with that of LEW rats, determined the effect of exogenous TNFalpha on the course of AA in LEW rats, and examined various mechanisms involved in TNFalpha-induced disease modulation. A cohort each of LEW and WKY rats was immunised subcutaneously with heat-killed Mycobacterium tuberculosis H37Ra (Mtb). At different time points thereafter, subgroups of rats were killed and their draining lymph node cells were tested for cytokine production. Another group of LEW rats was injected with TNFalpha intraperitoneally daily for a total of 10 injections, 3 before and 6 after Mtb challenge, and then observed for signs of AA. In parallel, TNFalpha-treated rats were examined for changes in other cytokines, in CD4+CD25+ T cell frequency, and in indoleamine 2,3-dioxygenase (IDO) mRNA expression levels. LEW rats displayed a TNFalpha secretion profile that was opposite to that of the WKY rats. Furthermore, TNFalpha treatment significantly down modulated the severity of AA in LEW rats, and decreased the interferon (IFN)-gamma secretion in response to the pathogenic determinant of the disease-related antigen. No significant alterations were observed in other parameters tested. The role of endogenous TNFalpha in the induction and propagation of arthritis is well established. However, exogenous TNFalpha can down modulate the course of AA, displaying an immunoregulatory functional attribute of this cytokine.


How patients and nurses experience the acute care psychiatric environment.
The concept of the therapeutic milieu was developed when patients' hospitalizations were long, medications were few, and one-to-one nurse-patient interactions were the norm. However, it is not clear how the notion of 'therapeutic milieu' is experienced in American acute psychiatric environments today. This phenomenological study explored the experience of patients and nurses in an acute care psychiatric unit in the USA, by asking them, 'What stands out to you about this psychiatric hospital environment?' Three figural themes emerged, contextualized by time, which was a source of stress to both groups: for patients there was boredom, and for nurses, pressure and chaos. Although they shared some themes, nurses and patients experienced them differently. For instance, nurses felt caged-in by the Plexiglas-enclosed nursing station, and patients felt caged-in by the locked doors of the unit. The findings from this US study do not support the existence of the therapeutic milieu as described in the literature. Furthermore, although the nurse-patient relationship was yearned for by nurses, it was nearly absent from patients' descriptions. The caring experienced by patients was mainly derived from interactions with other patients.


Experimental Evaluation of an Optical Time Division Demultiplexer for Twenty-four Channels.
Experimental techniques for optical demultiplexing by use of sinusoidal polarization switches were evaluated. For this purpose the terminals of a twenty-four-channel optical PCM system were simulated by two channels separated in time by1/24th the pulse period. The complete twenty-four PCM channels would have an information rate of 6.7 Gbit/sec. The measured values of cross talk in the demultiplexer were -13 dB and -9 dB for the two channels used in the simulated system. The major contributions to the cross talk were (1) intrinsic cross talk due to the use of a sine wave rather than a square wave for polarization switching (-19.6 dB and -13.1 dB); (2) light leakage in the demultiplexer crystals due to rf heating that gives rise to a nonuniform birefringence (-19 dB, both channels); and (3) misadjustment of the demultiplexer.


Special issues in the treatment of paediatric bipolar disorder.
Paediatric bipolar disorder (PBD) is an increasingly diagnosed disorder affecting an estimated 1% of children and adolescents. Pharmacological treatment studies in PBD have lagged far behind those in adults. Children are currently treated with pharmacological agents, most of which have proven efficacy in adults. However, PBD is distinct from adult forms of bipolar disorder (BD) and may present unique treatment challenges. PBD often presents with rapid cycling and mixed manic states and a high co-morbidity with behavioural and attention disorders. Early onset depression may also be an early sign of PBD. Due to developmental considerations, the diagnosis of BD may be difficult to make in children without semi-structured interviews. This report discusses the special issues that should be considered when treating PBD and reviews the current literature regarding pharmacotherapy of this population. Mood stabilisers have been studied mostly in an open, uncontrolled fashion but there is growing evidence that lithium, divalproex and carbamazepine are effective in treating PBD. More recent treatment options include atypical antipsychotics and newer anticonvulsants. Other novel agents are currently being investigated in adult BD and may prove applicable to the paediatric form. Finally, based on the available data, a treatment algorithm for PBD is proposed.


Laboratory characterization of human T cell lymphotropic virus types 1 (HTLV-1) and 2 (HTLV-2) infections in blood donors from Sao Paulo, Brazil.
Serologic screening for human T cell lymphotropic virus types 1/2 (HTLV-1/2) infection in blood donors has been recently introduced in Brazil. Analysis of 351,639 blood donations in Sao Paulo from January 1992 to October 1993 identified 1,063 positive (0.30%) and 2,238 indeterminate (0.63%) samples based on serologic confirmation using a 21e Western blot. A detailed analysis (serologic, molecular, and virologic), based on a laboratory diagnostic algorithm for characterization of HTLV-1 and HTLV-2 infections was undertaken in 50 seropositive or seroindeterminate blood donors. Modified serologic assays (2.3 Western blot that incorporate type-specific recombinant peptides) performed in 29 HTLV-1/2 positive and 21 HTLV-1/2 indeterminate donors with the 21e Western blot identified 25 as infected with HTLV-1, four with HTLV-2, five with untypable HTLV-1/2, 15 as HTLV-1/2 indeterminate, and one as seronegative. Polymerase chain reaction (PCR) analysis using DNA amplification of proviral pol and tax sequences from peripheral blood mononuclear cells confirmed HTLV-1 and HTLV-2 infections in all 2.3 Western blot seropositive donors; of the five serologically untypable donors, three were confirmed to be HTLV-1 positive, one HTLV-2 positive, and one negative by PCR. All of the seroindeterminate donors were also negative by PCR. Furthermore, HTLV-1 could be isolated in cocultures from 10 of 18 infected donors. Cell lines developed from two HTLV-1-infected donors were of T cell phenotype (CD2+, CD3+), exhibiting surface markers of activated CD4 cells (CD4+ CD25+ HLA-DR+). Thus, we provide evidence for the high seroprevalence of HTLV infection in blood donor population in Sao Paulo, Brazil compared with North American donors and propose a comprehensive serologic and genotypic diagnostic algorithm for HTLV-infected donors that has strong implications for counseling of these individuals.


Repeated measurements with minimally destructive partial-transfer absorption imaging.
We demonstrate partial-transfer absorption imaging as a technique for repeatedly imaging an ultracold atomic ensemble with minimal perturbation. We prepare an atomic cloud in a state that is dark to the imaging light. We then use a microwave pulse to coherently transfer a small fraction of the ensemble to a bright state, which we image using in situ absorption imaging. The amplitude or duration of the microwave pulse controls the fractional transfer from the dark to the bright state. For small transfer fractions, we can image the atomic cloud up to 50 times before it is depleted. As a sample application, we repeatedly image an atomic cloud oscillating in a dipole trap to measure the trap frequency.


Genetic Diversity and Phylogenetic Analysis of Citrus tristeza virus Isolates from Turkey.
The presence of Citrus tristeza virus (CTV) in Turkey has been known since the 1960s and the virus was detected in all citrus growing regions of the country. Even though serological and biological characteristics of CTV have been studied since the 1980s, molecular characteristics of CTV isolates have not been studied to date in Turkey. In this study, molecular characteristics of 15 CTV isolates collected from different citrus growing regions of Turkey were determined by amplification, cloning, and sequencing of their major coat protein (CP) genes. The sequence analysis showed that the CP genes were highly conserved among Turkish isolates. However, isolates from different regions showed more genetic variation than isolates from the same region. Turkish isolates were clustered into three phylogenetic groups showing no association with geographical origins, host, or symptoms induced in indicator plants. Phylogenetic analysis of Turkish isolates with isolates from different citrus growing regions of the world including well-characterized type isolates of previously established strain specific groups revealed that some Turkish isolates were closely related to severe quick decline or stem pitting isolates. The results demonstrated that although CTV isolates from Turkey are considered biologically mild, majority of them contain severe components potentially causing quick decline or stem pitting.


ABCA7 loss-of-function variants, expression, and neurologic disease risk.
To investigate and characterize putative "loss-of-function" (LOF) adenosine triphosphate-binding cassette, subfamily A member 7 (ABCA7) mutations reported to associate with Alzheimer disease (AD) risk. We genotyped 6 previously reported ABCA7 putative LOF variants in 1,465 participants with AD, 381 participants with other neuropathologies (non-AD), and 1,043 controls and assessed the overall mutational burden for association with different diagnosis groups. We measured brain ABCA7 protein and messenger RNA (mRNA) levels using Western blot and quantitative PCR, respectively, in 11 carriers of the 3 most common variants, and sequenced all 47 ABCA7 exons in these participants to screen for other coding variants. At least one of the investigated variants was identified in 45 participants with late-onset Alzheimer disease, 12 participants with other neuropathologies, and 11 elderly controls. Association analysis revealed a significantly higher burden of these variants in participants with AD (p = 5.00E-04) and those with other neuropathologies (p = 8.60E-03) when compared with controls. Concurrent analysis of brain ABCA7 mRNA and protein revealed lower protein but not mRNA in p.L1403fs carriers, lower mRNA but not protein in p.E709fs carriers, and additional deleterious mutations in some c.5570+5G>C carriers. Our results suggest that LOF may not be a common mechanism for these ABCA7 variants and expand the list of neurologic diseases enriched for them.


Direct white light emission from carbon nanodots (C-dots) in solution processed light emitting diodes.
We describe the preparation of inverted white light emitting diodes by solution processing. The active layer is formed uniquely by Carbon Nanodots (C-dots) that display white-light emission at voltage close to 5 V when combined with metal oxides as charge transport layers. Moreover, we have demonstrated that the white light is not the product of charge transfer between the polymer selective contact and the C-dots but the result of the different recombination processes within the C-dots.


"The midwife helped me ... otherwise I could have died": women's experience of professional midwifery services in rural Afghanistan - a qualitative study in the provinces Kunar and Laghman.
Afghanistan has one of the world's highest maternal mortality ratios, with more than 60% of women having no access to a skilled birth attendant in some areas. The main challenges for childbearing Afghan women are access to skilled birth attendance, emergency obstetric care and reliable contraception. The NGO-based project Advancing Maternal and Newborn Health in Afghanistan has supported education of midwives since 2002, in accordance with the national plan for midwifery education. The aim of this study is to explore women's experiences of professional midwifery care in four villages in Afghanistan covered by the project, so as to reveal challenges and improve services in rural and conflict-affected areas of the country. An exploratory case-study approach was adopted. Fourteen in-depth interviews and four focus-group discussions were conducted. A total of 39 women participated - 25 who had given birth during the last six months, 11 mothers-in-law and three community midwives in the provinces of Kunar and Laghman. Data generated by the interviews and observations was analysed using thematic content analysis. Many of the women greatly valued the trained midwives' life-saving experience, skills and care, and the latter were important reasons for choosing to give birth in a clinic. Women further appreciated midwives' promotion of immediate skin-to-skin contact and breastfeeding. However, some women experienced rudeness, discrimination and negligence on the part of the midwives. Moreover, relatives' disapproval, shame and problems with transport and security were important obstacles to women giving birth in the clinics. Local recruitment and professional education of midwives as promoted by Afghan authorities and applied in the project seem successful in promoting utilisation and satisfaction with maternal and neonatal health services in rural Afghanistan. Nevertheless, the quality of the services is still lacking, with some women complaining of disrespectful care. There seems to be a need to focus more on communication issues during the education of midwives. An increased focus on in-service training and factors promoting quality care and respectful communication is necessary and should be prioritised.


Randomized controlled trial of mindfulness-based stress reduction (MBSR) for survivors of breast cancer.
Considerable morbidity persists among survivors of breast cancer (BC) including high levels of psychological stress, anxiety, depression, fear of recurrence, and physical symptoms including pain, fatigue, and sleep disturbances, and impaired quality of life. Effective interventions are needed during this difficult transitional period. We conducted a randomized controlled trial of 84 female BC survivors (Stages 0-III) recruited from the H. Lee Moffitt Cancer and Research Institute. All subjects were within 18 months of treatment completion with surgery and adjuvant radiation and/or chemotherapy. Subjects were randomly assigned to a 6-week Mindfulness-Based Stress Reduction (MBSR) program designed to self-regulate arousal to stressful circumstances or symptoms (n=41) or to usual care (n=43). Outcome measures compared at 6 weeks by random assignment included validated measures of psychological status (depression, anxiety, perceived stress, fear of recurrence, optimism, social support) and psychological and physical subscales of quality of life (SF-36). Compared with usual care, subjects assigned to MBSR(BC) had significantly lower (two-sided p<0.05) adjusted mean levels of depression (6.3 vs 9.6), anxiety (28.3 vs 33.0), and fear of recurrence (9.3 vs 11.6) at 6 weeks, along with higher energy (53.5 vs 49.2), physical functioning (50.1 vs 47.0), and physical role functioning (49.1 vs 42.8). In stratified analyses, subjects more compliant with MBSR tended to experience greater improvements in measures of energy and physical functioning. Among BC survivors within 18 months of treatment completion, a 6-week MBSR(BC) program resulted in significant improvements in psychological status and quality of life compared with usual care.


Non-edible parts of Solanum stramoniifolium Jacq. - a new potent source of bioactive extracts rich in phenolic compounds for functional foods.
Extracts prepared from leaves, roots, and stems of Solanum stramoniifolium Jacq. (Solanaceae) in 80% ethanol have been tested for their in vitro antioxidant, anti-inflammatory, antimicrobial, and cytotoxic activities with an aim to find new sources of substances for functional foods and food additives. The root extract revealed the highest antioxidant activity in all assays exceeding the trolox capacity, and was the only extract that inhibited nitric oxide production in mouse macrophage cells, showing also the capacity to suppress the growth of all tested human tumor cell lines (MCF-7, NCI-H460, HeLa and HepG2). The leaf extract showed the strongest antimicrobial activity inhibiting all tested clinical isolates. To the author's best knowledge it was the first time that all individual parts of this plant were tested for biological activity together with the phenolic compound characterization.


Low-Dose Heparin Anticoagulation During Extracorporeal Life Support for Acute Respiratory Distress Syndrome in Conscious Sheep.
Over 32% of burned battlefield causalities develop trauma-induced hypoxic respiratory failure, also known as acute respiratory distress syndrome (ARDS). Recently, 9 out of 10 US combat soldiers' survived life-threatening trauma-induced ARDS supported with extracorporeal membrane oxygenation (ECMO), a portable form of cardiopulmonary bypass. Unfortunately, the size, incidence of coagulation complications, and the need for systematic anticoagulation for traditional ECMO devices have prevented widespread use of this lifesaving technology. Therefore, a compact, mobile, ECMO system using minimal anticoagulation may be the solution to reduce ARDS in critically ill military and civilian patients. We conducted a prospective cohort laboratory investigation to evaluate the coagulation function in an ovine model of oleic acid induced ARDS supported with veno-venous ECMO. The experimental design approximated the time needed to transport from a battlefield setting to an advanced facility and compared bolus versus standard heparin anticoagulation therapy. Comprehensive coagulation and hemostasis assays did not show any difference because of ECMO support over 10 h between the two groups but did show changes because of injury. Platelet count and function did decrease with support on ECMO, but there was no significant bleeding or clot formation during the entire experiment. A bolus heparin injection is sufficient to maintain ECMO support for up to 10 h in an ovine model of ARDS. With a reduced need for systematic anticoagulation, ECMO use for battlefield trauma could reduce significant morbidity and mortality from ventilator-induced lung injury and ARDS. Future studies will investigate the mechanisms and therapies to support patients for longer periods on ECMO without coagulation complications. V--therapeutic animal experiment.


Expression of CD44 and its clinical implication in diffuse-type and intestinal-type gastric adenocarcinomas.
Knowing the differential expression of CD44 isoforms in intestinal- and diffuse-type gastric carcinomas, we used antibodies against the standard form of CD44 (CD44s) and the domain encoded by exon v6 (CD44v6) in 103 patients with primary gastric adenocarcinomas to explore the role of CD44 isoforms in metastases of both types of gastric cancer. Carcinomas of the intestinal type were more frequently CD44s and CD44v6 positive than carcinomas of the diffuse type (p = 0.034 for CD44s and p = 0.022 for CD44v6). The reactivity to these two antibodies did not correlate with histopathological and clinical prognostic factors in intestinal-type carcinoma. In contrast, expression of CD44v6 was associated with infiltrative tumor growth (p = 0.021), depth of invasion (p = 0.012), lymph node involvement (p = 0.005) and a higher incidence of distant metastasis (p = 0.069) in cancers of the diffuse type. CD44s-expressing diffuse-type tumors had a higher incidence of distant metastasis at presentation (p = 0.001), but expression of CD44s was not correlated with other clinicopathologic indices. For all cases, there was a nonsignificant association between CD44s expression and poor survival. Unexpectedly, there was also no significant difference in survival regarding expression of CD44v6 for all cases or the diffuse-type subset. This study showed the role of CD44v6 in invasion and metastases of diffuse-type gastric carcinoma and demonstrated the necessity of subclassifying tumor types when studying the clinical significance of CD44 in human cancers.


Modeling the impact of the difference in cross-protection data between a human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and a human papillomavirus (HPV)-6/11/16/18 vaccine in Canada.
In Canada, two vaccines that have demonstrated high efficacy against infection with human papillomavirus (HPV) types -16 and -18 are available. The HPV-6/11/16/18 vaccine provides protection against genital warts (GW) while the HPV-16/18 vaccine may provide better protection against other oncogenic HPV types. In this analysis, the estimated clinical and economic benefit of each of these vaccines was compared in the Canadian setting. A Markov model of the natural history of HPV infection among women, cervical cancer (CC) and GW was used to estimate the impact of vaccinating a cohort of 100,000 12-year-old females on lifetime outcomes and healthcare system costs (no indirect benefit in males included). A budget impact model was used to estimate the impact of each vaccine by province. In the base case, vaccination with the HPV-16/18 vaccine was predicted to prevent 48 additional CC cases, and 16 additional CC deaths, while vaccination with the HPV-6/11/16/18 vaccine was predicted to prevent 6,933 additional GW cases. Vaccination with the HPV-16/18 vaccine was estimated to save 1 additional discounted quality adjusted life year (QALY) at an overall lower lifetime cost to the healthcare system compared to the HPV-6/11/16/18 vaccine (assuming vaccine price parity). In sensitivity analyses, the HPV-6/11/16/18 vaccine was associated with greater QALYs saved when the cross-protection efficacy of the HPV-16/18 vaccine was reduced, or the burden of GW due to HPV-6/11 was increased. In most scenarios with price parity, the lifetime healthcare cost of the strategy with the HPV-16/18 vaccine was predicted to be lower than the HPV-6/11/16/18 vaccine. In the probabilistic sensitivity analyses, the HPV-16/18 vaccine provided more QALY benefit than the HPV-6/11/16/18 vaccine in 49.2% of scenarios, with lower relative lifetime costs in 83.5% of scenarios. Overall, the predicted lifetime healthcare costs and QALYs saved by implementing each of the vaccines are similar. Vaccination with the HPV-16/18 vaccine is expected to be associated with reduced CC disease morbidity and mortality compared to vaccination with the HPV-6/11/16/18 vaccine. Differences in these outcomes depend on the extent of cervical disease prevented by cross-protection and the burden of GW caused by HPV-6/11.


Local Skin Inflammation in Cutaneous Leishmaniasis as a Source of Variable Pharmacokinetics and Therapeutic Efficacy of Liposomal Amphotericin B.
Disfiguring skin lesions caused by several species of the Leishmania parasite characterize cutaneous leishmaniasis (CL). Successful treatment of CL with intravenous (i.v.) liposomal amphotericin B (LAmB) relies on the presence of adequate antibiotic concentrations at the dermal site of infection within the inflamed skin. Here, we have investigated the impact of the local skin inflammation on the pharmacokinetics (PK) and efficacy of LAmB in two murine models of localized CL (Leishmania major and Leishmania mexicana) at three different stages of disease (papule, initial nodule, and established nodule). Twenty-four hours after the administration of one 25 mg/kg of body weight LAmB (i.v.) dose to infected BALB/c mice (n = 5), drug accumulation in the skin was found to be dependent on the causative parasite species (L. major > L. mexicana) and the disease stage (papule > initial nodule > established nodule > healthy skin). Elevated tissue drug levels were associated with increased vascular permeability (Evans blue assay) and macrophage infiltration (histomorphometry) in the infected skin, two pathophysiological parameters linked to tissue inflammation. After identical treatment of CL in the two models with 5 × 25 mg/kg LAmB (i.v.), intralesional drug concentrations and reductions in lesion size and parasite load (quantitative PCR [qPCR]) were all ≥2-fold higher for L. major than for L. mexicana In conclusion, drug penetration of LAmB into CL skin lesions could depend on the disease stage and the causative Leishmania species due to the influence of local tissue inflammation.