Action of Coriandrum sativum L. Essential Oil upon Oral Candida albicans Biofilm Formation.
The efficacy of extracts and essential oils from Allium tuberosum, Coriandrum sativum, Cymbopogon martini, Cymbopogon winterianus, and Santolina chamaecyparissus was evaluated against Candida spp. isolates from the oral cavity of patients with periodontal disease. The most active oil was fractionated and tested against C. albicans biofilm formation. The oils were obtained by water-distillation and the extracts were prepared with macerated dried plant material. The Minimal Inhibitory Concentration-MIC was determined by the microdilution method. Chemical characterization of oil constituents was performed using Gas Chromatography and Mass Spectrometry (GC-MS). C. sativum activity oil upon cell and biofilm morphology was evaluated by Scanning Electron Microscopy (SEM). The best activities against planktonic Candida spp. were observed for the essential oil and the grouped F(8-10) fractions from C. sativum. The crude oil also affected the biofilm formation in C. albicans causing a decrease in the biofilm growth. Chemical analysis of the F(8-10) fractions detected as major active compounds, 2-hexen-1-ol, 3-hexen-1-ol and cyclodecane. Standards of these compounds tested grouped provided a stronger activity than the oil suggesting a synergistic action from the major oil constituents. The activity of C. sativum oil demonstrates its potential for a new natural antifungal formulation.


Chemoresistance of colorectal cancer to 5-fluorouracil is associated with silencing of the BNIP3 gene through aberrant methylation.
Purpose To investigate the correlation between chemoresistance of colorectal cancer to 5-fluorouracil and BNIP3 and the underlying mechanism. Methods BNIP3 protein in specimens was evaluated using immunohistochemistry. Semi-quantitative reverse transcription PCR and Western blot was employed to assay gene expression. The promoter methylation status of BNIP3 was examined by methylation-specific PCR. Drug sensitivity was assayed using MTT assay. Results Specimens from 81 patients with colorectal cancer receiving 5-fluorouracil-based chemotherapy were analyzed. BNIP3 expression was negative in 42 cancer samples. The mean score of BNIP3 in cancer was 1.8±0.2 and it was 3.7±0.5 in adjacent colorectum (p<0.05). The response rate of the BNIP3 positive group was 63.6% and that of the negative group was 36.4% (p=0.021). The median PFS of the BNIP3 positive group was 9.25 months and that of the BNIP3 negative group was 6.5 months (p=0.011). BNIP3 mRNA was not detectable in 4 of 8 colorectal cell lines and all these 4 cell lines displayed BNIP3 methylated allele only. Other 4 cell lines what expressed detectable BNIP3 displayed BNIP3 unmethylated allele only or both unmethylated and methylated alleles. 5-Aza dramatically increased BNIP3 expression. Knockdown of DNMT1 increased BNIP3. Knockdown of DNMT3B alone did not detectably change BNIP3 expression while knockdown of both DNMT1 and DNMT3B increased BNIP3 expression more than knockdown of DNMT1 alone. Knockdown of BNIP3 decreased chemosensitivity to 5-fluorouracil and increasing BNIP3 through demethylation increased chemosensitivity. Conclusion Chemoresistance of colorectal cancer to 5-fluorouracil is associated with silencing of the BNIP3 gene through aberrant methylation via DNMT1/DNMT3B.


Domain and functional analysis of a novel breast tumor suppressor protein, SCUBE2.
Signal peptide CUB (complement proteins C1r/C1s, Uegf, and Bmp 1)-EGF domain-containing protein 2 (SCUBE2) is a secreted, membrane-associated multidomain protein composed of five recognizable motifs: an NH(2)-terminal signal peptide sequence, nine copies of epidermal growth factor (EGF)-like repeats, a spacer region, three cysteine-rich repeats, and one CUB domain at the COOH terminus. Our previous clinical study showed that SCUBE2 may act as a novel breast tumor suppressor gene and serve as a useful prognostic marker. However, the specific domain responsible for its tumor suppressor activity and the precise mechanisms of its anti-tumor effect remain unknown. Using a combination of biochemical, molecular, and cell biology techniques, we further dissected the molecular functions and signal pathways mediated by the NH(2)-terminal EGF-like repeats or COOH-terminal CUB domain of SCUBE2. Independent overexpression of the NH(2)-terminal EGF-like repeats or COOH-terminal CUB domain resulted in suppression of MCF-7 breast cancer cell proliferation and reduced MCF-7 xenograft tumor growth in nude mice. Molecular and biochemical analyses revealed that the COOH-terminal CUB domain could directly bind to and antagonize bone morphogenetic protein activity in an autocrine manner, whereas the NH(2)-terminal EGF-like repeats could mediate cell-cell homophilic adhesions in a calcium-dependent fashion, interact with E-cadherin (a master tumor suppressor), and decrease the β-catenin signaling pathway. Together, our data demonstrate that SCUBE2 has growth inhibitory effects through a coordinated regulation of two distinct mechanisms: antagonizing bone morphogenetic protein and suppressing the β-catenin pathway in breast cancer cells.


Pre- and postoperative headache in patients with meningioma.
Meningiomas are generally slowly growing intracranial tumors. They are often incidentally diagnosed, given that symptoms may be absent even in cases of an enormous tumor size. Headache is a frequent but not consistent symptom. Therefore, we examined the association between structural, biochemical and histochemical tumor parameters with preoperative as well as postoperative occurrence of headache. In our study, we prospectively investigated 69 consecutive patients enrolled for meningioma neurosurgery. Anatomical, histological and biochemical parameters were acquired, and headache parameters were registered from the clinical report and from a questionnaire filled by the patients before neurosurgery. The headache was re-evaluated one year after neurosurgery. The study was designed to exploratively investigate whether there is an association of acquired clinical and biological parameters with the occurrence of preoperative and postoperative headache. Edema diameter and the proliferation marker MIB-1 were negatively associated with the incidence and intensity of preoperative headache, while the content of prostaglandin E2 in the tumor tissue was positively associated with preoperative headache intensity. Headache was more prevalent when the meningioma was located in the area supplied by the ophthalmic trigeminal branch. Compared to preoperative headache levels, an overall reduction was observed one year postoperative, and patients with a larger tumor had a higher headache remission. In parietal and occipital meningiomas and in those with a larger edema, the percentage of the headache remission rate was higher compared to other locations or smaller edema. Multivariable analyses showed an involvement of substance P and prostaglandin E2 in preoperative headache. The study demonstrates new associations between meningiomas and headache. The postoperative headache outcome in the presented patient sample is encouraging for the performed neurosurgical intervention. These results should be tested in a prospective study that incorporates all patients with meningiomas.


Use of human cumulus granulosa cells for in vitro screening of reproductive toxicants.
We investigated the possibility that human granulosa cells from the cumulus mass obtained during human in vitro fertilization/embryo transfer (IVF/ET) might be useful for screening of potential reproductive toxicants in vitro. The cumulus granulosa cells detached from the zona pellucida after fertilization were allowed to spontaneously adhere to the incubation dish following transfer (removal) of the embryo. These cumulus cells survived in culture for at least four additional days, appeared on simple inspection to be morphologically normal luteinized granulosa cells, and produced large amounts of progesterone (P) over the culture interval. Production gradually declined during culture in the absence of human chorionic gonadotropin (hCG); however, inclusion of hCG (100 ng/mL) in the medium maintained P production at control (day 1) levels. Introduction of estrogenic agents previously shown to suppress P production in porcine or human culture systems using mural granulosa cells showed comparable effects in this human cumulus cell system. 17 beta-estradiol (10(-5) M), clomiphene citrate (10(-5) M), and o,p-DDT (10(-5)) significantly inhibited hCG-supported P production by human cumulus cells in vitro. This system has the advantages that (1) human cumulus granulosa cells are readily available from IVF/ET programs, (2) the techniques for maintaining the cells in culture are extremely simple, (3) a marker of highly differentiated granulosa cell function (P production) can be reliably measured, and (4) the cells respond predictably like other comparable granulosa cell systems. We conclude that human cumulus cells are a readily available and useful resource for in vitro screening of potential female reproductive toxicants.


Return Migration as Failure or Success?: The Determinants of Return Migration Intentions Among Moroccan Migrants in Europe.
Different migration theories generate competing hypotheses with regard to determinants of return migration. While neoclassical migration theory associates migration to the failure to integrate at the destination, the new economics of labour migration sees return migration as the logical stage after migrants have earned sufficient assets and knowledge and to invest in their origin countries. The projected return is then likely to be postponed for sustained or indefinite periods if integration is unsuccessful. So, from an indication or result of integration failure return is rather seen as a measure of success. Drawing on recent survey data (N = 2,832), this article tests these hypotheses by examining the main determinants of return intention among Moroccan migrants across Europe. The results indicate that structural integration through labour market participation, education and the maintenance of economic and social ties with receiving countries do not significantly affect return intentions. At the same time, investments and social ties to Morocco are positively related, and socio-cultural integration in receiving countries is negatively related to return migration intentions. The mixed results corroborate the idea that there is no uniform process of (return) migration and that competing theories might therefore be partly complementary.


Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial.
Treatment with cisplatin-based chemotherapy provides a modest survival advantage over supportive care alone in advanced non-small-cell lung cancer (NSCLC). To determine whether a new agent, paclitaxel, would further improve survival in NSCLC, the Eastern Cooperative Oncology Group conducted a randomized trial comparing paclitaxel plus cisplatin to a standard chemotherapy regimen consisting of cisplatin and etoposide. The study was carried out by a multi-institutional cooperative group in chemotherapy-naive stage IIIB to IV NSCLC patients randomized to receive paclitaxel plus cisplatin or etoposide plus cisplatin. Paclitaxel was administered at two different dose levels (135 mg/m(2) and 250 mg/m(2)), and etoposide was given at a dose of 100 mg/m(2) daily on days 1 to 3. Each regimen was repeated every 21 days and each included cisplatin (75 mg/m(2)). The characteristics of the 599 patients were well-balanced across the three treatment groups. Superior survival was observed with the combined paclitaxel regimens (median survival time, 9.9 months; 1-year survival rate, 38.9%) compared with etoposide plus cisplatin (median survival time, 7.6 months; 1-year survival rate, 31.8%; P =. 048). Comparing survival for the two dose levels of paclitaxel revealed no significant difference. The median survival duration for the stage IIIB subgroup was 7.9 months for etoposide plus cisplatin patients versus 13.1 months for all paclitaxel patients (P =.152). For the stage IV subgroup, the median survival time for etoposide plus cisplatin was 7.6 months compared with 8.9 months for paclitaxel (P =.246). With the exceptions of increased granulocytopenia on the low-dose paclitaxel regimen and increased myalgias, neurotoxicity, and, possibly, increased treatment-related cardiac events with high-dose paclitaxel, toxicity was similar across all three arms. Quality of life (QOL) declined significantly over the 6 months. However, QOL scores were not significantly different among the regimens. As a result of these observations, paclitaxel (135 mg/m(2)) combined with cisplatin has replaced etoposide plus cisplatin as the reference regimen in our recently completed phase III trial.


Towards witnessing quantum effects in complex molecules.
Whether many-body objects like organic molecules can exhibit full quantum behaviour, including entanglement, is an open fundamental question. We present a generic theoretical protocol for entangling two organic molecules, such as dibenzoterrylene in anthracene. The availability of organic dye molecules with two-level energy structures characterised by sharp and intense emission lines are characteristics that position them favourably as candidates for quantum information processing technologies involving single-photons. Quantum entanglement can in principle be generated between several organic molecules by carefully interfering their photoluminescence spectra. Major milestones have been achieved in the last 10 years showcasing entanglement in diverse systems including ions, cold atoms, superconductors, photons, quantum dots and NV-centres in diamond, but not yet in molecules.


TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several models of inflammation.
The pleiotropic activities of the potent proinflammatory cytokine TNF are mediated by two structurally related, but functionally distinct, receptors, p55 and p75, that are coexpressed on most cell types. The majority of biologic responses classically attributed to TNF are mediated by p55. In contrast, p75 has been proposed to function as both a TNF antagonist by neutralizing TNF and as a TNF agonist by facilitating the interaction between TNF and p55 at the cell surface. We have examined the roles of p55 and p75 in mediating and modulating the activity of TNF in vivo by generating and examining mice genetically deficient in these receptors. Selective deficits in several host defense and inflammatory responses are observed in mice lacking p55 or both p55 and p75, but not in mice lacking p75. In these models, the activity of p55 is not impaired by the absence of p75, arguing against a physiologic role for p75 as an essential element of p55-mediated signaling. In contrast, exacerbated pulmonary inflammation and dramatically increased endotoxin induced serum TNF levels in mice lacking p75 suggest a dominant role for p75 in suppressing TNF-mediated inflammatory responses. In summary, these data help clarify the biologic roles of p55 and p75 in mediating and modulating the biologic activity of TNF and provide genetic evidence for an antagonistic role of p75 in vivo.


Necrotizing fasciitis: a fatal outcome following minor trauma. Case report and literature review.
The death of a young healthy man, 11 days after he sustained minor trauma, illustrates the potential disaster of undiagnosed necrotizing fasciitis. Difficulty in early diagnosis often arises because the skin is initially spared and only later becomes secondarily involved. In this case, because of the lack of external manifestations, the diagnosis of necrotizing fasciitis was not considered until the postmortem examination. Necrotizing fasciitis should be considered a potentially serious problem that can follow minor trauma and eventually lead to death. The need for a high index of suspicion to make this diagnosis, along with the medicolegal implication of a diagnosis of necrotizing fasciitis, are both addressed in this report. Also of note is the fact that this patient was treated with nonsteroidal antiinflammatory drugs for pain and inflammation, which has recently been reported to be associated with an increased incidence of fulminant evolution of necrotizing fasciitis.


Psychiatric adjustment in chronic fatigue syndrome of childhood and in juvenile idiopathic arthritis.
High rates of psychopathology and of personality problems have been reported in children and adolescents with chronic fatigue syndrome (CFS). It is not clear whether this is consequent on the experience of chronic physical ill health. We compare psychiatric adjustment in children with CFS and in children suffering from another chronic physical disorder (juvenile idiopathic arthritis or JIA). Our sample consisted of 28 children with CFS and 30 with JIA attending tertiary paediatric centres (age range, 11 to 18 years, mean 15, S.D. 2.3). In order to assess psychiatric status and functioning, we used the K-SADS psychiatric interviews, CGAS and Harter Self-Esteem Questionnaire with child subjects; behavioural questionnaires (CBCL) and child personality assessment interviews (PAS) with parent informants. Psychiatric disorders in the year prior to interview had been present significantly more commonly in the CFS group (72% v. 34% in JIA) and were more impairing to them (CGAS scores of 45 v. 77). Most common diagnoses in both groups were depressive and anxiety disorders. Personality problems were also significantly more frequent in CFS subjects (48% disorder and 26% difficulty v. 11% and 11% in JIA). There were few differences between the two groups in self-esteem. Psychopathology and personality problems are common in children and adolescents with severe forms of CFS and cannot be explained strictly through the experience of chronic physical illness.


Increased Axial Length Corresponds to Decreased Retinal Light Dose: A Parsimonious Explanation for Decreasing AMD Risk in Myopia.
A recent systematic review indicated that higher sunlight exposure increased risk of AMD. The Beaver Dam study and the Pathologies Oculaires Liées à L'âge study both noted that wearing hats and/or sunglasses significantly decrease some AMD lesions, suggesting that reduced retinal light dose (RLD) may be related to reduced AMD risk. Given that myopes also have reduced AMD risk, we hypothesize its link to decreased RLD. Using a one-surface schematic eye and ray-tracing, spectacle power, vertex distance, corneal power, anterior chamber depth, and axial length to calculate relative light flux through the pupil and resultant image size on the retina in a randomly selected group of 71 eyes from the Reykjavik Eye Study. Pupil size is unaffected by refractive error; thus, RLD can be calculated. We verified this using a more complete set of ocular biometric variables and ray-tracing included in an optical design software (Opticsoft II). RLD is inversely proportional to axial length. Comparing the two methods for calculating RLD using a Bland-Altman plot demonstrated equivalence. The ray-tracing method indicated that the retina of a hyperope with a 21-mm axial length would always be receiving 1.8× more photons per square millimeter than the retina of a myope with a 27-mm axial length. RLD is inversely proportional to axial length, as is AMD risk. The RLD for our 21-mm axial length wearing a pair of inexpensive commercial sunglasses would be equivalent to the RLD for a 27-mm myope. This may explain the decreased AMD risk in highly myopic individuals.


Post-transcriptional regulation of immune responses by RNA binding proteins.
Cytokines are critical mediators of inflammation and host immune defense. Cytokine production is regulated at both transcriptional and post-transcriptional levels. Post-transcriptional damping of inflammatory mRNAs is mediated by a set of RNA binding proteins (RBPs) interacting with cis-elements, such as AU-rich elements (ARE) and stem-loop structures. Whereas ARE-binding proteins such as tristetraprolin and a stem-loop recognizing protein, Roquin, downregulate cytokine mRNA abundance by recruiting a CCR4-NOT deadenylase complex, another stem-loop RBP, Regnase-1, acts as an endoribonuclease, directly degrading target cytokine mRNAs. These RBPs control translation-active or -inactive mRNAs in distinct intracellular locations. The presence of various RBPs regulating mRNAs in distinct locations enables elaborate control of cytokines under inflammatory conditions. Dysregulation of cytokine mRNA decay leads to pathologies such as the development of autoimmune diseases or impaired activation of immune responses. Here we review current knowledge about the post-transcriptional regulation of immune responses by RBPs and the importance of their alteration during inflammatory pathology and autoimmunity.


Quantitative study of single molecule location estimation techniques.
Estimating the location of single molecules from microscopy images is a key step in many quantitative single molecule data analysis techniques. Different algorithms have been advocated for the fitting of single molecule data, particularly the nonlinear least squares and maximum likelihood estimators. Comparisons were carried out to assess the performance of these two algorithms in different scenarios. Our results show that both estimators, on average, are able to recover the true location of the single molecule in all scenarios we examined. However, in the absence of modeling inaccuracies and low noise levels, the maximum likelihood estimator is more accurate than the nonlinear least squares estimator, as measured by the standard deviations of its estimates, and attains the best possible accuracy achievable for the sets of imaging and experimental conditions that were tested. Although neither algorithm is consistently superior to the other in the presence of modeling inaccuracies or misspecifications, the maximum likelihood algorithm emerges as a robust estimator producing results with consistent accuracy across various model mismatches and misspecifications. At high noise levels, relative to the signal from the point source, neither algorithm has a clear accuracy advantage over the other. Comparisons were also carried out for two localization accuracy measures derived previously. Software packages with user-friendly graphical interfaces developed for single molecule location estimation (EstimationTool) and limit of the localization accuracy calculations (FandPLimitTool) are also discussed.


Validation of a deep learning computer aided system for CT based lung nodule detection, classification, and growth rate estimation in a routine clinical population.
In this study, we evaluated a commercially available computer assisted diagnosis system (CAD). The deep learning algorithm of the CAD was trained with a lung cancer screening cohort and developed for detection, classification, quantification, and growth of actionable pulmonary nodules on chest CT scans. Here, we evaluated the CAD in a retrospective cohort of a routine clinical population. In total, a number of 337 scans of 314 different subjects with reported nodules of 3-30 mm in size were included into the evaluation. Two independent thoracic radiologists alternately reviewed scans with or without CAD assistance to detect, classify, segment, and register pulmonary nodules. A third, more experienced, radiologist served as an adjudicator. In addition, the cohort was analyzed by the CAD alone. The study cohort was divided into five different groups: 1) 178 CT studies without reported pulmonary nodules, 2) 95 studies with 1-10 pulmonary nodules, 23 studies from the same patients with 3) baseline and 4) follow-up studies, and 5) 18 CT studies with subsolid nodules. A reference standard for nodules was based on majority consensus with the third thoracic radiologist as required. Sensitivity, false positive (FP) rate and Dice inter-reader coefficient were calculated. After analysis of 470 pulmonary nodules, the sensitivity readings for radiologists without CAD and radiologist with CAD, were 71.9% (95% CI: 66.0%, 77.0%) and 80.3% (95% CI: 75.2%, 85.0%) (p < 0.01), with average FP rate of 0.11 and 0.16 per CT scan, respectively. Accuracy and kappa of CAD for classifying solid vs sub-solid nodules was 94.2% and 0.77, respectively. Average inter-reader Dice coefficient for nodule segmentation was 0.83 (95% CI: 0.39, 0.96) and 0.86 (95% CI: 0.51, 0.95) for CAD versus readers. Mean growth percentage discrepancy of readers and CAD alone was 1.30 (95% CI: 1.02, 2.21) and 1.35 (95% CI: 1.01, 4.99), respectively. The applied CAD significantly increased radiologist's detection of actionable nodules yet also minimally increasing the false positive rate. The CAD can automatically classify and quantify nodules and calculate nodule growth rate in a cohort of a routine clinical population. Results suggest this Deep Learning software has the potential to assist chest radiologists in the tasks of pulmonary nodule detection and management within their routine clinical practice.


A mid-century ecological forecast with partitioned uncertainty predicts increases in loblolly pine forest productivity.
Ecological forecasting of forest productivity involves integrating observations into a process-based model and propagating the dominant components of uncertainty to generate probability distributions for future states and fluxes. Here, we develop a forecast for the biomass change in loblolly pine (Pinus taeda) forests of the southeastern United States and evaluate the relative contribution of different forms of uncertainty to the total forecast uncertainty. Specifically, we assimilated observations of carbon and flux stocks and fluxes from sites across the region, including global change experiments, into a forest ecosystem model to calibrate the parameter distributions and estimate the process uncertainty (i.e., model structure uncertainty revealed in the residuals of the calibration). Using this calibration, we forecasted the change in biomass within each 12-digit Hydrologic (H12) unit across the native range of loblolly pine between 2010 and 2055 under the Representative Concentration Pathway 8.5 scenario. Averaged across the region, productivity is predicted to increase by a mean of 31% between 2010 and 2055 with an average forecast 95% quantile interval of ±15 percentage units. The largest increases were predicted in cooler locations, corresponding to the largest projected changes in temperature. The forecasted mean change varied considerably among the H12 units (3-80% productivity increase), but only units in the warmest and driest extents of the loblolly pine range had forecast distributions with probabilities of a decline in productivity that exceeded 5%. By isolating the individual components of the forecast uncertainty, we found that ecosystem model process uncertainty made the largest individual contribution. Ecosystem model parameter and climate model uncertainty had similar contributions to the overall forecast uncertainty, but with differing spatial patterns across the study region. The probabilistic framework developed here could be modified to include additional sources of uncertainty, including changes due to fire, insects, and pests: processes that would result in lower productivity changes than forecasted here. Overall, this study presents an ecological forecast at the ecosystem management scale so that land managers can explicitly account for uncertainty in decision analysis. Furthermore, it highlights that future work should focus on quantifying, propagating, and reducing ecosystem model process uncertainty.


Three-dimensional collagen type I matrix up-regulates nuclear isoforms of the microtubule associated protein tau implicated in resistance to paclitaxel therapy in ovarian carcinoma.
Epithelial ovarian carcinoma is the deadliest gynecologic malignancy. One reason underlying treatment failure is resistance to paclitaxel. Expression of the microtubule associated protein tau has recently been proposed as a predictor of response to paclitaxel in ovarian carcinoma patients. Expression of tau was probed using immunohistochemistry in 312 specimens of primary, and 40 specimens of metastatic, ovarian carcinoma. Serous epithelial ovarian carcinoma cell line models were used to determine the expression of tau by Western blot and immunofluorescence staining. Subcellular fractionation and Western blot were employed to examine nuclear and cytoplasmic localization of tau. Gene silencing and clonogenic assays were used to evaluate paclitaxel response. Tau was expressed in 44% of all tested cases. Among the primary serous epithelial ovarian carcinoma cases, 46% were tau-positive. Among the metastatic serous epithelial ovarian carcinomas, 63% were tau-positive. Cell culture experiments demonstrated that tau was expressed in multiple isoforms. Three-dimensional collagen I matrix culture conditions resulted in up-regulation of tau protein. Silencing of tau with specific siRNAs in a combination with three-dimensional culture conditions led to a significant decrease of the clonogenic ability of cells treated with paclitaxel. The data suggest that reduction of tau expression may sensitize ovarian carcinoma to the paclitaxel treatment.


Feedback-based probabilistic category learning is selectively impaired in attention/hyperactivity deficit disorder.
Although Attention-Deficit Hyperactivity Disorder (ADHD) is closely linked to executive function deficits, it has recently been attributed to procedural learning impairments that are quite distinct from the former. These observations challenge the ability of the executive function framework solely to account for the diverse range of symptoms observed in ADHD. A recent neurocomputational model emphasizes the role of striatal dopamine (DA) in explaining ADHD's broad range of deficits, but the link between this model and procedural learning impairments remains unclear. Significantly, feedback-based procedural learning is hypothesized to be disrupted in ADHD because of the involvement of striatal DA in this type of learning. In order to test this assumption, we employed two variants of a probabilistic category learning task known from the neuropsychological literature. Feedback-based (FB) and paired associate-based (PA) probabilistic category learning were employed in a non-medicated sample of ADHD participants and neurotypical participants. In the FB task, participants learned associations between cues and outcomes initially by guessing and subsequently through feedback indicating the correctness of the response. In the PA learning task, participants viewed the cue and its associated outcome simultaneously without receiving an overt response or corrective feedback. In both tasks, participants were trained across 150 trials. Learning was assessed in a subsequent test without a presentation of the outcome or corrective feedback. Results revealed an interesting disassociation in which ADHD participants performed as well as control participants in the PA task, but were impaired compared with the controls in the FB task. The learning curve during FB training differed between the two groups. Taken together, these results suggest that the ability to incrementally learn by feedback is selectively disrupted in ADHD participants. These results are discussed in relation to both the ADHD dopaminergic dysfunction model and recent findings implicating procedural learning impairments in those with ADHD.


Gene expression and functional studies of the optic nerve head astrocyte transcriptome from normal African Americans and Caucasian Americans donors.
To determine whether optic nerve head (ONH) astrocytes, a key cellular component of glaucomatous neuropathy, exhibit differential gene expression in primary cultures of astrocytes from normal African American (AA) donors compared to astrocytes from normal Caucasian American (CA) donors. We used oligonucleotide Affymetrix microarray (HG U133A & HG U133A 2.0 chips) to compare gene expression levels in cultured ONH astrocytes from twelve CA and twelve AA normal age matched donor eyes. Chips were normalized with Robust Microarray Analysis (RMA) in R using Bioconductor. Significant differential gene expression levels were detected using mixed effects modeling and Statistical Analysis of Microarray (SAM). Functional analysis and Gene Ontology were used to classify differentially expressed genes. Differential gene expression was validated by quantitative real time RT-PCR. Protein levels were detected by Western blots and ELISA. Cell adhesion and migration assays tested physiological responses. Glutathione (GSH) assay detected levels of intracellular GSH. Multiple analyses selected 87 genes differentially expressed between normal AA and CA (P<0.01). The most relevant genes expressed in AA were categorized by function, including: signal transduction, response to stress, ECM genes, migration and cell adhesion. These data show that normal astrocytes from AA and CA normal donors display distinct expression profiles that impact astrocyte functions in the ONH. Our data suggests that differences in gene expression in ONH astrocytes may be specific to the development and/or progression of glaucoma in AA.


A single amino acid substitution in the core protein of West Nile virus increases resistance to acidotropic compounds.
West Nile virus (WNV) is a worldwide distributed mosquito-borne flavivirus that naturally cycles between birds and mosquitoes, although it can infect multiple vertebrate hosts including horses and humans. This virus is responsible for recurrent epidemics of febrile illness and encephalitis, and has recently become a global concern. WNV requires to transit through intracellular acidic compartments at two different steps to complete its infectious cycle. These include fusion between the viral envelope and the membrane of endosomes during viral entry, and virus maturation in the trans-Golgi network. In this study, we followed a genetic approach to study the connections between viral components and acidic pH. A WNV mutant with increased resistance to the acidotropic compound NH4Cl, which blocks organelle acidification and inhibits WNV infection, was selected. Nucleotide sequencing revealed that this mutant displayed a single amino acid substitution (Lys 3 to Glu) on the highly basic internal capsid or core (C) protein. The functional role of this replacement was confirmed by its introduction into a WNV infectious clone. This single amino acid substitution also increased resistance to other acidification inhibitor (concanamycin A) and induced a reduction of the neurovirulence in mice. Interestingly, a naturally occurring accompanying mutation found on prM protein abolished the resistant phenotype, supporting the idea of a genetic crosstalk between the internal C protein and the external glycoproteins of the virion. The findings here reported unveil a non-previously assessed connection between the C viral protein and the acidic pH necessary for entry and proper exit of flaviviruses.


Automated analysis of mouse serum peptidome using restricted access media and nanoliquid chromatography-tandem mass spectrometry.
We demonstrate use of restricted access media with reversed phase functionality (RAM-RP) for analysis of low molecular weight proteins and peptides in mouse serum (75 μl) using a custom designed modular automated processing system (MAPS). RAM-RP fractionation with simultaneous removal of high molecular weight and high abundance proteins is integrated with a follow-on buffer exchange module (BE) to ensure compatibility with subsequent processing steps (trypsin digestion and intact peptide separation prior to mass spectrometric analysis). The high sample capacity afforded by chromatographic methods generates enough sample to achieve comprehensive serum peptidome identification (357 proteins) through tandem mass spectrometric analysis of both intact and digested peptides. Sample losses during transfer between modules are minimized through precise fluidic control; no clogging occurred over several months of serum processing in our low back pressure system. Computer controlled operation of both modules and thorough optimization yield excellent run-to-run reproducibility and protein/peptide overlap in analytical repeats. The robustness of our results demonstrate that the RAM-RP-BE workflow executed on our MAPS platform shows tremendous potential for high throughput peptidome processing, particularly with regard to direct analysis of small-volume serum samples.


Structural changes in resistance and capacitance vessels in borderline hypertension.
Vascular resistance at rest may be normal in humans with borderline or mild hypertension. However, this finding is a facade which can obscure the presence of vascular structural alterations that may have an important influence on resistance and capacitance functions of the circulation. This paper reviews several studies regarding vascular structural changes in borderline hypertension (BHT). First, forearm vasodilator capacity is limited in BHT and in normotensive young men with a family history of hypertension; this suggests the presence of structural changes in forearm resistance vessels. Second, forearm venous distensibility is decreased in BHT. Most of this decrease is caused by nonadrenergic mechanisms--which suggests that there may be structural changes in veins in BHT. Third, the studies of Takeshita and colleagues suggest that sodium intake may influence vascular structural changes. In hypertensive patients who responded to salt loading with increased blood pressure and vascular resistance, salt loading limited vasodilator responses to 10 minutes of ischemia. This effect of salt loading on vasodilator responses occurred in some patients (salt-responders), but not in others (salt-nonresponders). Functional studies support the concept that structural changes in resistance and capacitance vessels occur during the early stages of human hypertension. These changes may not be entirely adaptive responses to elevated arterial pressure, since they occur in capacitance as well as resistance vessels. In addition, the structural changes appear to be responsive to factors such as sodium intake. These observations suggest that vascular structural changes in human hypertension may be related in part to neurohumoral influences or to primary vascular abnormalities.


A genome-wide quantitative linkage scan of niacin skin flush response in families with schizophrenia.
Schizophrenia patients frequently display reduced niacin flush responses, and similar characteristics are also observed in their nonpsychotic relatives. This study aimed to identify loci influencing flush response to niacin in schizophrenia using genome-wide quantitative linkage scan. In a nationwide sample of families with at least 2 siblings affected with schizophrenia in each family, 115 families that had at least 2 affected siblings with information on the niacin skin test were subjected to quantitative trait loci linkage analysis, either involving affected individuals only or the whole family. Nonparametric linkage z (NPL-Z) scores were calculated for each of 386 microsatellite markers spaced at an average of 9-cM intervals. Niacin patches of 3 concentrations (0.001 M, 0.01, and 0.1 M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. Determination of genome-wide empirical significance was implemented using 1000 simulated genome scans. One linkage peak attaining genome-wide significance was identified at chromosomal region 14q32.12 for 0.01 M concentration at 5 minutes (NPL-Z scores = 3.39, genome-wide empirical P = .03) in affected individuals, and the corresponding linkage signal remained strong (NPL-Z scores = 2.87) for the analyses of the whole family. This locus is distinct from the chromosomal region identified in the previous genome-wide scan for the diagnosis of schizophrenia, and the signal was higher than the peak linkage signal in that study. These findings indicate that there might be modifier or susceptibility-modifier genes at 14q32.12 for schizophrenia-related attenuation of flush response to niacin.


Antibodies to neurofilament protein in retinitis pigmentosa.
Antibodies reactive with heterologous neural tissue were detected by indirect immunofluorescence microscopy in the sera of 17 of 34 patients with retinitis pigmentosa, one of 30 normal control sera, and a variable percentage of sera derived from subjects with diverse ocular and neurological diseases. These antibodies were also found both in disease-free first degree relatives and in spouses of patients with retinitis pigmentosa. Analytical sodium dodecyl sulfate-polyacrylamide gel electrophoresis of human spinal cord components followed by immunoblots with sera under study revealed that the serum antibody was specific for the high molecular weight protein subunit of neurofilaments. No correlation was found between the presence of these antibodies and other immunological and clinical parameters in retinitis pigmentosa. These findings suggest that release of piled-up neurofilaments from damaged neurones in retinitis pigmentosa triggers B lymphocytes autoreactive to neurofilament antigens.


Facile synthesis of magnetic molecularly imprinted polymers and its application in magnetic solid phase extraction for fluoroquinolones in milk samples.
In this work, we proposed a simple co-mixing method to fabricate magnetic molecularly imprinted polymers (magnetic MIPs). MIPs were commercial products while magnetic nanoparticles (MNPs) were prepared by chemical oxidation and solvothermal methods. When MNPs and MIPs (with mass ratio 1:1) were co-mixed and vortexed evenly in methanol, they could assemble into magnetic composites spontaneously and thus be magnetically separable. To testify the feasibility of the magnetic composites in sample preparation, the resultant magnetic MIPs were applied as sorbents for magnetic solid-phase extraction (MSPE) of fluoroquinolones (FQs) in milk samples. Under optimized conditions, a rapid, convenient, and efficient method for the determination of three FQs in milk samples was established by magnetic MIPs based MSPE coupling with high performance liquid chromatography with ultraviolet detector (HPLC-UV). The limits of detection (LODs) for three FQs were found to be 1.8-3.2ng/g. The intra- and inter-day relative standard deviations (RSDs) were less than 9.5% and 12.5%, respectively. The recoveries of FQs for two spiked milk samples were in the range from 94.0% to 124.4% with the RSDs less than 11.6%.


Talin1 and Rap1 are critical for osteoclast function.
To determine talin1's role in osteoclasts, we mated TLN1(fl/fl) mice with those expressing cathepsin K-Cre (CtsK-TLN1) to delete the gene in mature osteoclasts or with lysozyme M-Cre (LysM-TLN1) mice to delete TLN1 in all osteoclast lineage cells. Absence of TLN1 impairs macrophage colony-stimulating factor (M-CSF)-stimulated inside-out integrin activation and cytoskeleton organization in mature osteoclasts. Talin1-deficient precursors normally express osteoclast differentiation markers when exposed to M-CSF and receptor activator of nuclear factor κB (RANK) ligand but attach to substrate and migrate poorly, arresting their development into mature resorptive cells. In keeping with inhibited resorption, CtsK-TLN1 mice exhibit an ∼5-fold increase in bone mass. Osteoclast-specific deletion of Rap1 (CtsK-Rap1), which promotes talin/β integrin recognition, yields similar osteopetrotic mice. The fact that the osteopetrosis of CtsK-TLN1 and CtsK-Rap1 mice is substantially more severe than that of those lacking αvβ3 is likely due to added failed activation of β1 integrins. In keeping with osteoclast dysfunction, mice in whom talin is deleted late in the course of osteoclastogenesis are substantially protected from ovariectomy-induced osteoporosis and the periarticular osteolysis attending inflammatory arthritis. Thus, talin1 and Rap1 are critical for resorptive function, and their selective inhibition in mature osteoclasts retards pathological bone loss.


Financial risk of seeking maternal and neonatal healthcare in southern Ethiopia: a cohort study of rural households.
Ethiopian households' out-of-pocket healthcare payments constitute one-third of the national healthcare budget and are higher than the global and low-income countries average, and even the global target. Such out-of-pocket payments pose severe financial risks, can be catastrophic, impoverishing, and one of the causal barriers for low utilisation of healthcare services in Ethiopia. This study aimed to assess the financial risk of seeking maternal and neonatal healthcare in southern Ethiopia. A population-based cohort study was conducted among 794 pregnant women, 784 postpartum women, and their 772 neonates from 794 households in rural kebeles of the Wonago district, southern Ethiopia. The financial risk was estimated using the incidence of catastrophic healthcare expenditure, impoverishment, and depth of poverty. Annual catastrophic healthcare expenditure was determined if out-of-pocket payments exceeding 10% of total household or 40% of non-food expenditure. Impoverishment was analysed based on total household expenditure and the international poverty line of ≈ $1.9 per capita per day. Approximately 93% (735) of pregnant women, 31% (244) of postpartum women, and 48% (369) of their neonates experienced illness. However, only 56 households utilised healthcare services. The median total household expenditure was $527 per year (IQR = 390: 370,760). The median out-of-pocket healthcare payment was $46 per year (IQR = 46: 46, 92) with two episodes per household, and shared 19% of the household's budget. The poorer households paid more than did the richer for healthcare, during pregnancy-related and neonatal illness. However, the richer paid more than did the poorer during postpartum illness. Forty-six percent of households faced catastrophic healthcare expenditure at the threshold of 10% of total household expenditure, or 74% at a 40% non-food expenditure, and associated with neonatal illness (aRR: 2.56, 95%CI: 1.02, 6.44). Moreover, 92% of households were pushed further into extreme poverty and the poverty gap among households was 45 Ethiopian Birr per day. The average household size among study households was 4.7 persons per household. This study demonstrated that health inequity in the household's budget share of total OOP healthcare payments in southern Ethiopia was high. Besides, utilisation of maternal and neonatal healthcare services is very low and seeking such healthcare poses a substantial financial risk during illness among rural households. Therefore, the issue of health inequity should be considered when setting priorities to address the lack of fairness in maternal and neonatal health.


Year in Review in Cardiac Electrophysiology.
In the past year, there have been numerous advances in our understanding of arrhythmia mechanisms, diagnosis, and new therapies. We have seen advances in basic cardiac electrophysiology with data suggesting that secretoneurin may be a biomarker for patients at risk of ventricular arrhythmias, and we have learned of the potential role of an NPR-C (natriuretic peptide receptor-C) in atrial fibrosis and the role of an atrial specific 2-pore potassium channel TASK-1 as a therapeutic target for atrial fibrillation. We have seen studies demonstrating the role of sensory neurons in sleep apnea-related atrial fibrillation and the association between bariatric surgery and atrial fibrillation ablation outcomes. Artificial intelligence applied to electrocardiography has yielded estimates of age, sex, and overall health. We have seen new tools for collection of patient-centered outcomes following catheter ablation. There have been significant advances in the ability to identify ventricular tachycardia termination sites through high-density mapping of deceleration zones. We have learned that right ventricular dysfunction may be a predictor of survival benefit after implantable cardioverter-defibrillator implantation in patients with nonischemic cardiomyopathy. We have seen further insights into the role of His bundle pacing on improving outcomes. As our understanding of cardiac laminopathies advances, we may have new tools to predict arrhythmic event rates in gene carriers. Finally, we have seen numerous advances in the treatment of arrhythmias in patients with congenital heart disease.


High-Resolution Benthic Mg/Ca Temperature Record of the Intermediate Water in the Denmark Strait Across D-O Stadial-Interstadial Cycles.
Dansgaard-Oeschger (D-O) climate instabilities that took place during Marine Isotope Stage 3 are connected to changes in ocean circulation patterns and sea ice cover. Here we explore in detail the configuration of the water column of the Denmark Strait during D-O events 8-5. How the ocean currents and water masses within the Denmark Strait region responded and were connected to the North Atlantic are discussed. We investigate sediment core GS15-198-36CC, from the northern side of the Greenland-Iceland Ridge, at 30-year temporal resolution. Stable carbon and oxygen isotope reconstructions based on benthic foraminifera, together with a high-resolution benthic foraminiferal record of Mg/Ca paleothermometry, is presented. The site was bathed by warm intermediate waters during stadials and cool but gradually warming intermediate water during interstadials. We suggest that stadial conditions in the Denmark Strait are characterized by a well-stratified water column with a warm intermediate water mass that lies beneath a cold fresh body of water where sea ice and brine rejection work in consort to uphold the halocline conditions. Interstadial periods are not a pure replicate of modern times, but rather have two modes of operation, one similar to today, and the other incorporating a brief period of warm intermediate water and increased ventilation.


Preconception Cardiovascular Risk Factor Differences Between Gestational Hypertension and Preeclampsia: Cohort Norway Study.
Preconception predictors of gestational hypertension and preeclampsia may identify opportunities for early detection and improve our understanding of the pathogenesis and life course epidemiology of these conditions. Female participants in community-based Cohort Norway health surveys, 1994 to 2003, were prospectively followed through 2012 via record linkages to Medical Birth Registry of Norway. Analyses included 13 217 singleton pregnancies (average of 1.59 births to 8321 women) without preexisting hypertension. Outcomes were gestational hypertension without proteinuria (n=237) and preeclampsia (n=429). Mean age (SD) at baseline was 27.9 years (4.5), and median follow-up was 4.8 years (interquartile range 2.6-7.8). Gestational hypertension and preeclampsia shared several baseline risk factors: family history of diabetes mellitus, pregravid diabetes mellitus, a high total cholesterol/high-density lipoprotein cholesterol ratio (>5), overweight and obesity, and elevated blood pressure status. For preeclampsia, a family history of myocardial infarction before 60 years of age and elevated triglyceride levels (≥1.7 mmol/L) also predicted risk while physical activity was protective. Preterm preeclampsia was predicted by past-year binge drinking (≥5 drinks on one occasion) with an adjusted odds ratio of 3.7 (95% confidence interval 1.3-10.8) and by past-year physical activity of ≥3 hours per week with an adjusted odds ratio of 0.5 (95% confidence interval 0.3-0.8). The results suggest similarities and important differences between gestational hypertension, preeclampsia, and preterm preeclampsia. Modifiable risk factors could be targeted for improving pregnancy outcomes and the short- and long-term sequelae for mothers and offspring.


Poliovirus-specific CD4+ Th1 clones with both cytotoxic and helper activity mediate protective humoral immunity against a lethal poliovirus infection in transgenic mice expressing the human poliovirus receptor.
The current understanding of the function of CD4+ T helper (Th) cells in immunity to infectious diseases is that Th1 cells, which secrete interleukin (IL)-2 and interferon-gamma, induce cellular immune responses, whereas Th2 cells, which secrete IL-4, IL-5, IL-6, and IL-10, provide helper function for humoral immunity. We have used a panel of poliovirus-specific murine CD4+ T cell clones and mice transgenic for the human poliovirus receptor to evaluate the role of Th cell subpopulations in protective immunity to poliovirus. The majority of T cell clones, as well as polyclonal T cells generated from mice infected or immunized with poliovirus, secreted IL-2 and interferon-gamma, but not IL-4, IL-5, or IL-10, a profile typical of Th1 cells. The Th1 clones displayed major histocompatibility complex class II-restricted cytotoxic T lymphocyte activity against specific poliovirus peptide-pulsed target cells, but also provided help for antipoliovirus neutralizing antibody production. To examine the mechanism of immunity in vivo, we have used poliovirus receptor-transgenic mice on a BALB/c (H-2d) background. These animals developed a poliomyelitis-like disease when challenged intravenously with a virulent wild-type strain of poliovirus, but not with an attenuated vaccine strain. Furthermore, mice immunized with the vaccine strain were protected against a subsequent challenge with wild-type virus. Using an adoptive transfer technique, we demonstrated that it was possible to confer protection with primed B cells in the presence of polyclonal poliovirus-specific T cells, but not when transgenic mice received either B cells or T cells alone. Furthermore, protection was observed when mice received primed B cells in the presence of a VP4-specific Th1 clone. The findings demonstrate that Th1 cells can mediate a protective immune response against poliovirus infection in vivo through helper activity for humoral immunity and that CD4+ T cells, specific for the internal poliovirus capsid protein, VP4, can provide effective help for a protective antibody response directed against surface capsid proteins.


Significant differences of brain blood flow in patients with chronic low back pain and acute low back pain detected by brain SPECT.
The aim of this study was to examine and compare the areas of brain blood flow in patients with chronic low back pain (CLBP) without structural abnormality and acute low back pain (ALBP) with lumber disc herniation (LDH). Functional neuroimaging studies provide evidence of abnormalities in the regional cerebral blood flow during low back pain. Recent studies have shown that CLBP is associated with plastic, pathophysiological changes in the brain. However, there has been no report yet statistically or by neuro-images on the compared brain single photon-emission computed tomography (SPECT) findings between CLBP and ALBP patients. The subjects comprised 14 patients, 7 CLBP and 7 ALBP patients. The CLBP group included the patients who had no or minor structural abnormality in the lumbar spine on magnetic resonance imaging (MRI) and met the criteria for a classification of "pain disorder" (chronic) according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. The ALBP group included the patients who had symptoms within 3 months of onset and LDH revealed by MRI. All patients were assessed using brain SPECT. We then performed a two-tailed view analysis using the easy Z score imaging system, determined the mean Z scores, and performed vBSEE software (Fujifilm RI Pharma, Tokyo, Japan) for both CLBP and ALBP patients. The CLBP group showed significantly reduced blood flow in the bilateral prefrontal cortex of the frontal lobe and increased blood flow in the bilateral posterior lobe of the cerebellum. SPECT images and statistical analyses revealed the brain blood flow alterations in the patients with ALBP and CLBP. These results may suggest that the dysfunction of the prefrontal cortex could lead to the appearance of unconscious pain behavior controlled by the cerebellum in the patients with CLBP.


Nipple adenoma of breast: a masquerader of malignancy.
ABSTRACT Nipple adenoma is a benign condition simulating malignancy such as breast carcinoma and/or Paget's disease clinically. In this study 19 cases diagnosed as nipple adenoma over a period of 14 years are described. The diagnosis was confirmed by histology alone. All patients were females with age ranging from 23 to 63 years. Most of the cases presented clinically with in duration and ulceration accompanied by pain and itching. The diagnosis was clinically suspected in only 3 cases. This highlights the importance of histological diagnosis in all suspicious breast lesions. In one case, the clinical and histological diagnosis was incorrect leading to mastectomy. Complete local excision with clear margins is curative.


Deficient motor timing in children with neurofibromatosis type 1.
Neurofibromatosis type 1 (NF1) is one of the most common single-gene disorders affecting fine and visual-motor skills. This case-control study investigated motor timing as a possible related performance deficit in children with NF1. A visual-motor reaction time (VRT) test was administered in 20 NF1 children (mean age 9 years 7 months) and 20 age- and gender-matched typically developing (TD) children. Copying and tracing performance were evaluated using the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI). Children with NF1 responded with an increased reaction time (RT) to temporally predictive stimuli compared to TD children, whereas RT at unpredictive stimuli did not differ between groups. Motor timing indexed by the RT decrease at predictive stimuli significantly associated with the Beery VMI copy and tracing outcomes. Deficient motor timing as an actual symptom may add to further research on the pathogenesis of NF1-associated motor impairment and the development of more effective treatment.


Characterisation of a multi-ligand binding chemoreceptor CcmL (Tlp3) of Campylobacter jejuni.
Campylobacter jejuni is the leading cause of human gastroenteritis worldwide with over 500 million cases annually. Chemotaxis and motility have been identified as important virulence factors associated with C. jejuni colonisation. Group A transducer-like proteins (Tlps) are responsible for sensing the external environment for bacterial movement to or away from a chemical gradient or stimulus. In this study, we have demonstrated Cj1564 (Tlp3) to be a multi-ligand binding chemoreceptor and report direct evidence supporting the involvement of Cj1564 (Tlp3) in the chemotaxis signalling pathway via small molecule arrays, surface plasmon and nuclear magnetic resonance (SPR and NMR) as well as chemotaxis assays of wild type and isogenic mutant strains. A modified nutrient depleted chemotaxis assay was further used to determine positive or negative chemotaxis with specific ligands. Here we demonstrate the ability of Cj1564 to interact with the chemoattractants isoleucine, purine, malic acid and fumaric acid and chemorepellents lysine, glucosamine, succinic acid, arginine and thiamine. An isogenic mutant of cj1564 was shown to have altered phenotypic characteristics of C. jejuni, including loss of curvature in bacterial cell shape, reduced chemotactic motility and an increase in both autoagglutination and biofilm formation. We demonstrate Cj1564 to have a role in invasion as in in vitro assays the tlp3 isogenic mutant has a reduced ability to adhere and invade a cultured epithelial cell line; interestingly however, colonisation ability of avian caeca appears to be unaltered. Additionally, protein-protein interaction studies revealed signal transduction initiation through the scaffolding proteins CheV and CheW in the chemotaxis sensory pathway. This is the first report characterising Cj1564 as a multi-ligand receptor for C. jejuni, we therefore, propose to name this receptor CcmL, Campylobacter chemoreceptor for multiple ligands. In conclusion, this study identifies a novel multifunctional role for the C. jejuni CcmL chemoreceptor and illustrates its involvement in the chemotaxis pathway and subsequent survival of this organism in the host.


Early and late complications among long-term colorectal cancer survivors with ostomy or anastomosis.
Among long-term (>or=5 y) colorectal cancer survivors with permanent ostomy or anastomosis, we compared the incidence of medical and surgical complications and examined the relationship of complications with health-related quality of life. The incidence and effects of complications on long-term health-related quality of life among colorectal cancer survivors are not adequately understood. Participants (284 survivors with ostomies and 395 survivors with anastomoses) were long-term colorectal cancer survivors enrolled in an integrated health plan. Health-related quality of life was assessed via mailed survey questionnaires from 2002 to 2005. Information on colorectal cancer, surgery, comorbidities, and complications was obtained from computerized data and analyzed by use of survival analysis and logistic regression. Ostomy and anastomosis survivors were followed up for an average of 12.1 and 11.2 years, respectively. Within 30 days of surgery, 19% of ostomy survivors and 10% of anastomosis survivors experienced complications (P < .01). From 31 days on, the percentages were 69% and 67% (after adjustment, P < .001). Bleeding and postoperative infection were common early complications. Common long-term complications included hernia, urinary retention, hemorrhage, skin conditions, and intestinal obstruction. Ostomy was associated with long-term fistula (odds ratio, 5.4; 95% CI 1.4-21.2), and among ostomy survivors, fistula was associated with reduced health-related quality of life (P < .05). Complication rates remain high despite recent advances in methods of surgical treatment. Survivors with ostomy have more complications early in their survivorship period, but complications among anastomosis survivors catch up after 20 years, when the 2 groups have convergent complication rates. Among colorectal cancer survivors with ostomy, fistula has especially important implications for health-related quality of life.


Identification of definitive serum biomarkers associated with disease activity in primary Sjögren's syndrome.
In this study, we sought to identify definitive biomarkers associated with disease activity in primary Sjögren's syndrome (pSS). Serum protein concentrations in pSS patients and healthy controls (HCs) were comprehensively screened using high-throughput proteomic analysis, and differentially expressed proteins were extracted. Correlation between differentially expressed proteins and European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) scores was analyzed and disease activity-associated biomarkers were identified. These biomarkers were validated by enzyme-linked immunosorbent assay (ELISA) in a separate pSS cohort. The serum concentrations of 1100 proteins were compared between 30 pSS patients and 30 HCs, with 82 differentially expressed proteins identified as pSS-associated proteins. Of these 82 proteins, 9 were identified as disease activity-associated biomarkers. These nine biomarkers underwent validation by ELISA in a separate pSS validation cohort (n = 58), with five proteins (CXCL13, TNF-R2, CD48, B-cell activating factor (BAFF), and PD-L2) subsequently being confirmed as candidate biomarkers. Of these five candidate biomarkers, CXCL13 exhibited the most significant correlation with the lymphadenopathy, glandular, and pulmonary domains of the ESSDAI. CXCL13, TNF-R2 and CD48 exhibited a positive correlation with the biological domain of the ESSDAI. TNF-R2 exhibited the most negative correlation with uptake in the submandibular gland on technetium 99m-pertechnetate salivary gland scintigraphy. Our approach successfully identified serum biomarkers associated with disease activity in pSS patients. These markers might be potential therapeutic targets in pSS patients.


Yoga for chronic pain management: a qualitative exploration.
To explore patients' perceptions of their pain while participating in a weekly yoga program. A consecutive convenience sample was recruited from a Multidisciplinary Pain Centre. Seven adult patients (six women), agreed to participate in an 8-week Hatha yoga program, including weekly group sessions and at-home practice. Data were gathered from participant observation and in-depth interviews. Interviews explored the experience of practicing yoga and its relationship to the participant's pain experience. An inductive analysis of the interviews explored emergent themes from participants' descriptions of their experience. Analyses identified three themes: renewed awareness of the body; transformed relationship with the body in pain; and acceptance. Participants' data suggested that they reframed what it meant to live with chronic pain. Some participants reported that the sensory aspects of pain did not change but that pain became less bothersome. They were better able to control the degree to which pain interfered with their daily life. Other participants reported less frequent or less intense pain episodes because they could recognize body signals and adjust themselves to alleviate painful sensations. The findings suggest that patients who benefit from yoga may do so in part because yoga enables changes in cognitions and behaviours towards pain.


Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer.
Small activating RNAs (saRNAs) are short double-stranded oligonucleotides that selectively increase gene transcription. Here, we describe the development of an saRNA that upregulates the transcription factor CCATT/enhancer binding protein alpha (CEBPA), investigate its mode of action, and describe its development into a clinical candidate. A bioinformatically directed nucleotide walk around the CEBPA gene identified an saRNA sequence that upregulates CEBPA mRNA 2.5-fold in human hepatocellular carcinoma cells. A nuclear run-on assay confirmed that this upregulation is a transcriptionally driven process. Mechanistic experiments demonstrate that Argonaute-2 (Ago2) is required for saRNA activity, with the guide strand of the saRNA shown to be associated with Ago2 and localized at the CEBPA genomic locus using RNA chromatin immunoprecipitation (ChIP) assays. The data support a sequence-specific on-target saRNA activity that leads to enhanced CEBPA mRNA transcription. Chemical modifications were introduced in the saRNA duplex to prevent activation of the innate immunity. This modified saRNA retains activation of CEBPA mRNA and downstream targets and inhibits growth of liver cancer cell lines in vitro. This novel drug has been encapsulated in a liposomal formulation for liver delivery, is currently in a phase I clinical trial for patients with liver cancer, and represents the first human study of an saRNA therapeutic.


Diaryl-substituted ortho-carboranes as a new class of hypoxia inducible factor-1α inhibitors.
Diaryl-substituted ortho-carboranes 1 were synthesized from the corresponding alkynes by decaborane coupling under microwave-irradiated conditions with a combination of N,N-dimethylaniline and chlorobenzene. Among the compounds synthesized, 1a and 1d exhibited significant inhibition of hypoxia-induced HIF-1 transcriptional activity. Both compounds similarly suppressed hypoxia-induced HIF-1α accumulation in a concentration-dependent manner without affecting HIF-1α mRNA expression.


Biomarkers for Traumatic Brain Injury: Data Standards and Statistical Considerations.
Recent biomarker innovations hold potential for transforming diagnosis, prognostic modeling, and precision therapeutic targeting of traumatic brain injury (TBI). However, many biomarkers, including brain imaging, genomics, and proteomics, involve vast quantities of high-throughput and high-content data. Management, curation, analysis, and evidence synthesis of these data are not trivial tasks. In this review, we discuss data management concepts and statistical and data sharing strategies when dealing with biomarker data in the context of TBI research. We propose that application of biomarkers involves three distinct steps-discovery, evaluation, and evidence synthesis. First, complex/big data has to be reduced to useful data elements at the stage of biomarker discovery. Second, inferential statistical approaches must be applied to these biomarker data elements for assessment of biomarker clinical utility and validity. Last, synthesis of relevant research is required to support practice guidelines and enable health decisions informed by the highest quality, up-to-date evidence available. We focus our discussion around recent experiences from the International Traumatic Brain Injury Research (InTBIR) initiative, with a specific focus on four major clinical projects (Transforming Research and Clinical Knowledge in TBI, Collaborative European NeuroTrauma Effectiveness Research in TBI, Collaborative Research on Acute Traumatic Brain Injury in Intensive Care Medicine in Europe, and Approaches and Decisions in Acute Pediatric TBI Trial), which are currently enrolling subjects in North America and Europe. We discuss common data elements, data collection efforts, data-sharing opportunities, and challenges, as well as examine the statistical techniques required to realize successful adoption and use of biomarkers in the clinic as a foundation for precision medicine in TBI.


Codesign and development of a primary school based pathway for child anxiety screening and intervention delivery: a protocol, mixed-methods feasibility study.
Anxiety difficulties are among the most common mental health problems in childhood. Despite this, few children access evidence-based interventions, and school may be an ideal setting to improve children's access to treatment. This article describes the design, methods and expected data collection of the Identifying Child Anxiety Through Schools - Identification to Intervention (iCATS i2i) study, which aims to develop acceptable school-based procedures to identify and support child anxiety difficulties. METHODS AND ANALYSIS: iCATS i2i will use a mixed-methods approach to codesign and deliver a set of procedures-or 'pathway'-to improve access to evidence-based intervention for child anxiety difficulties through primary schools in England. The study will consist of four stages, initially involving in-depth interviews with parents, children, school staff and stakeholders (stage 1) to inform the development of the pathway. The pathway will then be administered in two primary schools, including screening, feedback to parents and the offer of treatment where indicated (stage 2), with participating children, parents and school staff invited to provide feedback on their experience (stages 3 and 4). Data will be analysed using Template Analysis. The iCATS i2i study was approved by the University of Oxford's Research Ethics Committee (REF R64620/RE001). It is expected that this codesign study will lead on to a future feasibility study and, if indicated, a randomised controlled trial. The findings will be disseminated in several ways, including via lay summary report, publication in academic journals and presentation at conferences. By providing information on child, parent, school staff and other stakeholder's experiences, we anticipate that the findings will inform the development of an acceptable evidence-based pathway for identification and intervention for children with anxiety difficulties in primary schools and may also inform broader approaches to screening for and treating youth mental health problems outside of clinics.


Effects of Waon therapy on chronic fatigue syndrome: a pilot study.
Chronic fatigue syndrome (CFS) is a disabling condition of unknown etiology, and no definitive therapy has been identified to date. We developed Waon therapy, a form of thermal therapy using a far-infrared dry sauna, and in this study herein examined its feasibility and safety in patients with CFS. Ten consecutive inpatients with CFS stayed in a 60°C sauna for 15 minutes and then rested on a bed under a blanket for an additional 30 minutes outside the sauna room. The treatments were performed once a day, five days a week for four weeks. Perceived fatigue, the primary outcome measure, was evaluated using a numerical rating scale before, during (two weeks after the commencement of therapy) and after therapy. The pain level, evaluated using a numerical rating scale, mood, assessed using the Profile of Mood States questionnaire, and performance status, assessed using a scale developed for CFS patients were also examined before and after therapy. Perceived fatigue significantly decreased after therapy, although no significant reductions were observed during therapy. In addition, a negative mood, including anxiety, depression and fatigue, and the performance status significantly improved after therapy. However, the levels of pain and vigor did not change significantly. No patients reported any adverse effects during the therapy. These findings suggest that Waon therapy may be a useful and safe treatment for CFS.


Clinical inactivity among pediatricians: prevalence and perspectives.
During their careers, physicians may have periods of clinical inactivity for a variety of reasons. Concerns have been raised about the impact of clinical inactivity on the growing physician workforce shortage. It is unknown how these periods of clinical inactivity impact physician competence and patient safety. With this study we sought to determine the rates of clinical inactivity, the duration of periods of inactivity, professional activities during those periods, and the perspective of pediatricians regarding future requirements of competency for return to clinical practice. A random sample of 6757 American Board of Pediatrics diplomates aged < or =65 years received a structured questionnaire by mail. The survey explored the prevalence of and reasons for clinical inactivity and perspectives on the return to clinical practice. Clinical inactivity was defined as a period of absence of > or =12 months from any direct or consultative clinical care. The response rate was 74%. Of respondents, 88% (n = 4176) were currently engaged in pediatric clinical care. Twelve percent (n = 554) indicated that they had experienced a period of clinical inactivity lasting > or =12 months. Women were more likely than men (16% vs 7%) to have had periods of clinical inactivity. Controlling for gender, generalists were no more likely than subspecialists to report a past period of clinical inactivity. More than one third of the respondents (n = 1672 [36%]) agreed that pediatricians who return from clinical inactivity after >1 year should undergo a competency evaluation. Almost 1 in 8 pediatricians has suspended clinical care for > or =1 year, and a similar proportion of respondents were inactive at the time of our survey. Currently, all of these physicians may maintain both their licensure and board certification during these periods. The impact of clinical inactivity on patient care and patient safety is unknown.


Seasonal patterns in human A (H5N1) virus infection: analysis of global cases.
Human cases of highly pathogenic avian influenza (HPAI) A (H5N1) have high mortality. Despite abundant data on seasonal patterns in influenza epidemics, it is unknown whether similar patterns exist for human HPAI H5N1 cases worldwide. Such knowledge could help decrease avian-to-human transmission through increased prevention and control activities during peak periods. We performed a systematic search of published human HPAI H5N1 cases to date, collecting month, year, country, season, hemisphere, and climate data. We used negative binomial regression to predict changes in case incidence as a function of season. To investigate hemisphere as a potential moderator, we used AIC and the likelihood-ratio test to compare the season-only model to nested models including a main effect or interaction with hemisphere. Finally, we visually assessed replication of seasonal patterns across climate groups based on the Köppen-Geiger climate classification. We identified 617 human cases (611 with complete seasonal data) occurring in 15 countries in Southeast Asia, Africa, and the Middle East. Case occurrence was much higher in winter (n = 285, p = 0.03) than summer (n = 64), and the winter peak occurred across diverse climate groups. There was no significant interaction between hemisphere and season. Across diverse climates, HPAI H5N1 virus infection in humans increases significantly in winter. This is consistent with increased poultry outbreaks and HPAI H5N1 virus transmission during cold and dry conditions. Prioritizing prevention and control activities among poultry and focusing public health messaging to reduce poultry exposures during winter months may help to reduce zoonotic transmission of HPAI H5N1 virus in resource-limited settings.


Pros and cons of different therapeutic antibody formats for recombinant antivenom development.
Antibody technologies are being increasingly applied in the field of toxinology. Fuelled by the many advances in immunology, synthetic biology, and antibody research, different approaches and antibody formats are being investigated for the ability to neutralize animal toxins. These different molecular formats each have their own therapeutic characteristics. In this review, we provide an overview of the advances made in the development of toxin-targeting antibodies, and discuss the benefits and drawbacks of different antibody formats in relation to their ability to neutralize toxins, pharmacokinetic features, propensity to cause adverse reactions, formulation, and expression for research and development (R&D) purposes and large-scale manufacturing. A research trend seems to be emerging towards the use of human antibody formats as well as camelid heavy-domain antibody fragments due to their compatibility with the human immune system, beneficial therapeutic properties, and the ability to manufacture these molecules cost-effectively.


Risk for domestic violence: factors associated with perpetration and victimization.
The extent and potential dangerousness of the problem of domestic violence warrants systematic screening and assessment in all mental health settings. Few empirical studies have approached the question of domestic violence with the aim of identifying risk markers, making it impossible to identify a particular characteristic or set of characteristics that can be used to identify individuals at risk for perpetrating or becoming the victims of domestic violence. However, there are a number of factors that have been identified as correlates of domestic violence that may eventually prove useful for identifying individuals at risk, but the extant literature does not provide the empirical support at this time. Because many of these correlates may be brought to the attention of mental health and medical professionals (e.g., depression, substance use/abuse, physical injuries) and given the absence of established risk factors for domestic violence, there is a need for clinicians to systematically assess for violence among all of their patients. By identifying factors that might help clinicians realize that many of their patients are at risk for domestic violence, we hope to encourage them to attend to this potentially dangerous problem. Ongoing assessment in the context of knowledge regarding correlates of domestic violence can provide important information for evaluating risk of a particular violent incident. In addition, we outline strategies for assessing violence and violence risk in both perpetrators and victims in order to assist clinicians in approaching this difficult topic in a clinical setting. A careful assessment of the potential for violence within clients' ongoing relationships is necessary for clinicians to provide appropriate clinical care.


Evaluation of a whole system approach to diet and healthy weight in the east of Scotland: Study protocol.
Obesity is a global epidemic affecting all age groups, populations and income levels across continents. The causes of obesity are complex and are routed in health behaviours, environmental factors, government policy and the cultural and built environment. Consequently, a Whole System Approach (WSA) which considers the many causes of obesity and shifts the focus away from individuals as points of intervention and puts an emphasis on understanding and improving the system in which people live in is required. This protocol describes a programme of research that will: critically evaluate the evidence for WSAs; assess longitudinally the implementation of a WSA to diet and healthy weight to explore the range of levers (drivers) and opportunities to influence relevant partnerships and interventions to target obesity in East Scotland. The programme consists of four workstreams within a mixed methods framework: 1) Systematic review of reviews of WSAs to diet and healthy weight; 2) Longitudinal qualitative process evaluation of implementing two WSAs in Scotland; 3) Quantitative and Qualitative momentary analysis evaluation of a WSA; and 4) the application of System Dynamics Modelling (SDM) methodology to two council areas in Scotland. A Public Involvement in Research group (PIRg) have informed each stage of the research process. The research programme's breadth and its novel nature, mean that it will provide valuable findings for the increasing numbers who commission, deliver, support and evaluate WSAs to diet and healthy weight nationally and internationally.


Articular-surface-based automatic anatomical coordinate systems for the knee bones.
Increasing use of patient-specific surgical procedures in orthopaedics means that patient-specific anatomical coordinate systems (ACSs) need to be determined. For knee bones, automatic algorithms constructing ACSs exist and are assumed to be more reliable than manual methods, although both approaches are based on non-unique numerical reconstructions of true bone geometries. Furthermore, determining the best algorithms is difficult, as algorithms are evaluated on different datasets. Thus, in this study, we developed 3 algorithms, each with 3 variants, and compared them with 5 from the literature on a dataset comprising 24 lower-limb CT-scans. To evaluate algorithms' sensitivity to the operator-dependent reconstruction procedure, the tibia, patella and femur of each CT-scan were each reconstructed once by three different operators. Our algorithms use principal inertia axis (PIA), cross-sectional area, surface normal orientations and curvature data to identify the bone region underneath articular surfaces (ASs). Then geometric primitives are fitted to ASs, and the ACSs are constructed from the geometric primitive points and/or axes. For each bone type, the algorithm displaying the least inter-operator variability is identified. The best femur algorithm fits a cylinder to posterior condyle ASs and a sphere to the femoral head, average axis deviations: 0.12°, position differences: 0.20 mm. The best patella algorithm identifies the AS PIAs, average axis deviations: 0.91°, position differences: 0.19 mm. The best tibia algorithm finds the ankle AS center and the 1st PIA of a layer around a plane fitted to condyle ASs, average axis deviations: 0.38°, position differences: 0.27 mm.


ATM, ATR and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers.
Ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia mutated and rad3 related (ATR) and DNA-dependent protein kinase catalytic sub-unit (DNA-PKcs) play critical roles in DNA damage response (DDR) by linking DNA damage sensing to DDR effectors that regulate cell cycle progression and DNA repair. Our objective was to evaluate if ATM, ATR and DNA-PKcs expressions could predict response to therapy and clinical outcome in epithelial ovarian cancers. We investigated ATM, ATR, and DNA-PKcs expressions in ovarian epithelial cancers [protein expression (n = 194 patients), mRNA expression (n = 156 patients)] and correlated to clinicopathological outcomes as well as expression of X-ray repair cross-complementing protein 1 (XRCC1), cell division cycle-45 (CDC45), cyclin-dependent kinase 1(CDK1) and Ki-67 in tumours. High ATM protein expression was associated with serous cystadenocarcinomas (p = 0.021) and platinum resistance (p = 0.017). High DNA-PKcs protein expression was associated with serous cystadenocarcinomas (p = 0.006) and advanced stage tumours (p = 0.018). High ATM protein (p = 0.001), high ATM mRNA (p = 0.018), high DNA-PKcs protein (p = 0.002), high DNA-PKcs mRNA (p = 0.044) and high ATR protein (p = 0.001) expressions are correlated with poor ovarian cancer specific survival (OCSS). In multivariate Cox model, high DNA-PKcs (p = 0.006) and high ATR (p = 0.043) protein expressions remain independently associated with poor OCSS. ATM, ATR and DNA-PKcs expressions may have prognostic and predictive significances in epithelial ovarian cancer. The data presented here provides evidence that ATM, ATR and DNA-PKcs involved in DDR are not only promising biomarkers but are also rational targets for personalized therapy in ovarian cancer.


Combined inhibition of PAK7, MAP3K7 and CK2alpha kinases inhibits the growth of MiaPaCa2 pancreatic cancer cell xenografts.
A panel of kinases whose inhibition increased apoptosis of pancreatic adenocarcinoma cells in vitro was recently established. The aim of this work was to observe in a mouse xenograft model whether inhibition of these kinases would alter pancreatic tumor growth. Rate of apoptosis, caspase-3 activity and cell viability were assessed in two pancreatic cancer cell lines, MiaPaCa2 and BxPC3, after inhibiting selected kinases by transfection of specific siRNAs. For in vivo experiments, MiaPaCa2 cells were injected into the pancreas of nude mice, where they formed tumors. Inhibition of kinases was obtained by repeated intraperitoneal (i.p.) injections of modified O-Methyl (OMe) siRNAs specific for the selected kinases. Tumor volumes were assessed after 21 days. Among selected kinases, PAK7, MAP3K7 and CK2alpha were those whose inhibition increased apoptosis the most in vitro. Simultaneous inhibition of two of them increased apoptosis up to five times. Moreover, inhibiting these kinases had little effect on 10 non-pancreatic cell lines, suggesting pancreatic specificity. In vivo, OMe-siRNAs induced significant but incomplete inhibition of kinase expression (45-75%). Nevertheless, such inhibition resulted in a twofold increase in caspase-3 activity in tumors and a strong reduction in tumor volume (about 75%). In vivo inhibition by OMe-siRNAs of three survival kinases apparently specific for pancreatic cancer cells, PAK7, MAP3K7 and CK2alpha, decreases significantly the growth of xenografted MiaPaCa2 cells. This strategy is therefore of potential clinical interest.


Red and processed meat consumption and risk of incident coronary heart disease, stroke, and diabetes mellitus: a systematic review and meta-analysis.
Meat consumption is inconsistently associated with development of coronary heart disease (CHD), stroke, and diabetes mellitus, limiting quantitative recommendations for consumption levels. Effects of meat intake on these different outcomes, as well as of red versus processed meat, may also vary. We performed a systematic review and meta-analysis of evidence for relationships of red (unprocessed), processed, and total meat consumption with incident CHD, stroke, and diabetes mellitus. We searched for any cohort study, case-control study, or randomized trial that assessed these exposures and outcomes in generally healthy adults. Of 1598 identified abstracts, 20 studies met inclusion criteria, including 17 prospective cohorts and 3 case-control studies. All data were abstracted independently in duplicate. Random-effects generalized least squares models for trend estimation were used to derive pooled dose-response estimates. The 20 studies included 1 218 380 individuals and 23 889 CHD, 2280 stroke, and 10 797 diabetes mellitus cases. Red meat intake was not associated with CHD (n=4 studies; relative risk per 100-g serving per day=1.00; 95% confidence interval, 0.81 to 1.23; P for heterogeneity=0.36) or diabetes mellitus (n=5; relative risk=1.16; 95% confidence interval, 0.92 to 1.46; P=0.25). Conversely, processed meat intake was associated with 42% higher risk of CHD (n=5; relative risk per 50-g serving per day=1.42; 95% confidence interval, 1.07 to 1.89; P=0.04) and 19% higher risk of diabetes mellitus (n=7; relative risk=1.19; 95% confidence interval, 1.11 to 1.27; P<0.001). Associations were intermediate for total meat intake. Consumption of red and processed meat were not associated with stroke, but only 3 studies evaluated these relationships. Consumption of processed meats, but not red meats, is associated with higher incidence of CHD and diabetes mellitus. These results highlight the need for better understanding of potential mechanisms of effects and for particular focus on processed meats for dietary and policy recommendations.


Treatment of massive obesity with rice/reduction diet program. An analysis of 106 patients with at least a 45-kg weight loss.
One hundred six massively obese patients, who each lost at least 45 kg, were treated as outpatients with the rice/reduction diet, exercise, and motivational enhancement under daily supervision. Average weight loss was 63.9 kg. Forty-three patients achieved normal weight. Men lost weight at a greater rate than women. Concomitant with weight reduction, there were significant decrements in blood pressure; fasting and two-hour postprandial blood glucose, serum triglyceride, and serum uric acid levels, and heart-chest ratio as evidenced on chest x-ray film. Electrocardiographic and retinal venous changes improved. Serum cholesterol level did not change significantly. This study demonstrates that massively obese persons can achieve marked weight reduction, even normalization of weight, without hospitalization, surgery, or pharmacologic intervention. Accompanying cardiovascular risk factors show great decrements concomitant with weight loss.


Crawling-induced floor dust resuspension affects the microbiota of the infant breathing zone.
Floor dust is commonly used for microbial determinations in epidemiological studies to estimate early-life indoor microbial exposures. Resuspension of floor dust and its impact on infant microbial exposure is, however, little explored. The aim of our study was to investigate how floor dust resuspension induced by an infant's crawling motion and an adult walking affects infant inhalation exposure to microbes. We conducted controlled chamber experiments with a simplified mechanical crawling infant robot and an adult volunteer walking over carpeted flooring. We applied bacterial 16S rRNA gene sequencing and quantitative PCR to monitor the infant breathing zone microbial content and compared that to the adult breathing zone and the carpet dust as the source. During crawling, fungal and bacterial levels were, on average, 8- to 21-fold higher in the infant breathing zone compared to measurements from the adult breathing zone. During walking experiments, the increase in microbial levels in the infant breathing zone was far less pronounced. The correlation in rank orders of microbial levels in the carpet dust and the corresponding infant breathing zone sample varied between different microbial groups but was mostly moderate. The relative abundance of bacterial taxa was characteristically distinct in carpet dust and infant and adult breathing zones during the infant crawling experiments. Bacterial diversity in carpet dust and the infant breathing zone did not correlate significantly. The microbiota in the infant breathing zone differ in absolute quantitative and compositional terms from that of the adult breathing zone and of floor dust. Crawling induces resuspension of floor dust from carpeted flooring, creating a concentrated and localized cloud of microbial content around the infant. Thus, the microbial exposure of infants following dust resuspension is difficult to predict based on common house dust or bulk air measurements. Improved approaches for the assessment of infant microbial exposure, such as sampling at the infant breathing zone level, are needed.


Monte Carlo simulation of light scattering in the atmosphere and effect of atmospheric aerosols on the point spread function.
We present a Monte Carlo simulation for the scattering of light in the case of an isotropic light source. The scattering phase functions are studied particularly in detail to understand how they can affect the multiple light scattering in the atmosphere. We show that, although aerosols are usually in lower density than molecules in the atmosphere, they can have a non-negligible effect on the atmospheric point spread function. This effect is especially expected for ground-based detectors when large aerosols are present in the atmosphere.


Respiration-induced movement correlation for synchronous noninvasive renal cancer surgery.
Noninvasive surgery (NIS), such as high-intensity focused ultrasound (HIFU)-based ablation or radiosurgery, is used for treating tumors and cancers in various parts of the body. The soft tissue targets (usually organs) deform and move as a result of physiological processes such as respiration. Moreover, other deformations induced during surgery by changes in patient position, changes in physical properties caused by repeated exposures and uncertainties resulting from cavitation also occur. In this paper, we present a correlation-based movement prediction technique to address respiration-induced movement of the urological organs while targeting through extracorporeal trans-abdominal route access. Among other organs, kidneys are worst affected during respiratory cycles, with significant three-dimensional displacements observed on the order of 20 mm. Remote access to renal targets such as renal carcinomas and cysts during noninvasive surgery, therefore, requires a tightly controlled real-time motion tracking and quantitative estimate for compensation routine to synchronize the energy source(s) for precise energy delivery to the intended regions. The correlation model finds a mapping between the movement patterns of external skin markers placed on the abdominal access window and the internal movement of the targeted kidney. The coarse estimate of position is then fine-tuned using the Adaptive Neuro-Fuzzy Inference System (ANFIS), thereby achieving a nonlinear mapping. The technical issues involved in this tracking scheme are threefold: the model must have sufficient accuracy in mapping the movement pattern; there must be an image-based tracking scheme to provide the organ position within allowable system latency; and the processing delay resulting from modeling and tracking must be within the achievable prediction horizon to accommodate the latency in the therapeutic delivery system. The concept was tested on ultrasound image sequences collected from 20 healthy volunteers. The results indicate that the modeling technique can be practically integrated into an image-guided noninvasive robotic surgical system with an indicative targeting accuracy of more than 94%. A comparative analysis showed the superiority of this technique over conventional linear mapping and modelfree blind search techniques.


Midarch Foot Pain: Entrapment Neuropathy of the Distal Medial Plantar Nerve and Its Branches.
Medial forefoot pain, or midarch pain, is usually attributed to plantar fasciitis. The authors present their findings of a previously unreported nerve entrapment of the medial proper plantar digital nerve (MPPDN). Ten fresh-frozen cadaveric specimens were analyzed for anatomical variance in the nerve distribution of the MPPDN. In addition, clinical results from a retrospective review of nine patients who underwent surgical nerve decompression of the MPPDN are presented. Significant anatomical variance was found for the MPPDN in the cadaveric dissection of 10 fresh-frozen specimens. Nine patients with a clinical diagnosis of entrapment of the MPPDN all obtained excellent pain relief with surgical external neurolysis. Only one complication occurred: a hypertrophic scar formation that was successfully treated with intralesional steroid injections. The authors believe that this MPPDN entrapment is often overlooked or misdiagnosed as plantar fasciitis. Surgical peripheral nerve decompression of this nerve can provide positive outcomes for patients suffering from midarch foot pain caused by this pain generator.


Low-cost high-speed multichannel fiber-optic correlator.
It is shown that, for stationary signals, by use of a microwave switchable delay line the number of channels in a multichannel fiber-optic correlator may be simply expanded. By replacing one optical tree with an electrical tree and by performing the AND operation with double-gate metal-oxide semiconductor field-effect transistors, we demonstrate two methods of reducing the cost of a multichannel architecture without a reduction in speed. Using optical implementation for delays longer than 5 ns and microwave implementation for delays shorter than 5 ns, we obtain 20 points of the correlation function of a 500-MHz signal.