Detection of RNAP-DNA complexes using solid state nanopores.
Transcription is the first step in gene expression where DNA is copied into RNA. It is extensively studied at the bulk level especially the regulation mechanism, which in cancerous cells is impaired. We were interested in studying E. coli RNAP enzyme at the single-molecule level for its functional as well as molecular motor properties. With nanopore sensing, we were able to observe RNA polymerase-DNA complexes translocate through nanopores and able to distinguish between individual complexes and bare RNA polymerase. We were also able to observe orientation of RNA polymerase in the nanopore whether flow or electric field predominates. The complexity of the signals from the protein-DNA complexes experiment motivated us to develop level detection software. This software is based on a change detection method called the CUSUM algorithm. OpenNanpore software was designed to analyze in details current blockages in nanopore signals with very little prior knowledge on the signal. With this work one can separate events according to their number of levels and study those sub-populations separately.


Aggressive dereplication using UHPLC-DAD-QTOF: screening extracts for up to 3000 fungal secondary metabolites.
In natural-product drug discovery, finding new compounds is the main task, and thus fast dereplication of known compounds is essential. This is usually performed by manual liquid chromatography-ultraviolet (LC-UV) or visible light-mass spectroscopy (Vis-MS) interpretation of detected peaks, often assisted by automated identification of previously identified compounds. We used a 15 min high-performance liquid chromatography-diode array detection (UHPLC-DAD)-high-resolution MS method (electrospray ionization (ESI)(+) or ESI(-)), followed by 10-60 s of automated data analysis for up to 3000 relevant elemental compositions. By overlaying automatically generated extracted-ion chromatograms from detected compounds on the base peak chromatogram, all major potentially novel peaks could be visualized. Peaks corresponding to compounds available as reference standards, previously identified compounds, and major contaminants from solvents, media, filters etc. were labeled to differentiate these from compounds only identified by elemental composition. This enabled fast manual evaluation of both known peaks and potential novel-compound peaks, by manual verification of: the adduct pattern, UV-Vis, retention time compared with log D, co-identified biosynthetic related compounds, and elution order. System performance, including adduct patterns, in-source fragmentation, and ion-cooler bias, was investigated on reference standards, and the overall method was used on extracts of Aspergillus carbonarius and Penicillium melanoconidium, revealing new nitrogen-containing biomarkers for both species.


Prevalence and correlation of human papilloma virus and its types with prognostic markers in patients with invasive ductal carcinoma of the breast in kuwait.
This study aimed to document the association of human papilloma virus (HPV) and its types in breast carcinoma tissues in Kuwaiti women, and correlate this with known prognostic markers. The clinicopathological data of archived tissue from 144 cases of invasive ductal breast carcinoma were studied (age, histological grade, size of tumour, lymph node metastases, oestrogen/progesterone receptors and human epidermal growth factor receptor 2 status). HPV frequency was documented using immunohistochemistry (IHC) and chromogenic in-situ hybridisation (CISH). HPV types were documented by CISH using HPV probes. CISH and IHC techniques were compared and HPV correlated with prognostic parameters. The HPV prevalence as determined by CISH and IHC was 51 (35.4%) and 24 (16.7%) cases, respectively. The sensitivity of HPV by IHC was 37.3% and specificity was 94.6%. The sensitivity and specificity of HPV-CISH compared to HPVIHC was statistically significant (P <0.001). HPV-CISH was seen in 51 cases. A combination of HPV 6 and 11, and 16 and 18 was seen in 2 (3.9%) cases, and a combination of HPV 6, 11, 31 and 33 was seen in 7 (13.7%) cases. All three HPV probes: 6 and 11, 16 and 18, as well as 31 and 33 were present in 2 (3.9%) cases. The prevalence of HPVCISH in the Kuwaiti and non-Kuwaiti populations was 27 (52.9%) and 19 (37.2%), respectively. No correlation was observed with the prognostic parameters. The frequency of HPV in breast carcinoma cases in Kuwait was 35.4% (CISH). Of those, 52.9% were Kuwaitis in whom both low- and high-risk HPV types were detected.


Improving Anesthesia Safety in Low-Resource Settings.
The safety of anesthesia characteristic of high-income countries today is not matched in low-resource settings with poor infrastructure, shortages of anesthesia providers, essential drugs, equipment, and supplies. Health care is delivered through complex systems. Achieving sustainable widespread improvement globally will require an understanding of how to influence such systems. Health outcomes depend not only on a country's income, but also on how resources are allocated, and both vary substantially, between and within countries. Safety is particularly important in anesthesia because anesthesia is intrinsically hazardous and not intrinsically therapeutic. Nevertheless, other elements of the quality of health care, notably access, must also be considered. More generally, there are certain prerequisites within society for health, captured in the Jakarta declaration. It is necessary to have adequate infrastructure (notably for transport and primary health care) and hospitals capable of safely carrying out the "Bellwether Procedures" (cesarean delivery, laparotomy, and the treatment of compound fractures). Surgery, supported by safe anesthesia, is critical to the health of populations, but avoidable harm from health care (including very high mortality rates from anesthesia in many parts of the world) is a major global problem. Thus, surgical and anesthesia services must not only be provided, they must be safe. The global anesthesia workforce crisis is a major barrier to achieving this. Many anesthetics today are administered by nonphysicians with limited training and little access to supervision or support, often working in very challenging circumstances. Many organizations, notably the World Health Organization and the World Federation of Societies of Anaesthesiologists, are working to improve access to and safety of anesthesia and surgery around the world. Challenges include collaboration with local stakeholders, coordination of effort between agencies, and the need to influence national health policy makers to achieve sustainable improvement. It is conceivable that safe anesthesia and perioperative care could be provided for essential surgical services today by clinicians with moderate levels of training using relatively simple (but appropriately designed and maintained) equipment and a limited number of inexpensive generic medications. However, there is a minimum standard for these resources, below which reasonable safety cannot be assured. This minimum (at least) should be available to all. Not only more resources, but also more equitable distribution of existing resources is required. Thus, the starting point for global access to safe anesthesia is acceptance that access to health care in general should be a basic human right everywhere.


[The archeology of San Vincente de Paul Hospital in Santiago, Chile].
The San Vicente de Paul Hospital was the first Clinical Hospital of the University of Chile and was located at the same place of present School of Medicine. The School area contains several old buildings, which are probably remains of the San Vicente de Paul Hospital. After a careful study of the current plans of the Faculty of Medicine of the University of Chile and those of the San Vicente de Paul Hospital, and after checking measurements on the actual site, we were able to demonstrate that two and a half clinical rooms of the original building and some parts of the old laundry still remain intact. At present, these constructions are being used as storerooms, student's union offices, and other activities. We expect that this article may contribute to improve the knowledge of our roots by our own as well as by future generations and that it may inspire our authorities to take care and preserve this important patrimonial remains of our national medicine.


Excess calorie intake early in life increases susceptibility to colitis in adulthood.
Epidemiological data reveal an association between obesity and inflammatory bowel disease (IBD). Furthermore, animal models demonstrate that maternal high-fat diet (HFD) and maternal obesity increase susceptibility to IBD in offspring. Here we report that excess calorie intake by neonatal mice, as a consequence of maternal HFD, forced feeding of neonates or low litter competition, leads to an increase during weaning in intestinal permeability, expression of pro-inflammatory cytokines and hydrogen sulfide production by the microbiota. These intestinal changes engage in mutual positive feedback that imprints increased susceptibility to colitis in adults. The pathological imprinting is prevented by the neutralization of IFN-γ and TNF-α or the production of hydrogen sulfide, or by normalization of intestinal permeability during weaning. We propose that excess calorie intake by neonates leads to multiple causally linked perturbations in the intestine that imprint the individual with long-term susceptibility to IBD.


Brief report: visual acuity in children with autism spectrum disorders.
Recently, there has been heightened interest in suggestions of enhanced visual acuity in autism spectrum disorders (ASD) which was sparked by evidence that was later accepted to be methodologically flawed. However, a recent study that claimed children with ASD have enhanced visual acuity (Brosnan et al. in J Autism Dev Disord 42:2491-2497, 2012) repeated a critical methodological flaw by using an inappropriate viewing distance for a computerised acuity test, placing the findings in doubt. We examined visual acuity in 31 children with ASD and 33 controls using the 2 m 2000 Series Revised Early Treatment Diabetic Retinopathy Study chart placed at twice the conventional distance to better evaluate possible enhanced acuity. Children with ASD did not demonstrate superior acuity. The current findings strengthen the argument that reports of enhanced acuity in ASD are due to methodological flaws and challenges the reported association between visual acuity and systemising type behaviours.


Comparison of robotic surgery and laparoscopy to perform total hysterectomy with pelvic adhesions or large uterus.
Currently, benefits of robotic surgery in patients with benign gynecological conditions remain unclear. In this study, we compared the surgical outcome of robotic and laparoscopic total hysterectomies and evaluated the feasibility of robotic surgery in cases with pelvic adhesions or large uterus. A total of 216 patients receiving total hysterectomy via robotic or laparoscopic approach were included in this study. Of all 216 patients, 88 underwent robotic total hysterectomy and 128 underwent laparoscopic total hysterectomy. All cases were grouped by surgical type, adhesion score, and uterine weight to evaluate the interaction or individual effect to the surgical outcomes. The perioperative parameters, including operation time, blood loss, postoperative pain score, time to full diet resumption, length of hospital stay, conversion rate, and surgery-related complications were compared between the groups. Operation time and blood loss were affected by both surgical type and adhesion score. For cases with severe adhesions (adhesion score greater than 4), robotic surgery was associated with a shortened operation time (113.9 ± 38.4 min versus 164.3 ± 81.4 min, P = 0.007) and reduced blood loss (187.5 ± 148.7 mL versus 385.7 ± 482.6, P=0.044) compared with laparoscopy. Moreover, robotic group showed a lower postoperative pain score than laparoscopic group, as the effect was found to be independent of adhesion score or uterine weight. The grade-II complication rate was also found to be lower in the robotic group. Comparing to laparoscopic approach, robotic surgery is a feasible and potential alternative for performing total hysterectomy with severe adhesions.


Open-source image registration for MRI-TRUS fusion-guided prostate interventions.
We propose two software tools for non-rigid registration of MRI and transrectal ultrasound (TRUS) images of the prostate. Our ultimate goal is to develop an open-source solution to support MRI-TRUS fusion image guidance of prostate interventions, such as targeted biopsy for prostate cancer detection and focal therapy. It is widely hypothesized that image registration is an essential component in such systems. The two non-rigid registration methods are: (1) a deformable registration of the prostate segmentation distance maps with B-spline regularization and (2) a finite element-based deformable registration of the segmentation surfaces in the presence of partial data. We evaluate the methods retrospectively using clinical patient image data collected during standard clinical procedures. Computation time and Target Registration Error (TRE) calculated at the expert-identified anatomical landmarks were used as quantitative measures for the evaluation. The presented image registration tools were capable of completing deformable registration computation within 5 min. Average TRE was approximately 3 mm for both methods, which is comparable with the slice thickness in our MRI data. Both tools are available under nonrestrictive open-source license. We release open-source tools that may be used for registration during MRI-TRUS-guided prostate interventions. Our tools implement novel registration approaches and produce acceptable registration results. We believe these tools will lower the barriers in development and deployment of interventional research solutions and facilitate comparison with similar tools.


Optical Properties of Meloxicam in the Far-Infrared Spectral Region.
One of the most commonly used nonsteroidal anti-inflammatory active pharmaceutical ingredient called Meloxicam has been characterized spectroscopically both by Terahertz (THz) time domain spectroscopy (THz-TDS) and by Fourier Transform Infrared (FTIR) spectroscopy in far-IR regions of electromagnetic spectrum; 0.2 THz to 20 THz. While many relatively sharp features are observed in the far-IR range between 2 THz to 20 THz as expected for being an organic substance, very distinct and relatively strong absorption bands are also observed at 1.00, 1.66, 2.07 and 2.57 THz in the THz range. These well separated, defined, and fairly strong spectral features can be used for discrimination and quantification of Meloxicam in drug analysis. Frequency dependent refractive index of the drug was determined in a range of 0.2 THz and 2.7 THz, where an almost constant index was observed with an average index of 1.75. Powder XRD, and solid-state Density Functional Theory (SS-DFT) calculations were utilized to determine the crystalline form of the Meloxicam sample in its enolic crystalline form. Single molecule DFT calculations were also performed in all four possible structures of Meloxicam. In addition, the capability of THz waves transmission through common packaging materials is demonstrated for possibility of future on-site analysis. The results suggest that drug analysis will be possible to perform not only at every stage of manufacturing without destruction but also directly at the shelf of a market after development of portable THz technologies.


Antagonistic roles of Drosophila Tctp and Brahma in chromatin remodelling and stabilizing repeated sequences.
Genome stability is essential for all organisms. Translationally controlled tumour protein (TCTP) is a conserved protein associated with cancers. TCTP is involved in multiple intracellular functions, but its role in transcription and genome stability is poorly understood. Here, we demonstrate new functions of Drosophila TCTP (Tctp) in transcription and the stability of repeated sequences (rDNA and pericentromeric heterochromatin). Tctp binds Brahma (Brm) chromatin remodeler to negatively modulate its activity. Tctp mutants show abnormally high levels of transcription in a large set of genes and transposons. These defects are ameliorated by brm mutations. Furthermore, Tctp promotes the stability of repeated sequences by opposing the Brm function. Additional regulation of pericentromeric heterochromatin by Tctp is mediated by su(var)3-9 transcriptional regulation. Altogether, Tctp regulates transcription and the stability of repeated sequences by antagonizing excess Brm activity. This study provides insights into broader nuclear TCTP functions for the maintenance of genome stability.


Platelet--arterial synthetic graft interaction and its modification.
We compared the in vivo platelet reactivity of two commonly used clinical grafts, Dacron and expanded polytetrafluoroethylene (PTFE), with that of a control autogenous artery graft and assessed whether platelet reactivity was modified by the platelet-antiaggregating agent prostacyclin (PGI2) (epoprostenol). Grafts were randomly placed into the carotid arteries of 21 baboons. Platelets labeled with indium 111 were infused within one hour after implantation graft for gamma camera scanning of platelet uptake. The accumulation of platelets on Dacron grafts began almost immediately after injection and reached a peak after one to two hours. The PTFE and control autogenous artery grafts accumulated comparable small amounts of platelets. Prostacyclin was then infused in a second series of baboons with Dacron grafts, at a rate of 150 to 200 ng/kg/min. It prevented the usual platelet uptake when administered concomitant with graft implantation and reduced previously established platelet activity.


Inversion-induced disruption of the Hoxd cluster leads to the partition of regulatory landscapes.
The developmental regulation of vertebrate Hox gene transcription relies on the interplay between local and long-range controls. To study this complex genomic organization, we designed a strategy combining meiotic and targeted recombinations to induce large chromosomal rearrangements in vivo without manipulating embryonic stem cells. With this simple approach (called STRING), we engineered a large 7-cM inversion, which split the Hoxd cluster into two independent pieces. Expression analyses showed a partition of global enhancers, allowing for their precise topographic allocation on either side of the cluster. Such a functional organization probably contributed to keeping these genes clustered in the course of vertebrate evolution. This approach can be used to study the relationship between genome architecture and gene expression, such as the effects of genome rearrangements in human diseases or during evolution.


Endocrine (plasma cortisol and glucose) and behavioral (locomotor and self-feeding activity) circadian rhythms in Senegalese sole (Solea senegalensis Kaup 1858) exposed to light/dark cycles or constant light.
The existence of daily rhythms under light/dark (LD) cycles in plasma cortisol, blood glucose and locomotor and self-feeding activities, as well as their persistence (circadian nature) under constant light (LL), was investigated in Senegalese sole (Solea senegalensis). For the cortisol and glucose rhythms study, 48 soles were equally distributed in 8 tanks and exposed to a 12:12 LD cycle and natural water temperature (experiment 1). After an acclimation period, blood was sampled every 3 h until a 24-h cycle was completed. Blood glucose levels were measured immediately after sampling, while plasma cortisol was measured later by ELISA. In experiment 2, the fish were exposed to LL for 11 days, and after this period, the same sampling procedure was repeated. For the study of locomotor and self-feeding rhythms (experiment 3), two groups of sole were used: one exposed to LD and the other to LL. Each group was distributed within 3 tanks equipped with infrared photocells for the record of locomotor activity, and self-feeders for feeding behavior characterization. The results revealed a marked oscillation in cortisol concentrations during the daily cycle under LD, with a peak (35.65 ± 3.14 ng/ml) in the afternoon (15:00 h) and very low levels during the night (5.30 ± 1.09 ng/ml). This cortisol rhythm persisted under LL conditions, with lower values (mean cortisol concentration = 7.12 ± 1.11 ng/ml) and with the peak shifted by 3 h. Both rhythms were confirmed by COSINOR analysis (p < 0.05). The synchronizing role of temperature and feeding schedule, in addition to light, is also discussed. Diel rhythms of glucose were not evident in LD or LL. As to locomotor and self-feeding activity, a very marked rhythm was observed under LD, with higher activity observed during the night, with acrophases located at 2:14 and 3:37 h, respectively. The statistical significance of daily rhythms was confirmed by COSINOR analysis. Under LL, both feeding and locomotor rhythms persisted, with an endogenous period (τ) around 22.5 h. In short, our findings described for the first time the existence of circadian cortisol and behavioral circadian rhythms in flat fish. Such results revealed the importance of taking into account the time of day when assessing stress responses and evaluating physiological indicators of stress in fish.


Verrucous carcinoma of the esophagus eluding multiple sets of endoscopic biopsies and endoscopic ultrasound: a case report and review of the literature.
A 56-year-old woman was noted to have a 5 cm to 6 cm long, irregular narrowing of the distal esophagus on an upper gastrointestinal series. Initial endoscopy revealed a polypoid mass in the distal esophagus and concurrent endoscopic ultrasound revealed changes typical of inflammation but no evidence of an obvious neoplastic process. Repeated biopsies revealed only inflammation with no evidence of malignancy. Only after prolonged acid suppression did biopsies reveal verrucous carcinoma of the esophagus. The patient underwent a trans-hiatal esophagectomy and has remained well with no evidence of progression since. Verrucous carcinoma is a rare variant of squamous cell carcinoma, taking on a papillary or warty appearance grossly. Histological diagnosis may be difficult because this tumour typically shows no high-grade dysplasia. Therefore, diagnosis can be challenging, often requiring multiple sets of endoscopic biopsies due to the overlying hyperkeratotic layer. Of the 20 cases that have been reported, this is the second to provide an endosonographic description and the first to describe a change in endoscopic appearance with acid suppression.


p62, A TFIIH subunit, directly interacts with thyroid hormone receptor and enhances T3-mediated transcription.
Currently, little is known about the direct interactions of general transcription factors and nuclear hormone receptors. To investigate the potential role of the general transcription factor, TFIIH, in T3-mediated transcriptional activation, we examined thyroid hormone receptor (TR) interaction with individual TFIIH subunits in a yeast-two hybrid system. Among the nine subunits of TFIIH studied, only p62 subunit interacted with TRbeta in a ligand-dependent manner. Glutathione-S-transferase pull-down and in vivo coimmunoprecipitation studies also demonstrated direct TR/p62 interaction. Using chromatin immunoprecipitation assays, we showed that TFIIH subunits were corecruited on or near an endogenous thyroid hormone response element upon T3 addition. Cotransfection studies with TSA201 cells showed that p62 increased T3-mediated transcription, which could be further enhanced when p62 and another TFIIH subunit, p44, were cotransfected simultaneously. Taken together, these data suggest that TRs can interact directly with a subunit of TFIIH and may provide an alternative pathway for nuclear receptor communication with the general transcription machinery that circumvents coactivators.


Systolic anterior motion of the mitral valve-the mechanism of postural hypotension following left intrapericardial pneumonectomy.
Systolic anterior motion (SAM) is defined as displacement of the distal portion of the anterior leaflet of the mitral valve toward the left ventricular outflow tract obstruction. SAM can occur in patients without hypertrophic cardiomyopathy (HOCM) and is a well-recognized cause for unexplained sudden hypotension in perioperative settings. We present a case of persistent orthostatic hypotension caused by SAM following left intrapericardial pneumonectomy and mediastinal lymph node dissection for squamous cell carcinoma of the lung invading intrapericardial portion of the inferior pulmonary vein. Diagnosis of SAM was possible with the use of transesophageal echocardiography (TEE).


Prognostic markers in lung cancer: is it ready for prime time?
Non-small cell lung cancer (NSCLC) is a heterogeneity disease and to date, specific clinical factors and tumor stage are established as prognostic markers. Nevertheless, prognosis within stage may vary significantly. During the last 3 decades, genes/proteins that drive tumor initiation and progression, such as oncogenes and tumor suppressor genes have been studied as additional potential prognostic markers. The protein markers as evaluated by immunohistochemistry (IHC) have previously dominated these studies. However, with the development of high-throughput techniques to interrogate genome wide genetic or gene expression changes, DNA (copy number and mutation) and RNA (mRNA and microRNA) based markers have more recently been studied as prognostic markers. Largely due to the heterogeneity and complexity of NSCLC, single gene markers including KRAS mutation has not been validated as strong prognostic markers. In contrast, several gene expression signatures representing mRNA levels of multiple genes have been developed and validated in multiple microarray datasets of independent patient cohorts. The salient features of these gene signatures and their potential value to predict benefit from adjuvant chemotherapy is discussed.


Leflunomide Increases Hepatic Exposure to Methotrexate and Its Metabolite by Differentially Regulating Multidrug Resistance-Associated Protein Mrp2/3/4 Transporters via Peroxisome Proliferator-Activated Receptor α Activation.
Methotrexate (MTX) is the gold standard drug for the treatment of rheumatoid arthritis (RA), and it is frequently combined with leflunomide (LEF) to enhance its clinical efficacy. However, this combination can exacerbate liver toxicity, and the underlying mechanism has not yet been clarified. We investigated whether LEF affects the pharmacokinetics of MTX and its primary toxic metabolite, 7-hydroxyl methotrexate (7OH MTX), in mice. LEF significantly increased the plasma concentration (area under the plasma concentration-time curve) of MTX and 7OH MTX (2.4 and 4.5 times, respectively), decreased their bile excretion, and increased their accumulation in the liver and kidneys. When we investigated the effect of LEF on the MTX absorption, distribution, metabolism, and excretion process, we found that LEF had little effect on liver aldehyde oxidase and 7OH MTX formation. However, LEF significantly decreased the expression of the apical efflux transporter multidrug resistance-associated protein 2 (Mrp2) and increased that of the basolateral efflux transporters Mrp3/4, except there was no significant change in Mrp4 protein expression. Mrp2/3/4 alteration changed the distribution of MTX and 7OH MTX in plasma and tissues. Further studies suggested that LEF indirectly activated peroxisome proliferator-activated receptor α (PPARα), which was likely responsible for the Mrp2/3/4 alteration in the liver. The MTX plasma concentration change induced by LEF was reversed by the PPARα-specific antagonist GW6471. These results may partially explain the exacerbated liver toxicity caused by combination treatment with MTX and LEF and may raise concerns regarding the risk of potential drug-drug interactions between PPARα agonists and Mrp substrates in the clinic.


Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients.
Semiquantitative assessment of immune markers by immunohistochemistry (IHC) has significant limitations for describing the diversity of the immune response in cancer. Therefore, we evaluated a fluorescence-based multiplexed immunohistochemical method in combination with a multispectral imaging system to quantify immune infiltrates in situ in the environment of non-small-cell lung cancer (NSCLC). A tissue microarray including 57 NSCLC cases was stained with antibodies against CD8, CD20, CD4, FOXP3, CD45RO, and pan-cytokeratin, and immune cells were quantified in epithelial and stromal compartments. The results were compared with those of conventional IHC, and related to corresponding RNA-sequencing (RNAseq) expression values. We found a strong correlation between the visual and digital quantification of lymphocytes for CD45RO (correlation coefficient: r = 0.52), FOXP3 (r = 0.87), CD4 (r = 0.79), CD20 (r = 0.81) and CD8 (r = 0.90) cells. The correlation with RNAseq data for digital quantification (0.35-0.65) was comparable to or better than that for visual quantification (0.38-0.58). Combination of the signals of the five immune markers enabled further subpopulations of lymphocytes to be identified and localized. The specific pattern of immune cell infiltration based either on the spatial distribution (distance between regulatory CD8+ T and cancer cells) or the relationships of lymphocyte subclasses with each other (e.g. cytotoxic/regulatory cell ratio) were associated with patient prognosis. In conclusion, the fluorescence multiplexed immunohistochemical method, based on only one tissue section, provided reliable quantification and localization of immune cells in cancer tissue. The application of this technique to clinical biopsies can provide a basic characterization of immune infiltrates to guide clinical decisions in the era of immunotherapy. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Feasibility and Acceptability of an Interactive Cancer-Communication Video Program Using African American Breast Cancer Survivor Stories.
To examine the feasibility and acceptability of an interactive video program of African American breast cancer survivor stories, we explored story reactions among African American women with newly diagnosed breast cancer and associations between patient factors and intervention use. During a randomized controlled trial, patients in the intervention arm completed a baseline/pre-intervention interview, received the video intervention, and completed a post-intervention 1-month follow-up interview. Additional video exposures and post-exposure interviews occurred at 6- and 12-month follow-ups. Multivariable linear mixed-effects models examined interview and clinical data in association with changes in minutes and actions using the program. After Exposure1, 104 of 108 patients allocated to the intervention reported moderate-to-high levels of positive emotional reactions to stories and identification with storytellers. Exposure1 mean usage was high (139 minutes) but declined over time (p <.0001). Patients receiving surgery plus radiation logged about 50 more minutes and actions over 12-month follow-up than patients receiving surgery only (p <.05); patients reporting greater trust in storytellers logged 18.6 fewer actions over time (p =.04). Patients' topical interests evolved, with patients watching more follow-up care and survivorship videos at Exposure3. The intervention was feasible and evaluated favorably. New videos might satisfy patients' changing interests.


40 Gb/s wavelength conversion via four-wave mixing in a quantum-dot semiconductor optical amplifier.
The static and dynamic characteristics of degenerate four-wave mixing in a quantum dot semiconductor optical amplifier are investigated. A high chip conversion efficiency of 1.5 dB at 0.3 nm detuning, a low (< 5 dB) asymmetry of up and down conversion and a spectral conversion range of 15 nm with an optical signal-to-noise ratio above 20 dB is observed. The comparison of pumping near the gain peak and at the edge of the gain spectrum reveals the optical signal-to-noise ratio as the crucial parameter for error-free wavelength conversion. Small-signal bandwidths well beyond 40 GHz and 40 Gb/s error-free 5 nm wavelength down conversion with penalties below 1 dB are presented. Due to the optical signal-to-noise ratio limitation, wavelength up conversion is error-free at a pump wavelength of 1311 nm with a penalty of 2.5 dB, whereas an error floor is observed for pumping at 1291 nm. A dual pump configuration is demonstrated, to extend the wavelength conversion range enabling 15.4 nm error-free wavelength up conversion with 3.5 dB penalty caused by the additional saturation of the second pump. This is the first time that 40 Gb/s error-free wavelength conversion via four-wave mixing in quantum-dot semiconductor optical amplifiers is presented.


Cyclosporin-induced hypomagnesaemia and renal magnesium wasting in rats.
1. Twenty-four hour clearance studies were performed on three groups of rats to determine the hypomagnesaemic effect of cyclosporin. Group I rats served as controls, whereas group II rats received 10 mg of cyclosporin/kg and group III rats received 20 mg of cyclosporin/kg daily. 2. After 7 days of cyclosporin treatment, plasma magnesium concentration was 1.04 +/- 0.01 mmol/l in control rats compared with 0.85 +/- 0.01 mmol/l in group II and 0.81 +/- 0.02 mmol/l in group III. After 14 days of cyclosporin administration, group III rats developed severe hypomagnesaemia (0.67 +/- 0.01 mmol/l). This reduction in plasma magnesium was associated with an increase in the urinary excretion of magnesium. 3. This reduction in plasma magnesium and increment in magnesium excretion returned to normal 7 days after cessation of treatment. 4. Additional three-phase acute clearance experiments were performed on eight normal and 12 cyclosporin-treated rats (20 mg/kg). These animals were subjected to acute magnesium chloride infusion. After graded magnesium chloride infusion, despite a similar rise in plasma magnesium, the fractional magnesium excretion was significantly higher in the cyclosporin-treated animals. 5. Analysis of the fractional intestinal absorption of magnesium suggested that the development of hypomagnesaemia after cyclosporin treatment is due to magnesium loss by the kidney. Furthermore, this effect of cyclosporin on magnesium transport is only present during cyclosporin treatment and is reversible when treatment with cyclosporin is withdrawn.


Orientation-reversal and phase-reversal visual evoked potentials in full-term infants with brain lesions: a longitudinal study.
The onset and maturation of visual cortical mechanisms can be recorded by using steady-state visual evoked potentials. The aim of this study was to evaluate and compare orientation-reversal (OR) and phase-reversal (PH) VEP as indicators of the maturation of cortical function in a population of fullterm infants with brain lesions on neonatal MRI. Forty-six infants with brain lesions on neonatal MRI were tested on both PH and OR VEP at 8 reversals/second at the age of 5 months and, if the responses were not significant, at a lower temporal frequency (4 reversals/second). Children whose VEPs were not significant at 5 months were tested longitudinally at 6, 9, 12 and 18 months. The results showed that 23 of the 46 infants (50%) did not show significant responses at 5 months and that while in 7 of the 23 (14% of the whole cohort) the responses became significant between 5 and 12 months, in the other 16 infants (34%) the VEP responses were persistently abnormal. Children with focal lesions, such as focal infarction or haemorrhages, tended to show normal or only mildly delayed VEP while more generalised lesions, such as the ones seen in infants with hypoxic-ischaemic encephalopathy grade 2 and 3, tended to be associated with abnormal VEP responses. The involvement of the optic radiations and occipital cortex was not always associated with abnormal VEP responses but the concomitant involvement of the basal ganglia was always associated with abnormal VEP. We were also able to demonstrate that VEP can be also used as a prognostic indicator: while normal OR VEP are reliably associated with a normal visual and neurodevelopmental outcome, abnormal 4 OR or 8 PH at 5 months are consistently associated with abnormal outcome.


Ischaemic brain damage in the gerbil in the absence of 'no-reflow'.
Approximately 40% of gerbils subjected to one hour of unilateral carotid artery occlusion displayed neurological abnormalities during that time. Most such animals were subsequently found to have ischaemic neuronal alterations within the territory of the ipsilateral middle cerebral artery. In contrast, impaired reperfusion ('no-reflow') rarely occurred and cannot therefore be implicated in the pathogenesis of ischaemic brain damage.


Novel risk factors for acute kidney injury.
Acute kidney injury (AKI) is a serious problem. Understanding an individual patient's risk profile may offer opportunities for prevention or early intervention. The aim of this review is to describe novel nontraditional risk factors. The risk of AKI is determined by patient factors and nephrotoxic exposures. Hyperuricaemia, obesity, hypoalbuminaemia and certain genetic polymorphism have been found to be associated with an increased susceptibility to AKI, especially in surgical patients. However, there is no convincing evidence that albumin replacement or uric acid lowering ameliorates the risk. Genetic predisposition contributes to AKI in general and also drug-nephrotoxicity. The exact relationship between obesity and AKI has not been fully understood.Patients exposed to starches, chloride-rich fluids or mechanical ventilation have an increased risk of AKI. Starches in particular should be avoided in high-risk patients. Although chloride-rich fluids are associated with AKI based on observational studies, direct proof of harm is lacking. Novel risk factors for AKI have been identified but more work is necessary to investigate the nature of the association. There is no evidence that correction of hyperuricaemia or hypoalbuminaemia is beneficial but high-risk exposures should be avoided in patients at risk of AKI.


Fuzzy anatomical connectedness of the brain using single and multiple fibre orientations estimated from diffusion MRI.
A new fuzzy algorithm for assessing white matter connectivity in the brain using diffusion-weighted magnetic resonance images is presented. The proposed method considers anatomical paths as chains of linked neighbouring voxels. Links between neighbours are assigned weights using the respective fibre orientation estimates. By checking all possible paths between any two voxels, a connectedness value is assigned, representative of the weakest link of the strongest path connecting the voxel pair. Multiple orientations within a voxel can be incorporated, thus allowing the utilization of fibre crossing information, while fibre branching is inherently considered. Under the assumption that paths connected strongly to a seed will exhibit adequate orientational coherence, fuzzy connectedness values offer a relative measure of path feasibility. The algorithm is validated using simulations and results are shown on diffusion tensor and Q-ball images.


Child's play: Harnessing play and curiosity motives to improve child handwashing in a humanitarian setting.
In humanitarian emergency settings there is need for low cost and rapidly deployable interventions to protect vulnerable children, in- and out-of-school, from diarrhoeal diseases. Handwashing with soap can greatly reduce diarrhoea but interventions specifically targeting children's handwashing behaviour in humanitarian settings have not been tested. Traditional children's handwashing promotion interventions have been school-focused, resource-intensive and reliant on health-based messaging. However, recent research from non-humanitarian settings and targeting adults suggests that theory-based behaviour change interventions targeting specific motives may be more effective than traditional handwashing interventions. In this proof-of-concept study we test, for the first time, the distribution of a modified soap bar, designed to appeal to the motives of play and curiosity, in a household-level, rapidly deployable, handwashing promotion intervention for older children in a humanitarian setting - an internally displaced persons camp in Iraqi Kurdistan. Out of five total blocks within the camp, one was assigned to intervention and one to control. 40 households from each assigned block were then randomly chosen for inclusion in the study and the practice of handwashing with soap at key times was measured at baseline and four weeks after intervention delivery. Children in intervention households received transparent soaps with embedded toys, delivered within a short, fun, and interactive household session with minimal, non-health-based, messaging. The control group received plain soap delivered in a short standard, health-based, hygiene promotion session. At the 4-week follow-up, children in the intervention group were 4 times more likely to wash their hands with soap after key handwashing occasions than expected in the counterfactual (if there had been no intervention) based on the comparison to children in the control group (adjusted RR = 3.94, 95% CI 1.59-9.79). We show that distributing soaps with toys embedded inside, in a rapidly deployable intervention, can improve child handwashing behaviour in a humanitarian emergency context. Further studies are needed to determine the longer-term behavioural and health impact of such an intervention when delivered at a greater scale in a humanitarian context.


Studying chemical reactivity in a virtual environment.
Chemical reactivity of a set of reactants is determined by its potential (electronic) energy (hyper)surface. The high dimensionality of this surface renders it difficult to efficiently explore reactivity in a large reactive system. Exhaustive sampling techniques and search algorithms are not straightforward to employ as it is not clear which explored path will eventually produce the minimum energy path of a reaction passing through a transition structure. Here, the chemist's intuition would be of invaluable help, but it cannot be easily exploited because (1) no intuitive and direct tool for the scientist to manipulate molecular structures is currently available and because (2) quantum chemical calculations are inherently expensive in terms of computational effort. In this work, we elaborate on how the chemist can be reintroduced into the exploratory process within a virtual environment that provides immediate feedback and intuitive tools to manipulate a reactive system. We work out in detail how this immersion should take place. We provide an analysis of modern semi-empirical methods which already today are candidates for the interactive study of chemical reactivity. Implications of manual structure manipulations for their physical meaning and chemical relevance are carefully analysed in order to provide sound theoretical foundations for the interpretation of the interactive reactivity exploration.


Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity.
Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that occur spontaneously, or from benign plexiform neurofibromas, in the context of the genetic disorder Neurofibromatosis Type 1 (NF1). The current standard treatment includes surgical resection, high-dose chemotherapy, and/or radiation. To date, most targeted therapies have failed to demonstrate effectiveness against plexiform neurofibromas and MPNSTs. Recently, several studies suggested that the mTOR and MAPK pathways are involved in the formation and progression of MPNSTs. Everolimus (RAD001) inhibits the mTOR and is currently FDA approved for several types of solid tumors. PD-0325901 (PD-901) inhibits MEK, a component of the MAPK pathway, and is currently in clinical trials. Here, we show in vitro than MPNST cell lines are more sensitive to inhibition of cellular growth by Everolimus and PD-901 than immortalized human Schwann cells. In combination, these drugs synergistically inhibit cell growth and induce apoptosis. In two genetically engineered mouse models of MPNST formation, modeling both sporadic and NF1-associated MPNSTs, Everolimus, or PD-901 treatment alone each transiently reduced tumor burden and size, and extended lifespan. However, prolonged treatment of each single agent resulted in the development of resistance and reactivation of target pathways. Combination therapy using Everolimus and PD-901 had synergistic effects on reducing tumor burden and size, and increased lifespan. Combination therapy allowed persistent and prolonged reduction in signaling through both pathways. These data suggest that co-targeting mTOR and MEK may be effective in patients with sporadic or NF1-associated MPNSTs.


The human adenovirus type 5 E1B 55 kDa protein obstructs inhibition of viral replication by type I interferon in normal human cells.
Vectors derived from human adenovirus type 5, which typically lack the E1A and E1B genes, induce robust innate immune responses that limit their therapeutic efficacy. We reported previously that the E1B 55 kDa protein inhibits expression of a set of cellular genes that is highly enriched for those associated with anti-viral defense and immune responses, and includes many interferon-sensitive genes. The sensitivity of replication of E1B 55 kDa null-mutants to exogenous interferon (IFN) was therefore examined in normal human fibroblasts and respiratory epithelial cells. Yields of the mutants were reduced at least 500-fold, compared to only 5-fold, for wild-type (WT) virus replication. To investigate the mechanistic basis of such inhibition, the accumulation of viral early proteins and genomes was compared by immunoblotting and qPCR, respectively, in WT- and mutant-infected cells in the absence or presence of exogenous IFN. Both the concentration of viral genomes detected during the late phase and the numbers of viral replication centers formed were strongly reduced in IFN-treated cells in the absence of the E1B protein, despite production of similar quantities of viral replication proteins. These defects could not be attributed to degradation of entering viral genomes, induction of apoptosis, or failure to reorganize components of PML nuclear bodies. Nor was assembly of the E1B- and E4 Orf6 protein- E3 ubiquitin ligase required to prevent inhibition of viral replication by IFN. However, by using RT-PCR, the E1B 55 kDa protein was demonstrated to be a potent repressor of expression of IFN-inducible genes in IFN-treated cells. We propose that a primary function of the previously described transcriptional repression activity of the E1B 55 kDa protein is to block expression of IFN- inducible genes, and hence to facilitate formation of viral replication centers and genome replication.


Numerical simulations of vibration in phase-shifting interferometry.
Computer simulations predict the expected rms measurement error in a phase-shifting interferometer in the presence of mechanical vibrations. The simulations involve a numerical resolution of a nonlinear mathematical model and are performed over a range of vibrational frequencies and amplitudes for three different phase-shift algorithms. Experimental research with an interference microscope and comparison with analytical solutions verify the numerical model.


Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists.
Chemokine receptors are critical regulators of cell migration in the context of immune surveillance, inflammation, and development. The G protein-coupled chemokine receptor CXCR4 is specifically implicated in cancer metastasis and HIV-1 infection. Here we report five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5 to 3.2 angstrom resolution. All structures reveal a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling. The location and shape of the ligand-binding sites differ from other G protein-coupled receptors and are closer to the extracellular surface. These structures provide new clues about the interactions between CXCR4 and its natural ligand CXCL12, and with the HIV-1 glycoprotein gp120.


The impact of service user's suicide on mental health professionals.
Our principle objective was to examine the personal and professional impact of service user (SU) suicide on mental health professionals (MHPs). We also wished to explore putative demographic or clinical factors relating to SUs or MPHs that could influence the impact of SU suicide for MHPs and explore factors MHPs report as helpful in reducing distress following SU suicide. A mixed-method questionnaire with quantitative and thematic analysis was utilised. Quantitative data indicated SU suicide was associated with personal and professional distress with sadness (79.5%), shock (74.5%) and surprise (68.7%) particularly evident with these phenomena lasting less than a year for more than 90% of MHPs. MHPs also reported guilt, reduced self-confidence and a fear of negative publicity. Thematic analysis indicated that some MHPs had greater expertise when addressing SU suicidal ideation and in supporting colleagues after experiencing a SU suicide. Only 17.7% of MHPs were offered formal support following SU suicide. SU suicide impacts MHPs personally and professionally in both a positive and negative fashion. A culture and clear pathway of formal support for MHPs to ascertain the most appropriate individualised support dependent on the distress they experience following SU suicide would be optimal.


A new method for predicting recovery after stroke.
Several prognostic factors have been identified for outcome after stroke. However, there is a need for empirically derived models that can predict outcome and assist in medical management during rehabilitation. To be useful, these models should take into account early changes in recovery and individual patient characteristics. We present such a model and demonstrate its clinical utility. Data on functional recovery (Barthel Index) at 0, 2, 4, 6, and 12 months after stroke were collected prospectively for 299 stroke patients at 2 London hospitals. Multilevel models were used to model recovery trajectories, allowing for day-to-day and between-patient variation. The predictive performance of the model was validated with an independent cohort of 710 stroke patients. Urinary incontinence, sex, prestroke disability, and dysarthria affected the level of outcome after stroke; age, dysphasia, and limb deficit also affected the rate of recovery. Applying this to the validation cohort, the average difference between predicted and observed Barthel Index was -0.4, with 90% limits of agreement from -7 to 6. Predicted Barthel Index lay within 3 points of the observed Barthel Index on 49% of occasions and improved to 69% when patients' recovery histories were taken into account. The model predicts recovery at various stages of rehabilitation in ways that could improve clinical decision making. Predictions can be altered in light of observed recovery. This model is a potentially useful tool for comparing individual patients with average recovery trajectories. Patients at elevated risk could be identified and interventions initiated.


Mouse Conventional Dendritic Cells Can be Universally Classified Based on the Mutually Exclusive Expression of XCR1 and SIRPα.
Since the identification of mouse dendritic cells (DC) in the early 70s, all attempts to consistently classify the identified functional DC subpopulations according to their surface molecule expression failed. In the absence of DC lineage markers, a great variety of non-congruent surface molecules were used instead. Recent advances in the understanding of the involvement of transcription factors in the differentiation of DC subpopulations, together with the identification of a lineage marker for cross-presenting DC, have now allowed to establish a consistent and unified DC classification in the mouse. We demonstrate in the present article that all conventional DC in the mouse can be universally subdivided into either XCR1(+) ("cross-presenting") DC or SIRPα(+) DC, irrespective of their activation status. This advancement will greatly facilitate future work on the biology of mouse DC. We discuss this new classification in view of current DC classification systems in the mouse and the human.


Evolution of weaponry in female bovids.
Weaponry is ubiquitous in male ungulates and is driven by intrasexual selection, but the mystery surrounding its sporadic presence in females remains unsolved. Female horns are often smaller and shaped differently to male horns, suggesting a different function; indeed, hypotheses explaining the presence of female horns include competition for food, male mollification and defence against predators. Here we use comparative phylogenetic analyses to show that females are significantly more likely to bear horns in bovids that are conspicuous due to large body size and living in open habitats than inconspicuous species living in closed habitats or that are small. An inability to rely on crypsis or take refuge in deep vegetation has apparently driven the evolution of horns for defence against predators in female bovids, a finding supported by many field observations. Typically, exceptions are small species where females are territorial (e.g. duikers) and use horns in intrasexual contests. Furthermore, we suggest that conspicuousness and territoriality hypotheses may explain other instances of female cranial weaponry (i.e. antlers and ossicones) in other horned ruminants. Our phylogenetic reconstruction indicates that the primary function of horns in females is linked to antipredator defence in most clades, but occasionally to intrasexual competition in others.


Meningococcus genome informatics platform: a system for analyzing multilocus sequence typing data.
The Meningococcus Genome Informatics Platform (MGIP) is a suite of computational tools for the analysis of multilocus sequence typing (MLST) data, at http://mgip.biology.gatech.edu. MLST is used to generate allelic profiles to characterize strains of Neisseria meningitidis, a major cause of bacterial meningitis worldwide. Neisseria meningitidis strains are characterized with MLST as specific sequence types (ST) and clonal complexes (CC) based on the DNA sequences at defined loci. These data are vital to molecular epidemiology studies of N. meningitidis, including outbreak investigations and population biology. MGIP analyzes DNA sequence trace files, returns individual allele calls and characterizes the STs and CCs. MGIP represents a substantial advance over existing software in several respects: (i) ease of use-MGIP is user friendly, intuitive and thoroughly documented; (ii) flexibility--because MGIP is a website, it is compatible with any computer with an internet connection, can be used from any geographic location, and there is no installation; (iii) speed--MGIP takes just over one minute to process a set of 96 trace files; and (iv) expandability--MGIP has the potential to expand to more loci than those used in MLST and even to other bacterial species.


An alarming high prevalence of resistance-associated mutations to macrolides and fluoroquinolones in Mycoplasma genitalium in Belgium: results from samples collected between 2015 and 2018.
The number of reported cases of multiresistant Mycoplasma genitalium (MG) is increasing globally. The aim of this study was to estimate the prevalence of macrolide and possible fluoroquinolone resistance-associated mutations (RAMs) of MG in Belgium. The study was performed retrospectively on two sets of MG-positive samples collected in Belgium between 2015 and 2018. The first set of samples originated from routine surveillance activities and the second set came from a cohort of men who have sex with men (MSM) using pre-exposure prophylaxis to prevent HIV transmission. Detection of RAMs to macrolides and fluoroquinolones was performed on all samples using DNA sequencing of the 23S ribosomal RNA gene, the gyrA gene and the parC gene. Seventy-one per cent of the MG samples contained a mutation conferring resistance to macrolides or fluoroquinolones (ParC position 83/87). RAMs were more frequently found among men compared with women for fluoroquinolones (23.9% vs 9.1%) and macrolides (78.4% vs 27.3%). Almost 90% of the MG infections among MSM possessed a RAM to macrolides (88.4%). In addition, 18.0% of the samples harboured both macrolides and fluoroquinolone RAMs; 3.0% in women and 24.2% in MSM. Being MSM was associated with macrolide RAMs (OR 15.3), fluoroquinolone RAMs (OR 3.8) and having a possible multiresistant MG infection (OR 7.2). The study shows an alarmingly high prevalence of MG with RAMs to macrolides and fluoroquinolones in Belgium. These results highlight the need to improve antimicrobial stewardship in Belgium in order to avoid the emergence of untreatable MG.


Risk factors for gastroesophageal reflux disease symptoms related to lifestyle and diet.
Gastroesophageal reflux disease (GERD) is one of the most common diseases of the upper gastrointestinal tract. The most characteristic symptom of the disease is heartburn, which occurs at least once a week. The prevalence of the disease varies and, depending on the region of the world, it may affect from a few to over 30% of an adult population. It is estimated that in Poland this disease may affect up to 35.5% of adults reporting abdominal ailments. If untreated, the disease can lead to serious complications including precancerous conditions and esophageal adenocarcinoma. Pharmacotherapy is considered as the first-line treatment in GERD patients but lifestyle modifications, including diet changes, are an important element supporting the treatment of the disease. Many factors may contribute to the development of the disease. Among them, there are non-modifiable factors such as age, sex or genetic factors and modifiable factors, e.g. lifestyle, diet, excessive body weight. This review focuses on GERD risk factors related to lifestyle and nutrition that include both dietary components and nutritional behaviour. Lifestyle risk factors that may contribute to GERD symptoms include excessive body weight, particularly obesity, moderate/high alcohol consumption, smoking, postprandial and vigorous physical activity, as well as lack of regular physical activity. Many studies indicate fatty, fried, sour, spicy food/products, orange and grapefruit juice, tomatoes and tomato preserves, chocolate, coffee/tea, carbonated beverages, alcohol as triggers for GERD symptoms. Eating habits such as irregular meal pattern, large volume of meals, eating meals just before bedtime may correlate with the symptoms of GERD. The role of lifestyle, diet and eating habits as risk factors for GERD is not clearly understood, and the results of the available studies are often contradictory. Determination of modifiable risk factors for this disease and its symptoms is important for effective dietary prevention and diet therapy of GERD.


Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression.
Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) may both be susceptibility genes for schizophrenia. As part of the evaluation of their roles in psychosis, we used reverse transcription-polymerase chain reaction to measure COMT and PRODH mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, major depression, and normal controls (n = 15 subjects in each group). We also genotyped two common COMT polymorphisms (-287A/G and 158Val/Met) which might affect its expression. Neither COMT nor PRODH mRNA abundance differed between diagnostic groups, nor when controls were compared with all psychotic patients. COMT mRNA levels were unrelated to COMT genotypes. We conclude that any involvement of COMT and PRODH genes in schizophrenia is not accompanied by significant alterations in their overall mRNA expression, at least in dorsolateral prefrontal cortex. As COMT and PRODH are both located on chromosome 22q11, the results also argue against the hypothesis that schizophrenia is associated with a decrease in expression of all 22q11 genes, as had been suggested by the high prevalence of psychosis in people with hemizygous 22q11 deletions.


Fifty years of hemodialysis access literature: The fifty most cited publications in the medical literature.
Objectives The modern era of hemodialysis access surgery began with the publication in 1966 by Brescia et al. describing the use of a surgically created arteriovenous fistula. Since then, the number of patients on chronic hemodialysis and the number of publications dealing with hemodialysis access have steadily increased. We have chronicled the increase in publications in the medical literature dealing with hemodialysis access by evaluating the characteristics of the 50 most cited articles. Methods We queried the Science Citation Index from the years 1960-2014. Articles were selected based on a subject search and were ranked according to the number of times they were cited in the medical literature. Results The 50 most frequently cited articles were selected for further analysis and the number of annual publications was tracked. The landmark publication by Dr Brescia et al. was unequivocally the most cited article dealing with hemodialysis access (1109 citations). The subject matter of the papers included AV fistula and graft (9), hemodialysis catheter (9), complications and outcomes (24), and other topics (8). Most articles were published in nephrology journals (33), with fewer in surgery (7), medicine (7), and radiology (3) journals. Of the 17 journals represented, Kidney International was the clear leader, publishing 18 articles. There has been an exponential rise in the frequency of publications regarding dialysis access with 42 of 50 analyzed papers being authored after 1990. Conclusion As the number of patients on hemodialysis has increased dramatically over the past five decades, there has been a commensurate increase in the overall number of publications related to hemodialysis access.


Pediatric retrograde intra-renal surgery for renal stones <2 cm in solitary kidney.
Management of renal stones in children with a solitary kidney is a challenge. In the current study, the efficacy and safety of retrograde intrarenal surgery (RIRS) in these children were determined. Records of children with renal stones who were treated at our institute between August 2011 and August 2014 were retrospectively assessed. Inclusion criteria were: Children with single renal stone <2 cm size, in a solitary kidney. A 7.5 Fr flexible ureteroscope (FURS) was introduced into the ureter over a hydrophilic guidewire under visual and fluoroscopic guidance - applying a back-loading technique. The stone was completely dusted using 200 μm laser fiber (0.2-0.8 joules power and 10-30 Hz frequency). At the end of the maneuver, a 5 Fr JJ stent was inserted into the ureter. The children were discharged home 24 h postoperative - provided that no complications were detected. Fourteen children (3 girls and 11 boys) with median age 9.5 years (range 6-12) were included. The mean stone burden was 12.2 ± 1.5 mm (range 9-20). Stones were successfully accessed in all of the cases by the FURS except for 2 cases in whom a JJ stent was inserted into the ureter and left in place for 2 weeks to achieve passive dilatation. All of the stones were dusted completely. The immediate postoperative stone-free rate (SFR) was 79%, and the final SFR was 100% after 3 weeks. No intraoperative complications were observed. RIRS for renal stone <2 cm in children with a solitary kidney is a single-session procedure with a high SFR, low complication rate, and is a minimally invasive, natural orifice technique.


A preliminary analysis of correlations between chewing motor patterns and mandibular morphology across mammals.
The establishment of a publicly-accessible repository of physiological data on feeding in mammals, the Feeding Experiments End-user Database (FEED), along with improvements in reconstruction of mammalian phylogeny, significantly improves our ability to address long-standing questions about the evolution of mammalian feeding. In this study, we use comparative phylogenetic methods to examine correlations between jaw robusticity and both the relative recruitment and the relative time of peak activity for the superficial masseter, deep masseter, and temporalis muscles across 19 mammalian species from six orders. We find little evidence for a relationship between jaw robusticity and electromyographic (EMG) activity for either the superficial masseter or temporalis muscles across mammals. We hypothesize that future analyses may identify significant associations between these physiological and morphological variables within subgroups of mammals that share similar diets, feeding behaviors, and/or phylogenetic histories. Alternatively, the relative peak recruitment and timing of the balancing-side (i.e., non-chewing-side) deep masseter muscle (BDM) is significantly negatively correlated with the relative area of the mandibular symphysis across our mammalian sample. This relationship exists despite BDM activity being associated with different loading regimes in the symphyses of primates compared to ungulates, suggesting a basic association between magnitude of symphyseal loads and symphyseal area among these mammals. Because our sample primarily represents mammals that use significant transverse movements during chewing, future research should address whether the correlations between BDM activity and symphyseal morphology characterize all mammals or should be restricted to this "transverse chewing" group. Finally, the significant correlations observed in this study suggest that physiological parameters are an integrated and evolving component of feeding across mammals.


Tuber Rot of Potato Caused by Phytophthora nicotianae: Isolate Aggressiveness and Cultivar Susceptibility.
A study was undertaken in 2008 and 2009 to examine potato (Solanum tuberosum) cultivar susceptibility, the potential of other host species to act as sources of inoculum for potato infections, and other aspects of potato-Phytophthora nicotianae interactions. Twelve isolates of P. nicotianae collected from five leaf, one petiole, and six tuber infections of potato from five states, as well as isolates from a variety of other host species, were evaluated for ability to cause tuber rot of potato via inoculation studies. Additionally, the susceptibility of 27 potato cultivars commonly grown in the United States to tuber infection by P. nicotianae was determined. Eighty-three percent of the isolates recovered from potato were highly aggressive, infecting tubers at nearly four times greater incidences than isolates originating from nonpotato hosts. With the exception of two tobacco isolates, zoospores of all isolates recovered from nonpotato hosts were able to infect potato tubers. Russet cultivars were significantly less susceptible to P. nicotianae than red and white cultivars in 2008, and red cultivars in 2009. Umatilla Russet was the most resistant cultivar in both years, whereas Red Norland and Dakota Rose were the most susceptible in both years. Results of a survey for P. nicotianae conducted in four states from 2008 through 2010 confirmed previous observations of naturally occurring infections of potato in Missouri, Nebraska, and Texas, as well as infections of potato in Michigan (documented for the first time). All isolates recovered in the survey were sensitive to mefenoxam (EC50 < 1.0 μg/ml).


The relationship between breastfeeding and weight status in a national sample of Australian children and adolescents.
Breastfeeding has been shown consistently in observational studies to be protective of overweight and obesity in later life. This study aimed to investigate the association between breastfeeding duration and weight status in a national sample of Australian children and adolescents. A secondary analysis of the 2007 Australian National Children's Nutrition and Physical Activity Survey data involving 2066, males and females aged 9 to 16 years from all Australian states and territories. The effect of breastfeeding duration on weight status was estimated using multivariate logistic regression analysis. Compared to those who were never breastfed, children breastfed for ≥6 months were significantly less likely to be overweight (adjusted odds ratio: 0.64, 95%CI: 0.45, 0.91) or obese (adjusted odds ratio: 0.51, 95%CI: 0.29, 0.90) in later childhood, after adjustment for maternal characteristics (age, education and ethnicity) and children's age, gender, mean energy intake, level of moderate and vigorous physical activity, screen time and sleep duration. Breastfeeding for 6 or more months appears to be protective against later overweight and obesity in this population of Australian children. The beneficial short-term health outcomes of breastfeeding for the infant are well recognised and this study provides further observational evidence of a potential long-term health outcome and additional justification for the continued support and promotion of breastfeeding to six months and beyond.


Quantum mechanics simulation of protein dynamics on long timescale.
Protein structure and dynamics are the keys to a wide range of problems in biology. In principle, both can be fully understood by using quantum mechanics as the ultimate tool to unveil the molecular interactions involved. Indeed, quantum mechanics of atoms and molecules have come to play a central role in chemistry and physics. In practice, however, direct application of quantum mechanics to protein systems has been prohibited by the large molecular size of proteins. As a consequence, there is no general quantum mechanical treatment that not only exceeds the accuracy of state-of-the-art empirical models for proteins but also maintains the efficiency needed for extensive sampling in the conformational space, a requirement mandated by the complexity of protein systems. Here we show that, given recent developments in methods, a general quantum mechanical-based treatment can be constructed. We report a molecular dynamics simulation of a protein, crambin, in solution for 350 ps in which we combine a semiempirical quantum-mechanical description of the entire protein with a description of the surrounding solvent, and solvent-protein interactions based on a molecular mechanics force field. Comparison with a recent very high-resolution crystal structure of crambin (Jelsch et al., Proc Natl Acad Sci USA 2000;102:2246-2251) shows that geometrical detail is better reproduced in this simulation than when several alternate molecular mechanics force fields are used to describe the entire system of protein and solvent, even though the structure is no less flexible. Individual atomic charges deviate in both directions from "canonical" values, and some charge transfer is found between the N and C-termini. The capability of simulating protein dynamics on and beyond the few hundred ps timescale with a demonstrably accurate quantum mechanical model will bring new opportunities to extend our understanding of a range of basic processes in biology such as molecular recognition and enzyme catalysis.


Exploring self-conscious emotions in individuals with chronic obstructive pulmonary disease.
This study aimed to explore the extent to which self-conscious emotions are expressed, to explore any associations with adverse health outcomes, and to compare self-conscious emotions in individuals with chronic obstructive pulmonary disease (COPD) to healthy controls. A two-stage mixed-methods study design was employed. Interviews with 15 individuals with COPD informed the choice of questionnaires to assess self-conscious emotions which were completed by individuals with COPD and healthy controls. Five overarching themes were abstracted: grief, spectrum of blame, concern about the view of others, concealment, and worry about the future. The questionnaires were completed by 70 patients (mean( SD) age 70.8(9.4) years, forced expiratory volume in one second predicted 40.5(18.8), 44% male) and 61 healthy controls (mean( SD) age 62.2(12.9) years, 34% male]. Self-conscious emotions were associated with reduced mastery, heightened emotions, and elevated anxiety and depression (all p < 0.001). Individuals with COPD reported lower self-compassion, higher shame, and less pride than healthy controls (all p ≤ 0.01). There is a need to increase awareness of self-conscious emotions in individuals with COPD. Therapies to target such emotions may improve mastery, emotions, and psychological symptoms.


Green synthesis of silver nanoparticles: biomolecule-nanoparticle organizations targeting antimicrobial activity.
Since discovery of the first antibiotic drug, penicillin, in 1928, a variety of antibiotic and antimicrobial agents have been developed and used for both human therapy and industrial applications. However, excess and uncontrolled use of antibiotic agents has caused a significant growth in the number of drug resistant pathogens. Novel therapeutic approaches replacing the inefficient antibiotics are in high demand to overcome increasing microbial multidrug resistance. In the recent years, ongoing research has focused on development of nano-scale objects as efficient antimicrobial therapies. Among the various nanoparticles, silver nanoparticles have gained much attention due to their unique antimicrobial properties. However, concerns about the synthesis of these materials such as use of precursor chemicals and toxic solvents, and generation of toxic byproducts have led to a new alternative approach, green synthesis. This eco-friendly technique incorporates use of biological agents, plants or microbial agents as reducing and capping agents. Silver nanoparticles synthesized by green chemistry offer a novel and potential alternative to chemically synthesized nanoparticles. In this review, we discuss the recent advances in green synthesis of silver nanoparticles, their application as antimicrobial agents and mechanism of antimicrobial mode of action.


Patient medical costs for tuberculosis treatment and impact on adherence in China: a systematic review.
Charging for tuberculosis (TB) treatment could reduce completion rates, particularly in the poor. We identified and synthesised studies that measure costs of TB treatment, estimates of adherence and the potential impact of charging on treatment completion in China. Inclusion criteria were primary research studies, including surveys and studies using qualitative methods, conducted in mainland China. We searched MEDLINE, PUBMED, EMBASE, Science Direct, HEED, CNKI to June 2010; and web pages of relevant Chinese and international organisations. Cost estimates were extracted, transformed, and expressed in absolute values and as a percentage of household income. Low income patients, defined at household or district level, pay a total of US$ 149 to 724 (RMB 1241 to 5228) for medical costs for a treatment course; as a percentage of annual household income, estimates range from 42% to 119%. One national survey showed 73% of TB patients at the time of the survey had interrupted or suspended treatment, and estimates from 9 smaller more recent studies showed that the proportion of patients at the time of the survey who had run out of drugs or were not taking them ranged from 3 to 25%. Synthesis of surveys and qualitative research indicate that cost is the most cited reason for default. Despite a policy of free drug treatment for TB in China, health services charge all income groups, and costs are high. Adherence measured in cross sectional surveys is often low, and the cumulative failure to adhere is likely to be much higher. These findings may be relevant to those concerned with the development and spread of multi-drug resistant TB. New strategies need to take this into account and ensure patient adherence.


Scalable Bayesian nonparametric regression via a Plackett-Luce model for conditional ranks.
We present a novel Bayesian nonparametric regression model for covariates X and continuous response variable Y ∈ ℝ. The model is parametrized in terms of marginal distributions for Y and X and a regression function which tunes the stochastic ordering of the conditional distributions F (y|x). By adopting an approximate composite likelihood approach, we show that the resulting posterior inference can be decoupled for the separate components of the model. This procedure can scale to very large datasets and allows for the use of standard, existing, software from Bayesian nonparametric density estimation and Plackett-Luce ranking estimation to be applied. As an illustration, we show an application of our approach to a US Census dataset, with over 1,300,000 data points and more than 100 covariates.


External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor.
The Ether-a-go-go (EAG) superfamily of voltage-gated K(+) channels consists of three functionally distinct gene families (Eag, Elk, and Erg) encoding a diverse set of low-threshold K(+) currents that regulate excitability in neurons and muscle. Previous studies indicate that external acidification inhibits activation of three EAG superfamily K(+) channels, Kv10.1 (Eag1), Kv11.1 (Erg1), and Kv12.1 (Elk1). We show here that Kv10.2, Kv12.2, and Kv12.3 are similarly inhibited by external protons, suggesting that high sensitivity to physiological pH changes is a general property of EAG superfamily channels. External acidification depolarizes the conductance-voltage (GV) curves of these channels, reducing low threshold activation. We explored the mechanism of this high pH sensitivity in Kv12.1, Kv10.2, and Kv11.1. We first examined the role of acidic voltage sensor residues that mediate divalent cation block of voltage activation in EAG superfamily channels because protons reduce the sensitivity of Kv12.1 to Zn(2+). Low pH similarly reduces Mg(2+) sensitivity of Kv10.1, and we found that the pH sensitivity of Kv11.1 was greatly attenuated at 1 mM Ca(2+). Individual neutralizations of a pair of EAG-specific acidic residues that have previously been implicated in divalent block of diverse EAG superfamily channels greatly reduced the pH response in Kv12.1, Kv10.2, and Kv11.1. Our results therefore suggest a common mechanism for pH-sensitive voltage activation in EAG superfamily channels. The EAG-specific acidic residues may form the proton-binding site or alternatively are required to hold the voltage sensor in a pH-sensitive conformation. The high pH sensitivity of EAG superfamily channels suggests that they could contribute to pH-sensitive K(+) currents observed in vivo.


Soil microbial response to photo-degraded C60 fullerenes.
Recent studies indicate that while unfunctionalized carbon nanomaterials (CNMs) exhibit very low decomposition rates in soils, even minor surface functionalization (e.g., as a result of photochemical weathering) may accelerate microbial decay. We present results from a C60 fullerene-soil incubation study designed to investigate the potential links between photochemical and microbial degradation of photo-irradiated C60. Irradiating aqueous (13)C-labeled C60 with solar-wavelength light resulted in a complex mixture of intermediate products with decreased aromaticity. Although addition of irradiated C60 to soil microcosms had little effect on net soil respiration, excess (13)C in the respired CO2 demonstrates that photo-irradiating C60 enhanced its degradation in soil, with ∼ 0.78% of 60 day photo-irradiated C60 mineralized. Community analysis by DGGE found that soil microbial community structure was altered and depended on the photo-treatment duration. These findings demonstrate how abiotic and biotic transformation processes can couple to influence degradation of CNMs in the natural environment.


Performance and ease influence perceived speed.
According to the action-specific perception account, perception is a function of optical information and the perceiver's ability to perform the intended action. While most of the evidence for the action-specific perception account is on spatial perception, in the current experiments we examined similar effects in the perception of speed. Tennis players reproduced the time the ball traveled from the feeder machine to when they hit it. The players judged the ball to be moving faster on trials when they hit the ball out-of-bounds than on trials where they successfully hit the ball in-bounds. Follow-up experiments in the laboratory showed that participants judged virtual balls to be moving slower when they played with a bigger paddle in a modified version of Pong. These studies suggest that performance and task ease influence perceived speed.


Heat stress attenuates the increase in arterial blood pressure during the cold pressor test.
The mechanisms by which heat stress impairs the control of blood pressure leading to compromised orthostatic tolerance are not thoroughly understood. A possible mechanism may be an attenuated blood pressure response to a given increase in sympathetic activity. This study tested the hypothesis that whole body heating attenuates the blood pressure response to a non-baroreflex-mediated sympathoexcitatory stimulus. Ten healthy subjects were instrumented for the measurement of integrated muscle sympathetic nerve activity (MSNA), mean arterial blood pressure (MAP), heart rate, sweat rate, and forearm skin blood flow. Subjects were exposed to a cold pressor test (CPT) by immersing a hand in an ice water slurry for 3 min while otherwise normothermic and while heat stressed (i.e., increase core temperature ~0.7°C via water-perfused suit). Mean responses from the final minute of the CPT were evaluated. In both thermal conditions CPT induced significant increases in MSNA and MAP without altering heart rate. Although the increase in MSNA to the CPT was similar between thermal conditions (normothermia: Δ14.0 ± 2.6; heat stress: Δ19.1 ± 2.6 bursts/min; P = 0.09), the accompanying increase in MAP was attenuated when subjects were heat stressed (normothermia: Δ25.6 ± 2.3, heat stress: Δ13.4 ± 3.0 mmHg; P < 0.001). The results demonstrate that heat stress can attenuate the pressor response to a sympathoexcitatory stimulus.


Laser heat treatments driven by integrated beams: role of irradiation nonuniformities.
An analysis is given of how nonuniformities in the laser beam intensity translate into variations on the induced temperature distribution on an irradiated sample. The study involves materials with different thermal conductivities. By use of a reshaped irradiating beam obtained with a multifaceted integrating mirror, a three-dimensional numerical calculation allows us to establish both surface and in-depth temperature distributions. The results show that in the case of materials such as glass (i.e., with low thermal conductivity) large thermal gradients occur both on the surface and in depth during irradiation. However, the lateral heat flow is high enough to strongly reduce the surface gradients as soon as the laser irradiation ends. Conversely, in good thermal conductors such as nickel, the laser intensity nonuniformities induce a thermal peaking of the surface with lateral thermal gradients that are by no means negligible. Experimental evidence during laser glass polishing that confirms the numerical assessments are also provided.


The nuclear OXPHOS genes in insecta: a common evolutionary origin, a common cis-regulatory motif, a common destiny for gene duplicates.
When orthologous sequences from species distributed throughout an optimal range of divergence times are available, comparative genomics is a powerful tool to address problems such as the identification of the forces that shape gene structure during evolution, although the functional constraints involved may vary in different genes and lineages. We identified and annotated in the MitoComp2 dataset the orthologs of 68 nuclear genes controlling oxidative phosphorylation in 11 Drosophilidae species and in five non-Drosophilidae insects, and compared them with each other and with their counterparts in three vertebrates (Fugu rubripes, Danio rerio and Homo sapiens) and in the cnidarian Nematostella vectensis, taking into account conservation of gene structure and regulatory motifs, and preservation of gene paralogs in the genome. Comparative analysis indicates that the ancestral insect OXPHOS genes were intron rich and that extensive intron loss and lineage-specific intron gain occurred during evolution. Comparison with vertebrates and cnidarians also shows that many OXPHOS gene introns predate the cnidarian/Bilateria evolutionary split. The nuclear respiratory gene element (NRG) has played a key role in the evolution of the insect OXPHOS genes; it is constantly conserved in the OXPHOS orthologs of all the insect species examined, while their duplicates either completely lack the element or possess only relics of the motif. Our observations reinforce the notion that the common ancestor of most animal phyla had intron-rich gene, and suggest that changes in the pattern of expression of the gene facilitate the fixation of duplications in the genome and the development of novel genetic functions.


Psychosocial adjustment of Israeli veterans with disabilities: Does employment status matter?
Since its establishment in 1948, the state of Israel has been deeply committed to reintegrating veterans with disabilities into mainstream society. Prominently, the Israeli Ministry of Defence's rehabilitation division provides veterans with disabilities with a wide array of benefits and services aimed at restoring their physical and psychosocial functioning, especially in the workplace. The focus on employment is motivated by a prevailing assumption among professionals that successful adjustment to disability is contingent on an individual's ability to reacquire normative occupational function. To date, however, this widely accepted wisdom has not been empirically scrutinized. To empirically explore whether employment status is associated to psychological, social, and behavioural adjustment attributes. One hundred and one employed veterans were compared to 111 non-employed veterans in respect to their self-reported levels of hope, acceptance of disability, social networks size and social participation patterns. Employed veterans reported significantly higher levels psychological adjustment as manifested in elevated hope and acceptance of disability and lighter social network than their non-employed counterparts. However no differences were found between employed and non-employed veterans with respect to their social participation patterns. The value of these findings, as well as wider implications for rehabilitation professionals and policy makers, is discussed.


Comprehensive Glycomic Analysis Reveals That Human Serum Albumin Glycation Specifically Affects the Pharmacokinetics and Efficacy of Different Anticoagulant Drugs in Diabetes.
Long-term hyperglycemia in patients with diabetes leads to human serum albumin (HSA) glycation, which may impair HSA function as a transport protein and affect the therapeutic efficacy of anticoagulants in patients with diabetes. In this study, a novel mass spectrometry approach was developed to reveal the differences in the profiles of HSA glycation sites between patients with diabetes and healthy subjects. K199 was the glycation site most significantly changed in patients with diabetes, contributing to different interactions of glycated HSA and normal HSA with two types of anticoagulant drugs, heparin and warfarin. An in vitro experiment showed that the binding affinity to warfarin became stronger when HSA was glycated, while HSA binding to heparin was not significantly influenced by glycation. A pharmacokinetic study showed a decreased level of free warfarin in the plasma of diabetic rats. A preliminary retrospective clinical study also revealed that there was a statistically significant difference in the anticoagulant efficacy between patients with diabetes and patients without diabetes who had been treated with warfarin. Our work suggests that larger studies are needed to provide additional specific guidance for patients with diabetes when they are administered anticoagulant drugs or drugs for treating other chronic diseases.


Birth outcomes in women who have taken leflunomide during pregnancy.
In preclinical reproductive studies, leflunomide was found to be embryotoxic and teratogenic. Women treated with leflunomide are advised to avoid pregnancy; those who become pregnant are advised to reduce fetal exposure through a cholestyramine drug elimination procedure. The present study was undertaken to investigate pregnancy outcomes in women who received leflunomide and were treated with cholestyramine during pregnancy. Sixty-four pregnant women with rheumatoid arthritis (RA) who were treated with leflunomide during pregnancy (95.3% of whom received cholestyramine), 108 pregnant women with RA not treated with leflunomide, and 78 healthy pregnant women were enrolled in a prospective cohort study between 1999 and 2009. Information was collected via interview of the mothers, review of medical records, and specialized physical examination of infants. There were no significant differences in the overall rate of major structural defects in the exposed group (3 of 56 live births [5.4%]) relative to either comparison group (each 4.2%)(P = 0.13). The rate was similar to the 3-4% expected in the general population. There was no specific pattern of major or minor anomalies. Infants in both the leflunomide-exposed and non-leflunomide-exposed RA groups were born smaller and earlier relative to infants of healthy mothers; however, after adjustment for confounding factors, there were no significant differences between the leflunomide-exposed and non-leflunomide-exposed RA groups. Although the sample size is small, these data do not support the notion that there is a substantial increased risk of adverse pregnancy outcomes due to leflunomide exposure among women who undergo cholestyramine elimination procedure early in pregnancy. These findings can provide some reassurance to women who inadvertently become pregnant while taking leflunomide and undergo the washout procedure.


Minority recruitment in hereditary breast cancer research.
Although recruitment of ethnic and racial minorities in medical research has been evaluated in several studies, much less is known about the methods used to recruit these populations to participate in cancer genetics research. This report reviews the resources that have been used to identify and recruit ethnic and racial minorities to participate in hereditary breast cancer research. Overall, hospital-based resources were used most often to identify potential subjects, and active recruitment methods were used most frequently to enroll eligible subjects. This review suggests that there appears to be a finite number of resources and strategies to identify and recruit potential subjects to participate in cancer genetics research; however, options for improving awareness about cancer genetics research among ethnic and racial minorities have not been extensively evaluated. To study ethnic and racial minority participation in cancer genetics research, stronger evaluation components will need to be integrated into research methods. Both observational and experimental studies are needed to determine resources that are most effective for identifying potential subjects who are ethnic and racial minorities and to evaluate the effects of different recruitment strategies on enrollment decisions among these populations.


Phylogenetic analysis of the South American electric fishes (order Gymnotiformes) and the evolution of their electrogenic system: a synthesis based on morphology, electrophysiology, and mitochondrial sequence data.
The order Gymnotiformes (South American electric fishes) is a fascinating assemblage of freshwater fishes that share the unusual ability to produce and sense electric fields used for electrolocation and social communication. In the last few decades, the electrogenic and electrosensory systems (EES) of these fish have served as an excellent model to study motor and sensory physiology in vertebrates. In an attempt to the evolution of characters associated with the EES in the group, we applied maximum-parsimony (MP), minimum-evolution (ME), and maximum-likelihood (ML) methods to analyze 302 aligned bases of the mitochondrial 12S rRNA and 416 bases of the mitochondrial 16S rRNA of 19 gymnotiform genera representing all six recognized families. Six catfish genera (order Siluriformes) were also sequenced and used as outgroups. The phylogenetic hypothesis resultant from molecular data analysis differs in some respects from previous hypotheses based on morphological studies. Our results were most informative within the family level, as we were unable to elucidate the relationships among deeper branches in this order with sufficient confidence by using molecular data alone. The phylogenetic information of both mitochondrial DNA segments appears to be affected by functional constraints, and the resultant topologies were sensitive to different weighting schemes and the algorithm used. Nonetheless, we found unanimous support for the following phylogenetic relationships: (1) the family Sternopygidae is an unnatural group, and Sternopygus is the sole representative of a unique lineage within the order; (2) the family Hypopomidae is not monophyletic; and (3) the order Gymnotiformes is composed of at least six natural clades: Sternopygus, family Apteronotidae, a new clade consisting of the remaining sternopygids, families Hypopomidae + Rhamphicthyidae, family Electrophoridae, and family Gymnotidae. By combining molecular, morphological, and physiological information, we propose a new hypothesis for the phylogeny of this group and suggest a new family Eigenmanniidae n. (order Gymnotiformes).


Discordant patterns of mtDNA and ethno-linguistic variation in 14 Iranian Ethnic groups.
Present-day Iran has long represented a natural hub for the expansion of human genes and cultures. That being so, the overlapping of prehistoric and more recent demographic events interacting at different time scales with geographical and cultural barriers has yielded a tangled patchwork of anthropological types within this narrow area. This study aims to comprehensively evaluate this ethnic mosaic by depicting a fine-grained picture of the Iranian mitochondrial landscape. mtDNA variability at both HVS-I and coding regions was surveyed in 718 unrelated individuals belonging to 14 Iranian ethnic groups characterized by different languages, religions and patterns of subsistence. A discordant pattern of high ethno-linguistic and low mtDNA heterogeneity was observed for the whole examined Iranian sample. Geographical factors and cultural/linguistic differences actually represented barriers to matrilineal gene flow only for the Baloch, Lur from Yasouj, Zoroastrian and Jewish groups, for which unusual reduced levels of mtDNA variability and high inter-population distances were found. Deep rooting genealogies and endogamy in a few of the examined ethnic groups might have preserved ancestral lineages that can be representative of Proto-Indo-Iranian or prehistoric mitochondrial profiles which survived relatively recent external contributions to the Iranian gene pool.


Cost considerations in the management of cancer in the older patient.
Patients aged 65 years and older represent 12% of the US population yet account for approximately 56% of cancer cases and 69% of all cancer mortalities. The overall cost of cancer in 2005 was $209.9 billion--$74 billion for direct medical costs and $118.4 billion for indirect mortality costs. This paper considers the direct, indirect, and out-of-pocket expenditures incurred by cancer patients > or = 50 years of age. Several major empirical studies on supportive care for older patients and cancer-related costs were reviewed. Insurance coverage, hematologic malignancies, squamous cell carcinoma of the head and neck, and cancers of the breast, prostate, colorectum, and lung were evaluated. Major sources of direct medical expenditures covered by third-party insurers for patients aged 65 years and older include extended length of hospital stay, home health assistance following hospital discharge, adjuvant prescription medications, lower-risk treatment (for prostate cancer), and advent of new pharmaceuticals (for colorectal cancer). The mean total direct medical cost for breast cancer is $35,164, and the cumulative cost for prostate cancer is $42,570. Emerging targeted cancer drug costs range from $20,000 to $50,000 annually per patient. Additional clinical trials and cost-effective treatments are needed for older patients to ameliorate the disproportionate economic burden among older individuals with cancer. Additional research about cancer costs may also lead to reforms in cancer care reimbursement, and therefore provide access to affordable health care for older patients.