Median mandibular flexure at different mouth opening and its relation to different facial types: A prospective clinical study.
To measure the arch width and Median mandibular flexure (MMF) values at relative rest and maximum jaw opening in young adults with Dolichofacial, Mesofacial, and Brachyfacial types and tested whether the variation in the facial pattern is related to the MMF values in South Indian population. This Prospective clinical study consisted of sample of 60 young adults. The subjects were grouped into 3 groups: Group 1: Brachyfacial, Group 2: Mesofacial and types, Group 3: Dolichofacial. Impressions were taken for all the 60 subjects and the casts were scanned and digitized. The intermolar width was measured for Dolichofacial, Mesofacial, and Brachyfacial subjects at relative rest (R) and maximum opening (O). The statistical analysis of the observations included Descriptive and Inferential statistics. The statistical analysis was executed by means of Sigma graph pad prism software, USA Version-4. Kruskal wallis (ANOVA) followed by Dunns post hoc test was performed. Mann Whitney U-test was performed to assess the difference in MMF values between Males and Females of the three groups. The Mean (SD) Mandibular flexure in individuals with Brachyfacial type was 1.12 (0.09), Mesofacial type was 0.69 (0.21), and Dolichofacial type was 0.39 (0.08). The Mean intermolar width was maximum in Brachyfacial type and minimum in Dolichofacial type. MMF was maximum at the maximum mouth opening position and was maximum in individuals with Brachyfacial type.


Detection of Life Threatening Ventricular Arrhythmia Using Digital Taylor Fourier Transform.
Accurate detection and classification of life-threatening ventricular arrhythmia episodes such as ventricular fibrillation (VF) and rapid ventricular tachycardia (VT) from electrocardiogram (ECG) is a challenging problem for patient monitoring and defibrillation therapy. This paper introduces a novel method for detection and classification of life-threatening ventricular arrhythmia episodes. The ECG signal is decomposed into various oscillatory modes using digital Taylor-Fourier transform (DTFT). The magnitude feature and a novel phase feature namely the phase difference (PD) are evaluated from the mode Taylor-Fourier coefficients of ECG signal. The least square support vector machine (LS-SVM) classifier with linear and radial basis function (RBF) kernels is employed for detection and classification of VT vs. VF, non-shock vs. shock and VF vs. non-VF arrhythmia episodes. The accuracy, sensitivity, and specificity values obtained using the proposed method are 89.81, 86.38, and 93.97%, respectively for the classification of Non-VF and VF episodes. Comparison with the performance of the state-of-the-art features demonstrate the advantages of the proposition.


Analysis of individual and combined estrogenic effects of bisphenol, nonylphenol and diethylstilbestrol in immature rats with mathematical models.
Traditional toxicological studies focus on individual compounds. However, this single-compound approach neglects the fact that the mixture exposed to human may act additively or synergistically to induce greater toxicity than the single compounds exposure due to their similarities in the mode of action and targets. Mixture effects can occur even when all mixture components are present at levels that individually do not produce observable effects. So the individual chemical effect thresholds do not necessarily protect against combination effects, an understanding of the rules governing the interactive effects in mixtures is needed. The aim of the study was to test and analyze the individual and combined estrogenic effects of a mixture of three endocrine disrupting chemicals (EDCs), bisphenol A (BPA), nonylphenol (NP) and diethylstilbestrol (DES) in immature rats with mathematical models. In the present study, the data of individual estrogenic effects of BPA, NP and DES were obtained in uterotrophic bioassay respectively, the reference points for BPA, NP and DES were derived from the dose-response ralationship by using the traditional no observed adverse effect (NOAEL) or lowest observed adverse effect level (LOAEL) methods, and the benchmark dose (BMD) method. Then LOAEL values and the benchmark dose lower confidence limit (BMDL10) of single EDCs as the dose design basis for the study of the combined action pattern. Mixed prediction models, the 3 × 2 factorial design model and the concentration addition (CA) model, were employed to analyze the combined estrogenic effect of the three EDCs. From the dose-response relationship of estrogenic effects of BPA, NP and DES in the model of the prepuberty rats, the BMDL10(NOAEL) of the estrogenic effects of BPA, NP and DES were 90(120) mg/kg body weight, 6 mg/kg body weight and 0.10(0.25) μg/kg body weight, and the LOAEL of the the estrogenic effects of three EDCs were 240 mg/kg body weight, 15 mg/kg body weight and 0.50 μg/kg body weight, respectively. At BMDL10 doses based on the CA concept and the factorial analysis, the mode of combined effects of the three EDCs were dose addition. Mixtures in LOAEL doses, NP and DES combined effects on rat uterine/body weight ratio indicates antagonistic based on the CA concept but additive based on the factorial analysis. Combined effects of other mixtures are all additive by using the two models. Our results showed that CA model provide more accurate results than the factorial analysis, the mode of combined effects of the three EDCs were dose addition, except mixtures in LOAEL doses, NP and DES combined effects indicates antagonistic effects based on the CA model but additive based on the factorial analysis. In particular, BPA and NP produced combination effects that are larger than the effect of each mixture component applied separately at BMDL doses, which show that additivity is important in the assessment of chemicals with estrogenic effects. The use of BMDL as point of departure in risk assessment may lead to underestimation of risk, and a more balanced approach should be considered in risk assessment.


Evidence of an overweight/obesity transition among school-aged children and youth in Sub-Saharan Africa: a systematic review.
Prevalence of childhood overweight/obesity has increased considerably in recent years. The transition to higher rates of overweight/obesity has been well documented in high income countries; however, consistent or representative data from lower income countries is scarce. It is therefore pertinent to assess if rates of overweight/obesity are also increasing in lower income countries, to inform public health efforts. This systematic review aimed to investigate the evidence for an overweight/obesity transition occurring in school-aged children and youth in Sub Saharan Africa. Studies were identified by searching the MEDLINE, Embase, Africa Index Medicus, Global Health, Geobase, and EPPI-Centre electronic databases. Studies that used subjective or objective metrics to assess body composition in apparently healthy or population-based samples of children and youth aged 5 to 17 years were included. A total of 283 articles met the inclusion criteria, and of these, 68 were used for quantitative synthesis. The four regions (West, Central, East, and South) of Sub Saharan Africa were well represented, though only 11 (3.9%) studies were nationally representative. Quantitative synthesis revealed a trend towards increasing proportions of overweight/obesity over time in school-aged children in this region, as well as a persistent problem of underweight. Weighted averages of overweight/obesity and obesity for the entire time period captured were 10.6% and 2.5% respectively. Body composition measures were found to be higher in girls than boys, and higher in urban living and higher socioeconomic status children compared to rural populations or those of lower socioeconomic status. This review provides evidence for an overweight/obesity transition in school-aged children in Sub Saharan Africa. The findings of this review serve to describe the region with respect to the growing concern of childhood overweight/obesity, highlight research gaps, and inform interventions. CRD42013004399.


Constructions of lesbian, gay, bisexual and queer identities among young people in contemporary Australia.
This paper focuses on young people's construction of lesbian, gay, bisexual and queer (LGBQ) identities in contemporary Australia. Through the perspectives of young people, it seeks to position their understanding of LGBQ identities alongside current theoretical and empirical debates about the individual and social significance attached to these identity frames. In this qualitative study, 28 young people (aged 18 to 26 years) shared their stories of identifying as LGBQ through online, face-to-face or telephone interviews. The findings highlight how varying elements of LGBQ identities continue to have currency within this group and how young people adopt and refer to these terms interchangeably and in tandem. This is balanced alongside an awareness of both the limitations of lesbian, gay, bisexual and queer identity categories and of the homophobic discourses informing these subject positions. The paper concludes by arguing that health and social care professionals have a integral role to play in supporting LGBQ youth through a process of co-authorship - to work in partnership to construct more enabling self-stories that transcend restrictive identity frames.


Neural input is critical for arcuate hypothalamic neurons to mount intracellular signaling responses to systemic insulin and deoxyglucose challenges in male rats: implications for communication within feeding and metabolic control networks.
The hypothalamic arcuate nucleus (ARH) controls rat feeding behavior in part through peptidergic neurons projecting to the hypothalamic paraventricular nucleus (PVH). Hindbrain catecholaminergic (CA) neurons innervate both the PVH and ARH, and ablation of CA afferents to PVH neuroendocrine neurons prevents them from mounting cellular responses to systemic metabolic challenges such as insulin or 2-deoxy-d-glucose (2-DG). Here, we asked whether ablating CA afferents also limits their ARH responses to the same challenges or alters ARH connectivity with the PVH. We examined ARH neurons for three features: (1) CA afferents, visualized by dopamine-β-hydroxylase (DBH)- immunoreactivity; (2) activation by systemic metabolic challenge, as measured by increased numbers of neurons immunoreactive (ir) for phosphorylated ERK1/2 (pERK1/2); and (3) density of PVH-targeted axons immunoreactive for the feeding control peptides Agouti-related peptide and α-melanocyte-stimulating hormone (αMSH). Loss of PVH DBH immunoreactivity resulted in concomitant ARH reductions of DBH-ir and pERK1/2-ir neurons in the medial ARH, where AgRP neurons are enriched. In contrast, pERK1/2 immunoreactivity after systemic metabolic challenge was absent in αMSH-ir ARH neurons. Yet surprisingly, axonal αMSH immunoreactivity in the PVH was markedly increased in CA-ablated animals. These results indicate that (1) intrinsic ARH activity is insufficient to recruit pERK1/2-ir ARH neurons during systemic metabolic challenges (rather, hindbrain-originating CA neurons are required); and (2) rats may compensate for a loss of CA innervation to the ARH and PVH by increased expression of αMSH. These findings highlight the existence of a hierarchical dependence for ARH responses to neural and humoral signals that influence feeding behavior and metabolism.


Non-pathogenic Escherichia coli acquires virulence by mutating a growth-essential LPS transporter.
The molecular mechanisms that allow pathogenic bacteria to infect animals have been intensively studied. On the other hand, the molecular mechanisms by which bacteria acquire virulence functions are not fully understood. In the present study, we experimentally evaluated the evolution of a non-pathogenic strain of Escherichia coli in a silkworm infection model and obtained pathogenic mutant strains. As one cause of the high virulence properties of E. coli mutants, we identified amino acid substitutions in LptD (G580S) and LptE (T95I) constituting the lipopolysaccharide (LPS) transporter, which translocates LPS from the inner to the outer membrane and is essential for E. coli growth. The growth of the LptD and LptE mutants obtained in this study was indistinguishable from that of the parent strain. The LptD and LptE mutants exhibited increased secretion of outer membrane vesicles containing LPS and resistance against various antibiotics, antimicrobial peptides, and host complement. In vivo cross-linking studies revealed that the conformation of the LptD-LptE complex was altered in the LptD and LptE mutants. Furthermore, several clinical isolates of E. coli carried amino acid substitutions of LptD and LptE that conferred resistance against antimicrobial substances. This study demonstrated an experimental evolution of bacterial virulence properties in an animal infection model and identified functional alterations of the growth-essential LPS transporter that led to high bacterial virulence by conferring resistance against antimicrobial substances. These findings suggest that non-pathogenic bacteria can gain virulence traits by changing the functions of essential genes, and provide new insight to bacterial evolution in a host environment.


Development and Validation of a Clinical Assessment Tool for Platysmal Banding in Cervicomental Aesthetics of the Female Neck.
In facial aesthetics, grading systems are useful tools for planning aesthetic procedures. One key component of rejuvenation--the anterior neck--has been relatively overlooked. In the 1980s, criteria were established for the appearance of a youthful neck. Considering the significant contribution of the anterior neck to the aesthetics of the lower face, updated and more extensive clinical evaluation tools are critical to successful execution and measurement of rejuvenation. A validated assessment scale has yet to be created for platysmal banding, one component of the anterior neck that significantly contributes to the aesthetics. The purpose of this study was to establish a validated platysmal banding scale for clinical application. Three-dimensional standardized photographs from over 100 volunteer patients of various ages and ethnicities were analyzed to develop a five-point scale for platysmal banding. The scale was validated by a group of academic and nonacademic attending plastic surgeons as well as senior level plastic surgery residents then analyzed through a two stage process to ensure both interrater and intrarater validity. We measured the Intraclass Correlation Coefficients (ICC) for the interrater reliability. ICCs ranged from moderate to excellent agreement. Cronbach's alpha, which represents intrarater reliability, was also calculated for the same sample with all results being good to excellent. This study established a validated scale to assess the degree of platysmal banding in the female neck. This grading system has potential application in the preprocedure planning for patients considering face and neck rejuvenation to address platysmal banding.


Cultures of evidence across policy sectors: systematic review of qualitative evidence.
It is important to understand the decision-making process, and the role of research evidence within it, across sectors other than health, as interventions delivered within these sectors may have substantial impacts on public health and health inequalities. Systematic review of qualitative evidence. Twenty-eight databases covering a range of sectors were searched. Studies were eligible if they included local decision-makers in a policy field relevant to the social determinants of health (including housing, transport, urban planning and regeneration, crime, licensing or trading standards), were conducted in a high-income country, and reported primary qualitative data on perceptions of research evidence. Study quality was assessed and a thematic synthesis undertaken. Sixteen studies were included, most using interview designs, and most focusing on planning or transport policy. Several factors are seen to influence decision-makers' views of evidence, including practical factors such as resources or organizational support; the credibility of the evidence; its relevance or applicability to practice; considerations of political support or feasibility; and legislative constraints. There are limited data on how evidence is used: it is sometimes used to not only support decision-making, but also to lend legitimacy to decisions that have already been made. Although cultures of evidence in non-health sectors are similar to those in health in some ways, there are some key differences, particularly as regards the political context of decision-making. Intersectoral public health research could benefit from taking into account non-health decision makers' needs and preferences, particularly around relevance and political feasibility.


Allelopathic potential ofnuphar lutea (L.) Sibth. & Sm. (Nymphaeaceae).
Aqueous extracts ofNuphar lutea (L.) Sibth. & Sm. leaves (blades plus petioles) and roots plus rhizomes were tested for allelopathic activity using lettuce seedling andLemna minor L. assay systems. The 12.5, 25, 125, and 250 parts per thousand (ppt) treatments of both extracts killed the lettuce seedlings. At 2.5 ppt of extract, radicle growth of lettuce was 29% of the control for leaves and 31% of the control for roots plus rhizomes.Lemna minor frond number was reduced to 34% of the control by the 25 ppt leaf extract and to 43% of the control by the 25 ppt roots plus rhizomes extract.L. minor was killed by concentrations of 125 ppt and above of both plant part extracts. As expected, the frond number and total chlorophyll content measured by theL. minor assay were highly correlated. Osmotic potentials below 143 mOsmol/kg had no influence onL. minor growth. Neither the osmotic potential nor the pH of the undiluted extracts ofN. lutea were in the range known to influence the growth of either lettuce seedlings orL. minor. Nuphar lutea extracts were many times more inhibitory than 16 other hydrophytes we previously examined.


The role of leucocytes in the induction of fluid secretion by Salmonella typhimurium.
Nitrogen mustard (N2M) treatment of rabbits induced neutropenia, and, in ligated ileal loops, it inhibited fluid secretion induced by salmonella or by cholera toxin (CT). Pretreatment of rabbits with indomethacin almost abolished salmonella-induced fluid secretion and significantly reduced that induced by CT. Similar effects of N2M and indomethacin on fluid secretion induced by salmonella, but not by CT, have been reported by other workers and used to implicate prostaglandins, from the salmonella-induced inflammation, as mediators of fluid secretion. In contrast, we show that N2M treatment, in addition to reducing CT-induced secretion, caused severe morphological alterations to ileal mucosa. Irradiation techniques were developed for inducing neutropenia, but they did not totally inhibit salmonella-induced leucocyte influx into ileal mucosa. We propose an alternative mechanism for the inhibitory effect of N2M on salmonella- and CT-induced secretion, based on the known anti-mitotic activity of N2M. Also, the anti-secretory effect of indomethacin cannot be attributed uniquely to its anti-inflammatory activity because it depressed CT-induced secretion as well as salmonella-induced secretion. These results support the concept of pathophysiological secretion in infectious diarrhoea, developed previously for rotavirus and extended to bacterial infections.


Configuration Fuzzing for Software Vulnerability Detection.
Many software security vulnerabilities only reveal themselves under certain conditions, i.e., particular configurations of the software together with its particular runtime environment. One approach to detecting these vulnerabilities is fuzz testing, which feeds a range of randomly modified inputs to a software application while monitoring it for failures. However, typical fuzz testing makes no guarantees regarding the syntactic and semantic validity of the input, or of how much of the input space will be explored. To address these problems, in this paper we present a new testing methodology called configuration fuzzing. Configuration fuzzing is a technique whereby the configuration of the running application is randomly modified at certain execution points, in order to check for vulnerabilities that only arise in certain conditions. As the application runs in the deployment environment, this testing technique continuously fuzzes the configuration and checks "security invariants" that, if violated, indicate a vulnerability; however, the fuzzing is performed in a duplicated copy of the original process, so that it does not affect the state of the running application. In addition to discussing the approach and describing a prototype framework for implementation, we also present the results of a case study to demonstrate the approach's efficiency.


Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation.
There is overwhelming evidence that in vitro three-dimensional tumor cell cultures more accurately reflect the complex in vivo microenvironment than simple two-dimensional cell monolayers, not least with respect to gene expression profiles, signaling pathway activity and drug sensitivity. However, most currently available three-dimensional techniques are time consuming and/or lack reproducibility; thus standardized and rapid protocols are urgently needed. To address this requirement, we have developed a versatile toolkit of reproducible three-dimensional tumor spheroid models for dynamic, automated, quantitative imaging and analysis that are compatible with routine high-throughput preclinical studies. Not only do these microplate methods measure three-dimensional tumor growth, but they have also been significantly enhanced to facilitate a range of functional assays exemplifying additional key hallmarks of cancer, namely cell motility and matrix invasion. Moreover, mutual tissue invasion and angiogenesis is accommodated by coculturing tumor spheroids with murine embryoid bodies within which angiogenic differentiation occurs. Highly malignant human tumor cells were selected to exemplify therapeutic effects of three specific molecularly-targeted agents: PI-103 (phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor), 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (heat shock protein 90 (HSP90) inhibitor) and CCT130234 (in-house phospholipase C (PLC)γ inhibitor). Fully automated analysis using a Celigo cytometer was validated for tumor spheroid growth and invasion against standard image analysis techniques, with excellent reproducibility and significantly increased throughput. In addition, we discovered key differential sensitivities to targeted agents between two-dimensional and three-dimensional cultures, and also demonstrated enhanced potency of some agents against cell migration/invasion compared with proliferation, suggesting their preferential utility in metastatic disease. We have established and validated a suite of highly reproducible tumor microplate three-dimensional functional assays to enhance the biological relevance of early preclinical cancer studies. We believe these assays will increase the translational predictive value of in vitro drug evaluation studies and reduce the need for in vivo studies by more effective triaging of compounds.


SyllabO+: A new tool to study sublexical phenomena in spoken Quebec French.
Sublexical phonotactic regularities in language have a major impact on language development, as well as on speech processing and production throughout the entire lifespan. To understand the impact of phonotactic regularities on speech and language functions at the behavioral and neural levels, it is essential to have access to oral language corpora to study these complex phenomena in different languages. Yet, probably because of their complexity, oral language corpora remain less common than written language corpora. This article presents the first corpus and database of spoken Quebec French syllables and phones: SyllabO+. This corpus contains phonetic transcriptions of over 300,000 syllables (over 690,000 phones) extracted from recordings of 184 healthy adult native Quebec French speakers, ranging in age from 20 to 97 years. To ensure the representativeness of the corpus, these recordings were made in both formal and familiar communication contexts. Phonotactic distributional statistics (e.g., syllable and co-occurrence frequencies, percentages, percentile ranks, transition probabilities, and pointwise mutual information) were computed from the corpus. An open-access online application to search the database was developed, and is available at www.speechneurolab.ca/syllabo . In this article, we present a brief overview of the corpus, as well as the syllable and phone databases, and we discuss their practical applications in various fields of research, including cognitive neuroscience, psycholinguistics, neurolinguistics, experimental psychology, phonetics, and phonology. Nonacademic practical applications are also discussed, including uses in speech-language pathology.


Immunolocalization of Na/SO4-cotransport (NaSi-1) in rat kidney.
The proximal tubule is the major site for renal reabsorption of sulphate. A sodium-dependent transport system for sulphate (NaSi-1) has recently been identified from a rat kidney cortex cDNA library. Recent work demonstrated that NaSi-1 mRNA is expressed predominantly in proximal tubules. In the present work expression along the nephron of the Na/SO4-cotransporter NaSi-1 was studied by immunofluorescence. A polyclonal antibody was raised in rabbits against a fusion protein containing a 53-amino-acid polypeptide specific for the NaSi-1 sequence. The anti-NaSi-1 polyclonal antibody specifically detected a 68-kDa protein on Western blots and, by immunofluorescence specific staining, was observed in MDCK cells transfected with the NaSi-1 cotransporter. Using rat kidney cortex slices specific NaSi-1-related immunoreactivity was detected in proximal tubules and was restricted to the apical membrane. No immunoreactivity was observed in the other nephron segments. This was confirmed by Western blot analysis using proximal tubular apical and basolateral membranes isolated by free-flow electrophoresis. The results indicate that the Na/SO4-cotransporter NaSi-1 is expressed in the apical membrane of proximal tubular cells and is therefore likely to be involved in proximal reabsorption of sulphate.


Social flocculation in plant-animal worms.
Individual animals can often move more safely or more efficiently as members of a group. This can be as simple as safety in numbers or as sophisticated as aerodynamic or hydrodynamic cooperation. Here, we show that individual plant-animal worms (Symsagittifera roscoffensis) can move to safety more quickly through flocculation. Flocs form in response to turbulence that might otherwise carry these beach-dwelling worms out to sea. They allow the worms to descend much more quickly to the safety of the substrate than single worms could swim. Descent speed increases with floc size such that larger flocs can catch up with smaller ones and engulf them to become even larger and faster. To our knowledge, this is the first demonstration of social flocculation in a wild, multicellular organism. It is also remarkable that such effective flocculation occurs where the components are comparatively large multicellular organisms organized as entangled ensembles.


Erroneous placement of central venous catheter in the subclavian artery: retrieval and successful hemostasis with a femoral closure device.
Central venous catheter (CVC) placement, even if performed under duplex scan control, may be associated with incidental arterial injury leading to increased morbidity, mortality, and prolonged hospital stay. Erroneous CVC placement in the carotid or subclavian arteries has been usually treated surgically because those puncture sites may not be efficaciously compressed manually. However, surgery in this setting may be challenging because of difficulty of access for the catheters positioned in the subclavian artery and of the risk of cerebrovascular complications for carotid catheters. Recently, several cases have been published, describing the successful endovascular management of iatrogenic arterial injury using different types of vascular closure devices (VCD). However, in this setting, it remains difficult to be completely sure that the VCD has achieved complete hemostasis and that the patient does not subsequently incur in a clinically silent intrathoracic bleeding. We report the case of an erroneous CVC placement in the right subclavian artery successfully retrieved using an Angioseal VCD. The immediate and complete hemostasis at the puncture site was confirmed at angiography.


The interprofessional clinical experience: interprofessional education in the nursing home.
The interprofessional clinical experience (ICE) was designed to introduce trainees to the roles of different healthcare professionals, provide an opportunity to participate in an interprofessional team, and familiarize trainees with caring for older adults in the nursing home setting. Healthcare trainees from seven professions (dentistry, medicine, nursing, nutrition, occupational therapy, optometry and social work) participated in ICE. This program consisted of individual patient interviews followed by a team meeting to develop a comprehensive care plan. To evaluate the impact of ICE on attitudinal change, the UCLA Geriatric Attitudes Scale and a post-experience assessment were used. The post-experience assessment evaluated the trainees' perception of potential team members' roles and attitudes about interprofessional team care of the older adult. Attitudes toward interprofessional teamwork and the older adult were generally positive. ICE is a novel program that allows trainees across healthcare professions to experience interprofessional teamwork in the nursing home setting.


Three-dimensional analysis of normal ankle and foot mobility.
We defined foot and ankle motion with respect to the neutral position. Thirteen normal fresh-frozen specimens of the human foot were used. The foot was placed in the extreme positions of pronation, supination, dorsiflexion, and plantar flexion, and positions of multiple bones were monitored simultaneously with a magnetic tracking device to determine rotation of the talocrural, subtalar, metatarsal-navicular, and talonavicular joints under the various conditions. In pronation, the most rotation occurred at the metatarsal-navicular level, followed by the navicular-talar, talar-tibial, and calcaneal-talar levels. In supination, most rotation occurred at the navicular-talar level, followed by the calcaneal-talar, talar-tibial, and metatarsal-navicular levels. In dorsiflexion, most rotation occurred at the talar-tibial level, followed by the navicular-talar, calcaneal-talar, and metatarsal-navicular levels. In plantar flexion, most rotation occurred at the talar-tibial level, but there was considerable motion at the navicular-talar, metatarsal-navicular, and calcaneal-talar levels. Understanding the specific joint motions that occur with various positions of the foot and ankle is important because measurements of joint mobility may assist in establishing diagnoses, monitoring clinical conditions, determining indications for operative treatment, assessing results of treatment, and following the progress of rehabilitation.


The polyp prevention trial I: rationale, design, recruitment, and baseline participant characteristics.
The Polyp Prevention Trial (PPT) is a multicenter randomized controlled trial examining the effect of a low-fat (20% of total energy intake), high-fiber (18 g/1000 kcal), high-vegetable and -fruit (5-8 daily servings) dietary pattern on the recurrence of adenomatous polyps of the large bowel, precursors of most colorectal malignancies. Eligibility criteria include one or more adenomas removed within 6 months of randomization; complete nonsurgical polyp removal and complete colonic examination to the cecum at the qualifying colonoscopy: age 35 years of more; no history of colorectal cancer, inflammatory bowel disease, or large bowel resection; and satisfactory completion of a food frequency questionnaire and 4-day food record. Of approximately 38,277 potential participants with one or more polyps recently resected, investigators at eight clinical centers randomized 2,079 (5.4%; 1,037 in the intervention and 1,042 in the control arm) between June 1991 and January 1994, making the PPT the largest adenoma recurrence trial ever conducted. Of PPT participants, 35% are women and 10% are minorities. At study entry, participants averaged 61.4 years of age; 14% of them smoked, and 22% used aspirin. At the baseline colonoscopy, 35% of participants had two or more adenomas, and 29% had at least one large (> of = 1 cm) adenoma. Demographic, behavioral, dietary, and clinical characteristics are comparable across the two study arms. Participants have repeat colonoscopies after 1 (T(1)) and 4 (T(4)) years of follow-up. The primary end point is adenoma recurrence; secondary end points include number, size, location, and histology of adenomas. All resected lesions are reviewed centrally by gastrointestinal pathologists. The trial provides 90% power to detect a reduction of 24% in the annual adenoma recurrence rate. The primary analytic period, on which sample size calculations were based is 3 years (T(1) to T(4)), which permits a 1-year lag time for the intervention to work and allows a more definitive clearing of lesions at T(1), given that at least 10-15% of polyps may be missed at baseline. The final (T(4)) colonoscopies are expected to be completed in early 1998.


Conformational analysis of pepstatin and related renin inhibitors by 400 MHz 1H n.m.r. spectroscopy.
The conformational behaviour of pepstatin (Iva-Val-Val-Sta-Ala-Sta) and of two derived renin inhibitors, Boc-Phe-Nle-Sta-Ala-Sta-OMe, 1, and Boc-Phe-Nle-X-Ala-Sta-OMe, 2 (X = -NH-CH(iPr)-CHOH-CH2-CO-) was assessed in DMSO-d6 at various temperatures and in deuteriopyridine at -35 degrees. Complete assignment of almost all proton signals was achieved by 2D COSY, 2D NOESY and selective NOE experiments. The three compounds show similar extended conformations in both solvents, with the hydrophobic lateral chains extending away from the peptide backbone. In the case of pepstatin the solvated conformation is closely related to the structure found in the crystal of the pepstatin-Rhizopus chinensis complex. Strong NOE effects and precise determination of vicinal coupling constants show the lack of large structural differences between 1 and 2 at the level of the internal Sta or X residues, which are assumed to interact with the aspartyl residues of the renin active-site. This suggests that the 100-fold lower inhibitory potency of 2 is mainly due to unfavorable close contacts of the beta-branched residue X with constituent amino acids of the enzyme.


Relationship between clinic and ambulatory blood pressure and mortality: an observational cohort study in 59 124 patients.
Ambulatory blood pressure provides a more comprehensive assessment than clinic blood pressure, and has been reported to better predict health outcomes than clinic or home pressure. We aimed to examine associations of clinic and 24-h ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of primary care patients referred for assessment of hypertension. We did an observational cohort study using clinic and ambulatory blood pressure data obtained from March 1, 2004, to Dec 31, 2014, from the Spanish Ambulatory Blood Pressure Registry. This registry included patients from 223 primary care centres from the Spanish National Health System in all 17 regions of Spain. Mortality data (date and cause) were ascertained by a computerised search of the vital registry of the Spanish National Institute of Statistics. Complete data were available for age, sex, all blood pressure measures, and BMI. For each study participant, follow-up was from the date of their recruitment to the date of death or Dec 31, 2019, whichever occurred first. Cox models were used to estimate associations between usual clinic or ambulatory blood pressure and mortality, adjusted for confounders and additionally for alternative measures of blood pressure. For each measure of blood pressure, we created five groups (ie, fifths) defined by quintiles of that measure among those who subsequently died. During a median follow-up of 9·7 years, 7174 (12·1%) of 59 124 patients died, including 2361 (4·0%) from cardiovascular causes. J-shaped associations were observed for several blood pressure measures. Among the top four baseline-defined fifths, 24-h systolic blood pressure was more strongly associated with all-cause death (hazard ratio [HR] 1·41 per 1 - SD increment [95% CI 1·36-1·47]) than clinic systolic blood pressure (1·18 [1·13-1·23]). After adjustment for clinic blood pressure, 24-h blood pressure remained strongly associated with all-cause deaths (HR 1·43 [95% CI 1·37-1·49]), but the association between clinic blood pressure and all-cause death was attenuated when adjusted for 24-h blood pressure (1·04 [1·00-1·09]). Compared with the informativeness of clinic systolic blood pressure (100%), night-time systolic blood pressure was most informative about risk of all-cause death (591%) and cardiovascular death (604%). Relative to blood pressure within the normal range, elevated all-cause mortality risks were observed for masked hypertension (HR 1·24 [95% CI 1·12-1·37]) and sustained hypertension (1·24 [1·15-1·32]), but not white-coat hypertension, and elevated cardiovascular mortality risks were observed for masked hypertension (1·37 [1·15-1·63]) and sustained hypertension (1·38 [1·22-1·55]), but not white-coat hypertension. Ambulatory blood pressure, particularly night-time blood pressure, was more informative about the risk of all-cause death and cardiovascular death than clinic blood pressure. Spanish Society of Hypertension, Lacer Laboratories, UK Medical Research Council, Health Data Research UK, National Institute for Health and Care Research Biomedical Research Centres (Oxford and University College London Hospitals), and British Heart Foundation Centre for Research Excellence.


A monomeric red fluorescent protein.
All coelenterate fluorescent proteins cloned to date display some form of quaternary structure, including the weak tendency of Aequorea green fluorescent protein (GFP) to dimerize, the obligate dimerization of Renilla GFP, and the obligate tetramerization of the red fluorescent protein from Discosoma (DsRed). Although the weak dimerization of Aequorea GFP has not impeded its acceptance as an indispensable tool of cell biology, the obligate tetramerization of DsRed has greatly hindered its use as a genetically encoded fusion tag. We present here the stepwise evolution of DsRed to a dimer and then either to a genetic fusion of two copies of the protein, i.e., a tandem dimer, or to a true monomer designated mRFP1 (monomeric red fluorescent protein). Each subunit interface was disrupted by insertion of arginines, which initially crippled the resulting protein, but red fluorescence could be rescued by random and directed mutagenesis totaling 17 substitutions in the dimer and 33 in mRFP1. Fusions of the gap junction protein connexin43 to mRFP1 formed fully functional junctions, whereas analogous fusions to the tetramer and dimer failed. Although mRFP1 has somewhat lower extinction coefficient, quantum yield, and photostability than DsRed, mRFP1 matures >10 times faster, so that it shows similar brightness in living cells. In addition, the excitation and emission peaks of mRFP1, 584 and 607 nm, are approximately 25 nm red-shifted from DsRed, which should confer greater tissue penetration and spectral separation from autofluorescence and other fluorescent proteins.


Oligodendrocytes and their precursors require phosphatidylinositol 3-kinase signaling for survival.
Signal transduction in response to several growth factors that regulate oligodendrocyte development and survival involves the activation of phosphatidylinositol 3-kinase, which we detect in oligodendrocytes and their precursors. To investigate the role of this enzyme activity, we analyzed cell survival in cultures of oligodendrocytes treated with wortmannin or LY294002, two potent inhibitors of phosphatidylinositol 3-kinase. Cell survival was inhibited by 60-70% in these cultures within 24 hours, as quantitated by a tetrazolium staining assay for viable cells and by measurement of DNA content. Similar results were obtained with oligodendrocyte precursor cells. Nuclei of the dying cells contained fragmented DNA, as revealed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assays, indicating that the cells were dying by apoptosis. Moreover, a significant increase in the number of cells with fragmented nuclear DNA was detected as early as 4 hours, well before any significant differences could be detected in glucose transport or cell viability. Exogenous addition of insulin-like growth factor-I, neurotrophin-3, platelet-derived growth factor, basic fibroblast growth factor, ciliary neurotrophic factor, N-acetyl cysteine, vitamin C, vitamin E, progesterone or serum did not prevent cell death in the presence of wortmannin or LY294002. These findings indicate that survival of oligodendrocytes and their precursors depends on a phosphatidylinositol 3-kinase mediated signaling pathway. Inhibition of this critical enzyme activity induces apoptotic cell death, even in the presence of exogenous growth factors or serum.


Functional MRI with simultaneous EEG recording: feasibility and application to motor and visual activation.
The possibility of combining the high spatial resolution of functional magnetic resonance imaging (fMRI) with the high temporal resolution of electroencephalography (EEG) may provide a new tool in cognitive neurophysiology, as well as in clinical applications such as epilepsy. However, the simultaneous recording of EEG and fMRI raises important practical problems: 1) the patients' safety, in particular the risk of skin burns due to electrodes heating; 2) the impairment of the EEG recording by the static magnetic field, as well as by RF and magnetic field gradients used during MRI; and 3) the quality of MR images, which may be affected by the presence of conductors and electronic devices in the MRI bore. Here we present our experiences on 19 normal volunteers who underwent combined fMRI and 16-channel EEG examination. Consistent with previous reports, safety could be assured when performing EEG recordings during fMRI acquisition. Electrophysiological signals recorded with surface EEG were similar inside and outside the 1.5 T magnet. Furthermore, fMRI using motor or visual tasks revealed similar areas of activation when performed with and without 16-channel EEG recording. J. Magn. Reson. Imaging 2001;13:943-948.


Liquid polystyrene: a room-temperature photocurable soft lithography compatible pour-and-cure-type polystyrene.
Materials matter in microfluidics. Since the introduction of soft lithography as a prototyping technique and polydimethylsiloxane (PDMS) as material of choice the microfluidics community has settled with using this material almost exclusively. However, for many applications PDMS is not an ideal material given its limited solvent resistance and hydrophobicity which makes it especially disadvantageous for certain cell-based assays. For these applications polystyrene (PS) would be a better choice. PS has been used in biology research and analytics for decades and numerous protocols have been developed and optimized for it. However, PS has not found widespread use in microfluidics mainly because, being a thermoplastic material, it is typically structured using industrial polymer replication techniques. This makes PS unsuitable for prototyping. In this paper, we introduce a new structuring method for PS which is compatible with soft lithography prototyping. We develop a liquid PS prepolymer which we term as "Liquid Polystyrene" (liqPS). liqPS is a viscous free-flowing liquid which can be cured by visible light exposure using soft replication templates, e.g., made from PDMS. Using liqPS prototyping microfluidic systems in PS is as easy as prototyping microfluidic systems in PDMS. We demonstrate that cured liqPS is (chemically and physically) identical to commercial PS. Comparative studies on mouse fibroblasts L929 showed that liqPS cannot be distinguished from commercial PS in such experiments. Researchers can develop and optimize microfluidic structures using liqPS and soft lithography. Once the device is to be commercialized it can be manufactured using scalable industrial polymer replication techniques in PS--the material is the same in both cases. Therefore, liqPS effectively closes the gap between "microfluidic prototyping" and "industrial microfluidics" by providing a common material.


Evaluating the effectiveness of a mock oral educational program.
To obtain board certification, the American Board of Surgery requires graduates of general surgery training programs to pass both the written qualifying examination (QE) and the oral certifying examination (CE). In 2015, the pass rates for the QE and CE were 80% and 77%, respectively. In the 2011-2012 academic year, the University of Wisconsin instituted a mandatory, faculty-led, monthly CE preparation educational program (CE prep) as a supplement to their existing annual mock oral examination. We hypothesized that the implementation of these sessions would improve the first-time pass rate for residents taking the ABS CE at our institution. Secondary outcomes studied were QE pass rate, correlation with American Board of Surgery In-Training Examination (ABSITE) and mock oral examination scores, cost, and type of study materials used, perception of examination difficulty, and applicant preparedness. A sixteen question survey was sent to 57 of 59 residents who attended the University of Wisconsin between the years of 2007 and 2015. Email addresses for two former residents could not be located. De-identified data for the ABSITE and first-time pass rates for the QE and CE examination were retrospectively collected and analyzed along with survey results. Statistical analysis was performed using SPSS version 22 (IBM Corp., Armonk, NY). P values < 0.05 were considered significant. Survey response rate was 77.2%. Of the residents who have attempted the CE, first-time pass rate was 76.0% (19 of 25) before the implementation of the formal CE Prep and 100% (22 of 22) after (P = 0.025). Absolute ABSITE score, and mock oral annual examination grades were significantly improved after the CE Prep was initiated (P values < 0.001 and 0.003, respectively), however, ABSITE percentile was not significantly different (P = 0.415). ABSITE raw score and percentile, as well as mock oral annual examination scores were significantly associated with passing the QE (0.032, 0.027, and 0.020, respectively), whereas mock oral annual examination scores alone were associated with passing the CE (P = 0.001). Survey results showed that residents perceived the CE to be easier than the annual mock oral after the institution of the CE prep course (P = 0.036), however, there was no difference in their perception of preparedness. Overall, applicants felt extremely prepared for the CE (4.70 ± 0.5, Likert scale 1-5). Formal educational programs instituted during residency can improve resident performance on the ABS certifying examination. The institution of a formal, faculty-led monthly CE preparation educational program at the University of Wisconsin has significantly improved the first-time pass rate for the ABS CE. Mock oral annual examination scores were also significantly improved. Furthermore, ABSITE scores correlate with QE pass rates, and mock oral annual examination scores correlate with pass rates for both QE and CE.


Hyperpolarized Carbon 13 MRI: Clinical Applications and Future Directions in Oncology.
Hyperpolarized carbon 13 MRI (13C MRI) is a novel imaging approach that can noninvasively probe tissue metabolism in both normal and pathologic tissues. The process of hyperpolarization increases the signal acquired by several orders of magnitude, allowing injected 13C-labeled molecules and their downstream metabolites to be imaged in vivo, thus providing real-time information on kinetics. To date, the most important reaction studied with hyperpolarized 13C MRI is exchange of the hyperpolarized 13C signal from injected [1-13C]pyruvate with the resident tissue lactate pool. Recent preclinical and human studies have shown the role of several biologic factors such as the lactate dehydrogenase enzyme, pyruvate transporter expression, and tissue hypoxia in generating the MRI signal from this reaction. Potential clinical applications of hyperpolarized 13C MRI in oncology include using metabolism to stratify tumors by grade, selecting therapeutic pathways based on tumor metabolic profiles, and detecting early treatment response through the imaging of shifts in metabolism that precede tumor structural changes. This review summarizes the foundations of hyperpolarized 13C MRI, presents key findings from human cancer studies, and explores the future clinical directions of the technique in oncology. Keywords: Hyperpolarized Carbon 13 MRI, Molecular Imaging, Cancer, Tissue Metabolism © RSNA, 2023.


Immunopathology of multiple sclerosis.
Two decades of clinical experience with immunomodulatory treatments for multiple sclerosis point to distinct immunological pathways that drive disease relapses and progression. In light of this, we discuss our current understanding of multiple sclerosis immunopathology, evaluate long-standing hypotheses regarding the role of the immune system in the disease and delineate key questions that are still unanswered. Recent and anticipated advances in the field of immunology, and the increasing recognition of inflammation as an important component of neurodegeneration, are shaping our conceptualization of disease pathophysiology, and we explore the potential implications for improved healthcare provision to patients in the future.


Discrimination networks for maximum selection.
We construct a novel discrimination network using differentiating units for maximum selection. In contrast to traditional competitive architectures like MAXNET the discrimination network does not only signal the winning unit, but also provides information about its evidence. In particular, we show that a discrimination network converges to a stable state within finite time and derive three characteristics: intensity normalization (P1), contrast enhancement (P2), and evidential response (P3). In order to improve the accuracy of the evidential response we incorporate distributed redundancy into the network. This leads to a system which is not only robust against failure of single units and noisy data, but also enables us to sharpen the focus on the problem given in terms of a more accurate evidential response. The proposed discrimination network can be regarded as a connectionist model for competitive learning by evidence.


Intrazeolite ruthenium(0) nanoclusters: a superb catalyst for the hydrogenation of benzene and the hydrolysis of sodium borohydride.
The use of microporous materials with ordered porous structures as the hosts to encapsulate metal nanoclusters has attracted particular interest in catalysis because the pore size restriction could limit the growth of nanoclusters and lead to an increase in the percentage of the catalytically active surface atoms. This letter reports the preparation of ruthenium(0) nanoclusters stabilized by the framework of Zeolite-Y by using a simple, easy, efficient method and their superb catalytic activities in two important reactions: the hydrogenation of arenes (benzene, toluene, o-xylene, mesitylene) and the hydrolysis of sodium borohydride, all at room temperature. Particularly, the intrazeolite ruthenium(0) nanoclusters exhibit unprecedented catalytic activity in the hydrogenation of neat benzene at 22.0 +/- 0.1 degrees C and 40 +/- 1 psig H2 with a record TOF of 1040 mol benzene/mol Ru . h.


Acidic region tyrosines provide access points for allosteric activation of the autoinhibited Vav1 Dbl homology domain.
Autoinhibited proteins serve key roles in many signal transduction pathways, and therefore proper regulation of these proteins is critical for normal cellular function. Proto-oncogene Vav1 is an autoinhibited guanine nucleotide exchange factor (GEF) for Rho family GTPases. The core autoinhibitory module of Vav1 consists of the catalytic Dbl homology (DH) domain bound through its active site to an alpha helix centered about Tyr174 in the Acidic (Ac) region of the protein. Phosphorylation of Tyr174 and two other tyrosines in the Ac region, Tyr142 and Tyr160, relieves autoinhibition and activates the catalytic DH domain. In this study, we use biochemical and structural analyses of the Vav1 Ac and DH domains to examine the kinetic and thermodynamic properties of Vav1 activation by the Src family kinase, Lck, and the role of the Lck SH2 domain in this process. We find that in the Ac-DH fragment of Vav1, Tyr174, but not Tyr142 or Tyr160, is protected from phosphorylation by interactions with the DH domain. Binding of the Lck SH2 domain to phosphorylated Tyr142 increases kcat/KM for Tyr174 by 4-fold, likely because the kinase domain can act on the substrate effectively in an intramolecular fashion. These studies of the autoinhibited Ac-DH module provide the foundation for a quantitative structural and thermodynamic understanding of the regulation of full length Vav1. Moreover, kinetic pathways involving initial interactions with exposed sites or "access points", as observed here for Vav1, may be generally important in the regulation of many autoinhibited proteins.


The therapeutic effect of probiotics on rheumatoid arthritis: a systematic review and meta-analysis of randomized control trials.
Rheumatoid arthritis is an autoimmune disease in which probiotics appears to have an immune modulating action along with decreased inflammatory process. Therefore, we aim to investigate the efficacy of probiotics as an adjuvant therapy for rheumatoid arthritis. A comprehensive literature search was performed using nine databases including PubMed and Web of Science. Interesting data was extracted and meta-analyzed. We assessed the risk of bias using Cochrane Collaboration's tool. The protocol was registered in PROSPERO (CRD 42016036769). We found nine studies involving 361 patients who met our eligibility criteria. Our meta-analysis indicated that pro-inflammatory cytokine IL-6 was significantly lower in the probiotics compared with the placebo group (standardized mean difference = - 0.708; 95% confidence interval (CI) - 1.370 to 0.047, P = 0.036). However, there was no difference between probiotics and placebo in disease activity score (mean difference 0.023; 95% CI - 0.584 to 0.631, P = 0.940). Probiotics lowered pro-inflammatory cytokines IL-6 in RA; however, its clinical effect is still unclear. Hence, many high-quality randomized controlled trials (RCTs) are still needed to prove this effect.


Characterisation of PAUSE-1, a powerful silencer in the human plasminogen activator inhibitor type 2 gene promoter.
Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor traditionally regarded as a regulator of fibrinolysis and extracellular matrix degradation. More recently, PAI-2 has been implicated in diverse processes such as keratinocyte differentiation, cell death and viral pathogenesis. The PAI-2 promoter tightly regulates PAI-2 gene expression in a cell-specific manner and this control is mediated, in part, by the upstream silencer element, PAUSE-1. Here we have defined PAUSE-1 and investigated its activity as a silencer. A series of mutations were generated within the PAUSE-1 element and analysed for transcription factor binding and transcriptional silencing activity. These studies have defined the minimal functional PAUSE-1 element as TCTN(x)AGAN(3)T(4), where x = 0, 2 or 4. Examination of related elements present in other promoters, such as the human IFNbeta promoter, suggests that PAUSE-1 is a member of a family of universal silencers with the consensus sequence TCTN(x)AGA. UV crosslinking analyses determined that the PAUSE-1 binding protein was approximately 67 kDa. Insertion of PAUSE-1 into the heterologous (SV40) or the minimal PAI-2 promoters silenced transcription by 2.5-fold. These data show that PAUSE-1 acts as a powerful silencer of PAI-2 gene transcription and is likely to be important in the silencing of other genes as well.


Cone reconstruction in children with Ebstein anomaly: the Mayo Clinic experience.
Valve repair for pediatric patients with Ebstein anomaly has historically yielded varied results. The cone reconstruction (CR) first described by Da Silva has revolutionized the surgical approach to these patients. This study reports our recent experience with CR in children and young adults with Ebstein anomaly. Electronic medical records were reviewed for all patients < 21 years old who had surgery to repair Ebstein anomaly at Mayo Clinic Rochester between June 2007 and December 2012. Clinical data including preoperative demographics, intraoperative procedures, and postoperative outcomes were recorded. Eighty-four patients initially had a cone reconstruction (54% male, mean age 10.1 ± 5.9 years). Indications for operation included cardiomegaly (42%), cyanosis (19%), and heart failure (19%). The preoperative echocardiogram demonstrated severe tricuspid regurgitation in 91% of patients. There was one early death and 3 early CR breakdowns requiring reoperation (2 re-repair, 1 tricuspid replacement). Eighty-two patients (98%) had successful CR at the time of hospital discharge. Patient age, gender, cardiopulmonary bypass time, and aortic cross-clamp time were not associated with early CR failure. Use of a partial or eccentric annuloplasty ring correlated with successful initial CR (P = .01). There have been no early CR breakdowns since 2010. Follow-up information was available for 77 patients (longest follow-up 6.5 years; mean 0.8 ± 0.2 years). The most recent postoperative echocardiogram demonstrated mild or no tricuspid regurgitation in 83%. Tricuspid stenosis (mean gradient > 5 mm Hg) was present in 6 patients. There was one late death (motor vehicle accident) and one late re-repair of the tricuspid valve 4 years after initial operation. CR in children and young adults with Ebstein anomaly can be performed with low early mortality and excellent durability at short-term follow-up. CR represents an important surgical option for young patients. It is applicable to patients with a broad range of anatomic variability and precludes valve replacement in the vast majority. CR should be considered prior to the deleterious effects of chronic right ventricular volume overload and the development of systolic dysfunction, which hamper long-term prognosis. Therefore, early referral for surgical evaluation is recommended.


Toward Personalized Computer Simulation of Breast Cancer Treatment: A Multiscale Pharmacokinetic and Pharmacodynamic Model Informed by Multitype Patient Data.
The usefulness of mechanistic models to disentangle complex multiscale cancer processes, such as treatment response, has been widely acknowledged. However, a major barrier for multiscale models to predict treatment outcomes in individual patients lies in their initialization and parametrization, which needs to reflect individual cancer characteristics accurately. In this study, we use multitype measurements acquired routinely on a single breast tumor, including histopathology, MRI, and molecular profiling, to personalize parts of a complex multiscale model of breast cancer treated with chemotherapeutic and antiangiogenic agents. The model accounts for drug pharmacokinetics and pharmacodynamics. We developed an open-source computer program that simulates cross-sections of tumors under 12-week therapy regimens and used it to individually reproduce and elucidate treatment outcomes of 4 patients. Two of the tumors did not respond to therapy, and model simulations were used to suggest alternative regimens with improved outcomes dependent on the tumor's individual characteristics. It was determined that more frequent and lower doses of chemotherapy reduce tumor burden in a low proliferative tumor while lower doses of antiangiogenic agents improve drug penetration in a poorly perfused tumor. Furthermore, using this model, we were able to correctly predict the outcome in another patient after 12 weeks of treatment. In summary, our model bridges multitype clinical data to shed light on individual treatment outcomes. SIGNIFICANCE: Mathematical modeling is used to validate possible mechanisms of tumor growth, resistance, and treatment outcome.


Determination of topological charges of polychromatic optical vortices.
We introduce a simple, single beam method for determination of the topological charge of polychromatic optical vortices. It is based on astigmatic transformation of singular optical beams, where the intensity pattern of a vortex beam acquires a form of dark stripes in the focal plane of a cylindrical lens. The number of the dark stripes is equal to the modulus of the vortex topological charge, while the stripe tilt indicates the charge sign. We demonstrate experimentally the effectiveness of this technique by revealing complex topological structure of polychromatic singular beams.


Human peripheral blood leukocyte-reconstituted severe combined immunodeficient mouse: analysis of the human immune response against porcine islet transplantation.
Human peripheral blood leukocyte (PBL)-reconstituted severe combined immunodeficient (SCID) mice (Hu-PBL-SCID) were used as a model to study xenograft rejection in humans. SCID mice were reconstituted with human PBL using a protocol that included a booster injection with anti-human CD3 antibody-primed cells. This protocol enhanced chimera establishment in SCID mice and resulted in the detection of higher levels of human Ig when compared with SCID mice receiving unprimed PBL alone. Human xenoreactive natural antibodies (XNA), both IgM and IgG subtypes, which recognized porcine islets (PI), were detected in sera of Hu-PBL-SCID by cytofluorometric analysis. Pretreatment of porcine cells with GS-IB4 lectin inhibited the XNA binding, demonstrating the specificity of the XNA from Hu-PBL-SCID. Western blot analysis showed that XNA from normal human serum and Hu-PBL-SCID serum recognized similar xenoantigens on PI, indicating that Hu-PBL-SCID contained a XNA repertoire representative of normal human serum. Immunofluorescent staining of the tissue sections revealed that both human IgG and IgM bound in vivo to the PI engrafted beneath the kidney capsule of Hu-PBL-SCID. In addition, mouse complement (C3) was detected on xenografted PI. The function of xenografted islets were monitored by measuring porcine insulin concentration using a radioimmunoassay. Porcine insulin concentration in the sera of both Hu-PBL-SCID and plain SCID xenografted with PI was similar for up to 14 days after transplantation, after which the insulin levels in Hu-PBL-SCID decreased, thereby indicating rejection. Therefore, PI transplanted into the Hu-PBL-SCID should be a useful model for the study of cellular as well as acquired humoral immune response against xenoislets.


Effect of gluten-free diet on preventing recurrence of gastroesophageal reflux disease-related symptoms in adult celiac patients with nonerosive reflux disease.
In celiac disease (CD) the role of a gluten-free diet (GFD) on gastroesophageal reflux disease-related symptoms (GERD-rs) is unclear. The aim of this study was to establish the recurrence of GERD-rs, in CD patients with nonerosive reflux disease (NERD). From a total of 105 adult CD patients observed, 29 who presented with the NERD form were enrolled in the study. Thirty non-CD patients with NERD were studied as controls. Recurrence of GERD-rs was clinically assessed at 6, 12, 18, and 24 months follow-up (FU) after withdrawal of initial proton-pump inhibitor (PPI) treatment for 8 weeks. GERD-rs were resolved in 25 (86.2%) CD patients and in 20 (66.7%) controls after 8 weeks of PPI treatment. In the CD group, recurrence of GERD-rs was found in five cases (20%) at 6 months but in none at 12, 18, and 24 months while in the control group recurrence was found in six of 20 controls (30%), in another six (12/20, 60%), in another three (15/20, 75%), and in another two (17/20, 85%) at 6, 12, 18, and 24 months FU respectively. The present study is the first to have evaluated the effect of a GFD in the nonerosive form of GERD in CD patients, by means of clinical long-term follow-up, suggesting that GFD could be a useful approach in reducing GERD symptoms and in the prevention of recurrence.


Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds.
The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anticancer drugs targeting cancer stem cells. Naturally occurring dietary compounds have received increasing attention in cancer chemoprevention. The anticancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/β-catenin, Hedgehog and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine and vitamin D(3), are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor-initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival.


A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development.
Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histological analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal-appearing p53-positive epithelium that are similar to 'p53 signatures' in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these non-invasive precursor lesions, we also identified invasive adenocarcinoma in the ovaries of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and wild-type (WT) C57BL/6. One of these genes, Top2a, which encodes topoisomerase IIα, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and was specifically elevated in mouse STICs but not in the surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumourigenesis, as well as for developing novel approaches for the prevention, diagnosis and therapy of this disease.


Exploiting amphiphilicity: facile metal free access to thianthrenes and related sulphur heterocycles.
Benzodithioloimines are reacted with arynes or alkynes substituted with electron-withdrawing groups to afford the corresponding thianthrene or benzo[b][1,4]dithiine derivatives. The transformation takes place under mild reaction conditions without any transition metal. Furthermore, the reaction mode could be expanded to 2-thiocyanatopyrroles yielding pyrrolothiazoles.


Robust tracking of respiratory rate in high-dynamic range scenes using mobile thermal imaging.
The ability to monitor the respiratory rate, one of the vital signs, is extremely important for the medical treatment, healthcare and fitness sectors. In many situations, mobile methods, which allow users to undertake everyday activities, are required. However, current monitoring systems can be obtrusive, requiring users to wear respiration belts or nasal probes. Alternatively, contactless digital image sensor based remote-photoplethysmography (PPG) can be used. However, remote PPG requires an ambient source of light, and does not work properly in dark places or under varying lighting conditions. Recent advances in thermographic systems have shrunk their size, weight and cost, to the point where it is possible to create smart-phone based respiration rate monitoring devices that are not affected by lighting conditions. However, mobile thermal imaging is challenged in scenes with high thermal dynamic ranges (e.g. due to the different environmental temperature distributions indoors and outdoors). This challenge is further amplified by general problems such as motion artifacts and low spatial resolution, leading to unreliable breathing signals. In this paper, we propose a novel and robust approach for respiration tracking which compensates for the negative effects of variations in the ambient temperature and motion artifacts and can accurately extract breathing rates in highly dynamic thermal scenes. The approach is based on tracking the nostril of the user and using local temperature variations to infer inhalation and exhalation cycles. It has three main contributions. The first is a novel Optimal Quantization technique which adaptively constructs a color mapping of absolute temperature to improve segmentation, classification and tracking. The second is the Thermal Gradient Flow method that computes thermal gradient magnitude maps to enhance the accuracy of the nostril region tracking. Finally, we introduce the Thermal Voxel method to increase the reliability of the captured respiration signals compared to the traditional averaging method. We demonstrate the extreme robustness of our system to track the nostril-region and measure the respiratory rate by evaluating it during controlled respiration exercises in high thermal dynamic scenes (e.g. strong correlation (r = 0.9987) with the ground truth from the respiration-belt sensor). We also demonstrate how our algorithm outperformed standard algorithms in settings with different amounts of environmental thermal changes and human motion. We open the tracked ROI sequences of the datasets collected for these studies (i.e. under both controlled and unconstrained real-world settings) to the community to foster work in this area.


How to Make Swarms Open-Ended? Evolving Collective Intelligence Through a Constricted Exploration of Adjacent Possibles.
We propose an approach to open-ended evolution via the simulation of swarm dynamics. In nature, swarms possess remarkable properties, which allow many organisms, from swarming bacteria to ants and flocking birds, to form higher-order structures that enhance their behavior as a group. Swarm simulations highlight three important factors to create novelty and diversity: (a) communication generates combinatorial cooperative dynamics, (b) concurrency allows for separation of time scales, and (c) complexity and size increases push the system towards transitions in innovation. We illustrate these three components in a model computing the continuous evolution of a swarm of agents. The results, divided into three distinct applications, show how emergent structures are capable of filtering information through the bottleneck of their memory, to produce meaningful novelty and diversity within their simulated environment.


Neurosurgery and human immunodeficiency virus in the era of combination antiretroviral therapy: a review.
Human immunodeficiency virus (HIV) is a global health problem. It renders the central nervous system susceptible to infectious and noninfectious diseases. HIV-positive individuals may present to neurosurgical services with brain lesions of unknown etiology. The differential diagnosis in these cases is broad, including opportunistic infections and malignancies, and investigation should be tailored accordingly. Opportunistic infections of the central nervous system can be complicated by hydrocephalus, and the management is pathogen dependent. Patients may also present to a neurosurgical service with conditions unrelated to their HIV status. This review outlines important conditions that cause brain lesions and hydrocephalus. It addresses the issues of diagnosis and intervention in HIV-positive patients in the era of combination antiretroviral therapy, while not ignoring the potential for opportunistic central nervous system infection in undiagnosed patients. The care of HIV-positive patients presenting to neurosurgical services requires a multidisciplinary approach, which is reflected in the authorship of this review, as well as in the guidance given.


The Quality of Family Relationships, Diabetes Self-Care, and Health Outcomes in Older Adults.
The purpose of the study was to investigate the relationship between family support, diabetes self-care, and health outcomes in older, community-dwelling adults. Using the theoretical framework of the Self-Care of Chronic Illness Theory and a cross-sectional design, 60 participants completed questionnaires related to diabetes self-care activities of the individual, supportive and nonsupportive diabetes behaviors of the family, and the quality of family relations. Participants indicated that diabetes self-care behaviors were performed frequently, with exercise reported as the least-performed behavior. Multiple regression analyses revealed that the quality of family relations as measured by the Family Relationship Index contributed significantly (26.0%) to the variability in A1C levels (R 2 = 0.260, F(1, 40) = 14.037, P = 0.001). Neither family supportive behavior nor the quality of family relations contributed to diabetes self-care. It is recommended that health care providers include family members to assess diabetes family support and family relationships in the care of older adults with diabetes.


Factors affecting the health-related quality of life of patients with cervical dystonia and impact of treatment with abobotulinumtoxinA (Dysport): results from a randomised, double-blind, placebo-controlled study.
To describe the health-related quality of life (HRQOL) burden of cervical dystonia (CD) and report on the HRQOL and patient perception of treatment benefits of abobotulinumtoxinA (Dysport). The safety and efficacy of a single injection of abobotulinumtoxinA for CD treatment were evaluated in a previously reported international, multicenter, double-blind, randomised trial. HRQOL measures were assessed in the trial and have not been previously reported. Movement disorder clinics in the USA and Russia. Patients had to have a diagnosis of CD with symptoms for at least 18 months, as well as a total Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score of at least 30; a Severity domain score of at least 15; and a Disability domain score of at least 3. Key exclusion criteria included treatment with botulinum toxin type A (BoNT-A) or botulinum toxin type B (BoNT-B) within 16 weeks of enrolment. Patients were randomised to receive either 500 U abobotulinumtoxinA (n=55) or placebo (n=61). Efficacy assessments included TWSTRS total (primary end point) and subscale scores at weeks 0, 4, 8, 12; a pain visual analogue scale at weeks 0 and 4; and HRQOL assessed by the SF-36 Health Survey (SF-36; secondary end point) at weeks 0 and 8. Patients with CD reported significantly greater impairment for all SF-36 domains relative to US norms. Patients treated with abobotulinumtoxinA reported significantly greater improvements in Physical Functioning, Role Physical, Bodily Pain, General Health and Role Emotional domains than placebo patients (p≤0.03 for all). The TWSTRS was significantly correlated with Physical Functioning, Role Physical and Bodily Pain scores, for those on active treatment. CD has a marked impact on HRQOL. Treatment with a single abobotulinumtoxinA injection results in significant improvement in patients' HRQOL. The trial is registered at ClinicalTrials.gov, numbers NCT00257660 and NCT00288509.


gamma-Glutamyltranspeptidase from Escherichia coli K-12: purification and properties.
gamma-Glutamyltranspeptidase (GGT) (EC 18.104.22.168) was purified from the periplasmic fraction of Escherichia coli K-12 to electrophoretic homogeneity. The final purification step, chromatofocusing, gave two protein peaks showing GGT activity (fractions A and B). The major heavy fraction (fraction A) consisted of two different subunits, with molecular weights of 39,200 and 22,000. The minor light fraction (fraction B) consisted of those with molecular weights of 38,600 and 22,000. Fraction A catalyzes the hydrolysis and transpeptidation of all gamma-glutamyl compounds tested, but it prefers basic amino acids and aromatic amino acids as acceptors. The apparent Km values for glutathione and gamma-glutamyl-p-nitroanilide as gamma-glutamyl donors in the transpeptidation reaction were both 35 microM, and those for glycylglycine and L-arginine as acceptors were 0.59 and 0.21 M, respectively. The enzyme was inhibited by some amino acids and by protease inhibitors and affinity-labeling reagents for GGT. The temperature stability of the purified GGT supports our hypothesis that E. coli GGT is synthesized only at lower temperature rather than that the synthesized GGT is degraded or inactivated at higher temperature.


NiftyPET: a High-throughput Software Platform for High Quantitative Accuracy and Precision PET Imaging and Analysis.
We present a standalone, scalable and high-throughput software platform for PET image reconstruction and analysis. We focus on high fidelity modelling of the acquisition processes to provide high accuracy and precision quantitative imaging, especially for large axial field of view scanners. All the core routines are implemented using parallel computing available from within the Python package NiftyPET, enabling easy access, manipulation and visualisation of data at any processing stage. The pipeline of the platform starts from MR and raw PET input data and is divided into the following processing stages: (1) list-mode data processing; (2) accurate attenuation coefficient map generation; (3) detector normalisation; (4) exact forward and back projection between sinogram and image space; (5) estimation of reduced-variance random events; (6) high accuracy fully 3D estimation of scatter events; (7) voxel-based partial volume correction; (8) region- and voxel-level image analysis. We demonstrate the advantages of this platform using an amyloid brain scan where all the processing is executed from a single and uniform computational environment in Python. The high accuracy acquisition modelling is achieved through span-1 (no axial compression) ray tracing for true, random and scatter events. Furthermore, the platform offers uncertainty estimation of any image derived statistic to facilitate robust tracking of subtle physiological changes in longitudinal studies. The platform also supports the development of new reconstruction and analysis algorithms through restricting the axial field of view to any set of rings covering a region of interest and thus performing fully 3D reconstruction and corrections using real data significantly faster. All the software is available as open source with the accompanying wiki-page and test data.


Cryoreduction of methyl-coenzyme M reductase: EPR characterization of forms, MCR(ox1) and MCR (red1).
Methyl-coenzyme M reductase (MCR) catalyzes the formation of methyl-coenzyme M (CH(3)S-CH(2)CH(2)SO(3)) from methane. The active site is a nickel tetrahydrocorphinoid cofactor, factor 430, which in inactive form contains EPR-silent Ni(II). Two such forms, denoted MCR(silent) and MCR(ox1)(-)(silent), were previously structurally characterized by X-ray crystallography. We describe here the cryoreduction of both of these MCR forms by gamma-irradiation at 77 K, which yields reduced protein maintaining the structure of the oxidized starting material. Cryoreduction of MCR(silent) yields an EPR signal that strongly resembles that of MCR(red1), the active form of MCR; and stepwise annealing to 260-270 K leads to formation of MCR(red1). Cryoreduction of MCR(ox1)(-)(silent) solutions shows that our preparative method for this state yields enzyme that contains two major forms. One behaves similarly to MCR(silent), as shown by the observation that both of these forms give essentially the same redlike EPR signals upon cryoreduction, both of which give MCR(red1) upon annealing. The other form is assigned to the crystallographically characterized MCR(ox1)(-)(silent) and directly gives MCR(ox1) upon cryoreduction. X-band spectra of these cryoreduced samples, and of conventionally prepared MCR(red1) and MCR(ox1), all show resolved hyperfine splitting from four equivalent nitrogen ligands with coupling constants in agreement with those determined in previous EPR studies and from (14)N ENDOR of MCR(red1) and MCR(ox1). These experiments have confirmed that all EPR-visible forms of MCR contain Ni(I) and for the first time generated in vitro the EPR-visible, enzymatically active MCR(red1) and the activate-able "ready" MCR(ox1) from "silent" precursors. Because the solution Ni(II) species we assign as MCR(ox1)(-)(silent) gives as its primary cryoreduction product the Ni(I) state MCR(ox1), previous crystallographic data on MCR(ox1)(-)(silent) allow us to identify the exogenous axial ligand in MCR(ox1) as the thiolate from CoM; the cryoreduction experiments further allow us to propose possible axial ligands in MCR(red1). The availability of model compounds for MCR(red1) and MCR(ox1) also is discussed.


Cross-sectional evaluation of the prevalence and factors associated with soft tissue scarring after the removal of miniscrews.
To investigate the prevalence of distinguishable soft tissue scarring after the removal of temporary anchorage devices (TADs) such as orthodontic miniscrews and to analyze the factors associated with scar formation. The prevalence of soft tissue scarring in 66 patients (202 miniscrew removal sites) was clinically investigated at least 1 year after miniscrew removal. To determine the clinical factors associated with soft tissue scar formation, miniscrew stability; host factors including age, gender, and gingival biotype; and miniscrew-related factors such as insertion site, vertical position, and insertion period were evaluated. The prevalence of a distinguishable scar remaining at least 1 year after miniscrew removal was 44.6%. Patients with flat gingiva showed a significantly higher prevalence of soft tissue scar formation than did those with pronounced scalloped gingiva (P < .05). Maxillary buccal removal sites showed a significantly higher prevalence of soft tissue scar formation than did those in the mandible or palatal slope (P < .05). Miniscrew sites at the alveolar mucosa showed a significantly lower prevalence of soft tissue scar formation than did those in the mucogingival junction or the attached gingiva (P < .01). The prevalence of distinguishable scarring after miniscrew removal was fairly high. On the basis of our results, patients with flat gingiva and buccal interdental gingival insertion sites are more susceptible to scar formation.


Prospects and Challenges of MXenes as Emerging Sensing Materials for Flexible and Wearable Breath-Based Biomarker Diagnosis.
A fully integrated, flexible, and functional sensing device for exhaled breath analysis drastically transforms conventional medical diagnosis to non-invasive, low-cost, real-time, and personalized health care. 2D materials based on MXenes offer multiple advantages for accurately detecting various breath biomarkers compared to conventional semiconducting oxides. High surface sensitivity, large surface-to-weight ratio, room temperature detection, and easy-to-assemble structures are vital parameters for such sensing devices in which MXenes have demonstrated all these properties both experimentally and theoretically. So far, MXenes-based flexible sensor is successfully fabricated at a lab-scale and is predicted to be translated into clinical practice within the next few years. This review presents a potential application of MXenes as emerging materials for flexible and wearable sensor devices. The biomarkers from exhaled breath are described first, with emphasis on metabolic processes and diseases indicated by abnormal biomarkers. Then, biomarkers sensing performances provided by MXenes families and the enhancement strategies are discussed. The method of fabrications toward MXenes integration into various flexible substrates is summarized. Finally, the fundamental challenges and prospects, including portable integration with Internet-of-Thing (IoT) and Artificial Intelligence (AI), are addressed to realize marketization.


A study on infectivity of asymptomatic SARS-CoV-2 carriers.
An ongoing outbreak of coronavirus disease 2019 (COVID-19) has spread around the world. It is debatable whether asymptomatic COVID-19 virus carriers are contagious. We report here a case of the asymptomatic patient and present clinical characteristics of 455 contacts, which aims to study the infectivity of asymptomatic carriers. 455 contacts who were exposed to the asymptomatic COVID-19 virus carrier became the subjects of our research. They were divided into three groups: 35 patients, 196 family members and 224 hospital staffs. We extracted their epidemiological information, clinical records, auxiliary examination results and therapeutic schedules. The median contact time for patients was four days and that for family members was five days. Cardiovascular disease accounted for 25% among original diseases of patients. Apart from hospital staffs, both patients and family members were isolated medically. During the quarantine, seven patients plus one family member appeared new respiratory symptoms, where fever was the most common one. The blood counts in most contacts were within a normal range. All CT images showed no sign of COVID-19 infection. No severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections was detected in 455 contacts by nucleic acid test. In summary, all the 455 contacts were excluded from SARS-CoV-2 infection and we conclude that the infectivity of some asymptomatic SARS-CoV-2 carriers might be weak.


Beta-blockade, but not normoglycemia or hyperinsulinemia, markedly diminishes stress-induced hyperglycemia in diabetic dogs.
Stress-induced hyperglycemia can lead to significant deterioration in glycemic control in individuals with diabetes. Previously, we have shown in normal dogs that, after intracerebroventricular (ICV) administration of carbachol (a model of moderate stress), increases in both the metabolic clearance rate (MCR) of glucose and endogenous glucose production (GP) occur. However, in hyperglycemic diabetic dogs subjected to the same stress, the MCR of glucose does not increase and glycemia therefore markedly deteriorates because of stimulation of GP. Our aims were to determine the following: 1) whether insulin-induced acute normalization of glycemia, with or without beta-blockade, would correct glucose clearance and prevent the hyperglycemic effect of stress, and 2) whether hyperinsulinemia per se could correct these abnormalities. Stress was induced by ICV carbachol in 27 experiments in five alloxan-administered diabetic dogs subjected to the following protocols in random order: 1) basal insulin infusion (BI) to restore normoglycemia; 2) basal insulin infusion with beta-blockade (BI+block); 3) normoglycemic-hyperinsulinemic clamp with threefold elevation of insulin above basal (3x BI); and 4) normoglycemic-hyperinsulinemic clamp with fivefold elevation of insulin above basal (5 x BI). The BI+block protocol fully prevented stress-induced hyperglycemia, both by increasing MCR (deltaMCR at peak: 0.72 +/- 0.25 ml x kg(-1) x min(-1) vs. no change in BI, P < 0.05) and by diminishing the stress-induced increment in GP observed in BI (deltaGP at peak: 3.72 +/- 0.09 micromol x kg(-1) x min(-1) for BI+block vs. 14.10 +/- 0.31 micromol x kg(-1) x min(-1) for BI, P < 0.0001). In contrast, 3x BI and 5x BI treatments with normoglycemic-hyperinsulinemic clamps proportionately increased basal MCR at baseline, but paradoxically were not associated with an increase in MCR in response to stress, which induced a twofold increase in GP. Thus, in alloxan-administered diabetic dogs, stress increased GP but not MCR, despite normalization of glycemia with basal or high insulin. In contrast, beta-adrenergic blockade almost completely restored the metabolic response to stress to normal and prevented marked hyperglycemia, both by limiting the rise in GP and by increasing glucose MCR. We conclude that acute normalization of glycemia with basal insulin or hyperinsulinemia does not prevent hyperglycemic effects of stress unless accompanied by beta-blockade, and we speculate that short-term beta-blockade may be a useful treatment modality under some stress conditions in patients with diabetes.


Formulation development and manufacturing of a gastrin/CCK-2 receptor targeting peptide as an intermediate drug product for a clinical imaging study.
A DOTA-gastrin analogue (APH070) which, when labelled with (111)In, has high affinity for the gastrin/CCK-2 receptor (3nM) and low tumour to kidney ratio in animal models, has been formulated and manufactured for a clinical study. Oxidation of the peptide methionine residue greatly reduces receptor affinity, therefore development work focused on producing a stable intermediate drug product (iDP) whilst ensuring that the formulation, container, closure and manufacturing process did not inhibit the extremely sensitive radiolabelling reaction (itself a source of oxidation). Stress testing revealed that APH070 was stable at 2-8 degrees C at pH 6-9. Addition of an antioxidant (monothioglycerol) to the peptide formulation reduced stability when compared to buffer alone. Use of FluroTec (4023/50) stoppers (rather than FluroTec Plus (4110/40)) increased both the stability and radiolabelling efficiency of APH070. Long term stability (6 months) of the final formulation (1mg/ml APH070 in 0.01 M pH 7.2 phosphate buffer) stored at 5 degrees C in type I glass vials with FluroTec (4023/50) stoppers was 98.6+/-0.2% and 98.4+/-0.1% for upright and inverted samples, respectively. Clinical scale radiolabelling of the final formulation routinely achieves the specification of >85% (111)In-APH070 (unoxidised) stable for up to 2h after dilution with 0.9% w/v saline solution. Specific uptake of the radiopharmaceutical in CCK-2R-expressing AR42J tumours in nude mice has been demonstrated.


Autoimmune thyroid disease in Colombian patients with systemic lupus erythematosus.
To determine the prevalence and the predictive factors of autoimmune hypothyroidism (AH) within a systemic lupus erythematosus (SLE) cohort and to analyse the current information concerning the prevalence and impact of autoimmune thyroid disease (AITD) and thyroid autoimmunity in patients with SLE. A total of 376 patients with SLE were assessed for the presence of the following: (i) confirmed AH, (ii) positive thy-roperoxidase/thyroglobulin antibodies [TPOAb/TgAb] without hypothyroidism, (iii) nonautoimmune hypothyroidism and (iv) SLE patients with neither. Multivariate analysis and a classification and regression tree model were used to analyse data. The current information was discussed through a systematic literature review (SLR). In our cohort, the prevalence of confirmed AH was 12%. However, in euthyroid patients with SLE, TPOAb and TgAb were observed in 21% and 10%, respectively. Patients with confirmed AH were significantly older and had later age at onset of the disease. Smoking (adjusted odds ratio (AOR) 6·93, 95% CI 1·98-28·54, P = 0·004), Sjögren's Syndrome (SS) (AOR 23·2, 95% CI 1·89-359·53, P = 0·015) and positivity for anticyclic citrullinated peptide (anti-CCP) (AOR 10·35, 95% CI 1·04-121·26, P = 0·047) were associated with AH-SLE, regardless of gender and duration of the disease. Smoking and SS were confirmed as predictors of AH-SLE. In the SLR, the prevalence of AITD ranged from 1% to 60%. The factors associated with this polyautoimmunity were female gender, older age, smoking, certain autoantibodies, SS, and cutaneous and articular involvement. AITD is frequent in SLE and does not affect the severity of SLE. Identified risk factors will assist clinicians in the search for AITD. Our results encourage smoke-free policies in patients with SLE.


Tapping to a slow tempo in the presence of simple and complex meters reveals experience-specific biases for processing music.
Musical meters vary considerably across cultures, yet relatively little is known about how culture-specific experience influences metrical processing. In Experiment 1, we compared American and Indian listeners' synchronous tapping to slow sequences. Inter-tone intervals contained silence or to-be-ignored rhythms that were designed to induce a simple meter (familiar to Americans and Indians) or a complex meter (familiar only to Indians). A subset of trials contained an abrupt switch from one rhythm to another to assess the disruptive effects of contradicting the initially implied meter. In the unfilled condition, both groups tapped earlier than the target and showed large tap-tone asynchronies (measured in relative phase). When inter-tone intervals were filled with simple-meter rhythms, American listeners tapped later than targets, but their asynchronies were smaller and declined more rapidly. Likewise, asynchronies rose sharply following a switch away from simple-meter but not from complex-meter rhythm. By contrast, Indian listeners performed similarly across all rhythm types, with asynchronies rapidly declining over the course of complex- and simple-meter trials. For these listeners, a switch from either simple or complex meter increased asynchronies. Experiment 2 tested American listeners but doubled the duration of the synchronization phase prior to (and after) the switch. Here, compared with simple meters, complex-meter rhythms elicited larger asynchronies that declined at a slower rate, however, asynchronies increased after the switch for all conditions. Our results provide evidence that ease of meter processing depends to a great extent on the amount of experience with specific meters.


Early Childhood Risk Factors for Mealtime TV Exposure and Engagement in Low-Income Families.
To identify whether child and mother characteristics in early childhood predict TV exposure and engagement during mealtime in middle childhood. A total of 220 low-income mother-child dyads participated. Children were 4.26 years old (SD = 0.51) at baseline and 5.94 years (SD = 0.68) at 2-year follow-up. Mothers completed baseline measures of child negative emotionality and parenting practices. Family mealtimes were video recorded and coded for background TV exposure and child TV engagement. Multinomial logistic regression tested whether child emotionality and parenting practices during early childhood predicted risk of child TV exposure or engagement during mealtime, relative to no TV use, 2 years later. Children with greater negative emotionality in early childhood were more likely to engage with TV during mealtime than to have no TV. Similarly, early parenting disciplinary practices characterized by over-reactivity and laxness increased the risk for child TV engagement versus no TV during mealtime approximately 2 years later. We identified 2 factors that associated with an increased risk for TV viewing during meals. Helping parents manage child negative emotionality using positive parenting strategies might reduce later child TV engagement and improve the quality of family mealtimes.