Regional Variation in Utilization and Outcomes of Liver Allografts From Donors With High Body Mass Index and Graft Macrosteatosis: A Role for Liver Biopsy.
Obesity, defined as a high body mass index (hBMI) of 30 kg/m or greater, is a growing epidemic worldwide and is associated with multiple comorbidities. High BMI individuals account for an increasing portion of potential liver donors. Here we evaluate trends in the utilization and outcomes of hBMI donors on a national and regional level and the potential role of liver biopsy in donor evaluation. United Network for Organ Sharing Standard Transplant Analysis and Research database was evaluated for deceased donor liver transplants between 2006 and 2016 across 11 Organ Procurement and Transplantation Network regions. High BMI donors were compared with lower BMI counterparts and evaluated for biopsy rates, utilization rates and allograft outcomes. Univariate and multivariable analyses were performed. Seventy-seven thousand fifty potential donors were identified and 60 200 transplants were evaluated. Utilization rates for hBMI donors were 66.1% versus 78.1% for lower BMI donors (P < 0.001). Pretransplant biopsy was performed more frequently in hBMI donors (52.1% vs 33.1%, P < 0.001) and macrosteatosis of 30% or greater was identified more often (21.1% vs 12.2%, P < 0.001). Biopsy performance increased utilization rate of hBMI donors in 7 of 11 Organ Procurement and Transplantation Network regions. region 6 showed the highest rate of biopsy performance, high rate of hBMI donor utilization, and highest 5-year estimated graft survival rates of all regions. High BMI donors have not previously been associated with worse graft survival in multivariable analyses; however, they are used much less frequently. Liver biopsy may increase the utilization rate of hBMI donors and improve donor selection. Further evaluation of regions with high rates of utilization and good outcomes is warranted.


Gene transfer to liver cancer cells of B7-1 plus interleukin 12 changes immunoeffector mechanisms and suppresses helper T cell type 1 cytokine production induced by interleukin 12 alone.
To investigate the cooperative effect of B7-1 and IL-12 in the induction of antitumor activity, we have developed retroviral vectors encoding human B7-1, murine IL-12, or both B7-1 and IL-12 coordinately. Murine transformed liver cells (BNL) were engineered to stably express B7-1, IL-12, or both by infection with corresponding retroviruses. No tumor was observed in 20, 75, and 95% of mice receiving, respectively, B7-1-, IL-12-, and B7-1/IL-12-modified tumor cells after 250 days of inoculation. In contrast, injection of parental BNL or BNL/Neo cells resulted in lethal tumor progression in all mice. Protection against rechallenge with parental tumor cells was observed only in mice who had rejected BNL/IL-12, but not in animals that rejected BNL/B7-1 or BNL/B7-1-IL-12. Growth of parental tumor cells was significantly delayed by simultaneous injection in a distant site of irradiated tumor cells engineered to express IL-12 or both B7-1 and IL-12 but not B7-1 alone. BNL/B7-1 and BNL/B7-1-IL-12 showed similar efficacy in these experiments. Antitumor immunity induced by B7, with or without IL-12, was found to depend mainly on CD4+ T cells with a minor contribution of a non-T cell mechanism; whereas the effect of IL-12 was dependent on CD8+ T cells and on non-T cell effectors. Immunization of mice with IL-12-modified BNL cells induced secretion of a Thl pattern of cytokines while immunization with cells expressing both IL-12 and B7-1 resulted in inhibition of IFN-gamma production. Immunization with BNL/B7-1-IL-12 cells in the presence of anti-human B7-1 MAb resulted in restoration of IFN-gamma production to the levels found in animals injected with BNL/IL-12 cells. To summarize, in our model coexpression of B7-1 and IL-12 in tumor cells does not result in improved antitumoral activity as compared with expression of IL-12 alone. This may be related to the fact that B7-1 changes the mechanisms of antitumor immunity and inhibits IFN-gamma production induced by IL-12 in vivo.


Constrained statistical inference: sample-size tables for ANOVA and regression.
Researchers in the social and behavioral sciences often have clear expectations about the order/direction of the parameters in their statistical model. For example, a researcher might expect that regression coefficient β1 is larger than β2 and β3. The corresponding hypothesis is H: β1 > {β2, β3} and this is known as an (order) constrained hypothesis. A major advantage of testing such a hypothesis is that power can be gained and inherently a smaller sample size is needed. This article discusses this gain in sample size reduction, when an increasing number of constraints is included into the hypothesis. The main goal is to present sample-size tables for constrained hypotheses. A sample-size table contains the necessary sample-size at a pre-specified power (say, 0.80) for an increasing number of constraints. To obtain sample-size tables, two Monte Carlo simulations were performed, one for ANOVA and one for multiple regression. Three results are salient. First, in an ANOVA the needed sample-size decreases with 30-50% when complete ordering of the parameters is taken into account. Second, small deviations from the imposed order have only a minor impact on the power. Third, at the maximum number of constraints, the linear regression results are comparable with the ANOVA results. However, in the case of fewer constraints, ordering the parameters (e.g., β1 > β2) results in a higher power than assigning a positive or a negative sign to the parameters (e.g., β1 > 0).


Factors influencing infant-feeding choices selected by HIV-infected mothers: perspectives from Zimbabwe.
To assess factors influencing infant-feeding methods selected by HIV-infected mothers. A descriptive quantitative study was conducted among 80 mothers with babies aged 0-6 months who were randomly selected and interviewed. Descriptive statistics were used to summarize the findings. Factors considered by women in choosing the infant-feeding methods included sociocultural acceptability (58.8%), feasibility and support from significant others (35%), knowledge of the selected method (55%), affordability (61.2%), implementation of the infant-feeding method without interference (62.5%), and safety (47.5%). Exclusive breast-feeding was the most preferred method of infant feeding. Disclosure of HIV status by a woman to her partner is a major condition for successful replacement feeding method, especially within the African cultural context. However, disclosure of HIV status to the partner was feared by most women as only 16.2% of the women disclosed their HIV status to partners. The factors considered by women in choosing the infant-feeding option were ability to implement the options without interference from significant others, affordability, and sociocultural acceptability. Knowledge of the selected option, its advantages and disadvantages, safety, and feasibility were also important factors. Nurses and midwives have to educate clients and support them in their choice of infant-feeding methods.


Antimicrobial Resistance in the Food Chain in the European Union.
Consumers require safety foods but without losing enough supply and low prices. Food concerns about antimicrobial residues and antimicrobial-resistant (AMR) bacteria are not usually appropriately separated and could be perceived as the same problem. The monitoring of residues of antimicrobials in animal food is well established at different levels (farm, slaughterhouse, and industry), and it is preceded by the legislation of veterinary medicines where maximum residues limits are required for medicines to be used in food animal. Following the strategy of the World Health Organization, one of the proposed measures consists in controlling the use of critical antibiotics. The European Union surveillance program currently includes the animal species with the highest meat production (pigs, chickens, turkeys, and cattle) and the food derived from them, investigating antimicrobial resistance of zoonotic (Salmonella and Campylobacter) and indicator (Escherichia coli and enterococci) bacteria. AMR mechanisms encoded by genes have a greater impact on transfer than mutations. Sometimes these genes are found in mobile genetic elements such as plasmids, transposons, or integrons, capable of passing from one bacterium to another by horizontal transfer. It is important to know that depending on how the resistance mechanism is transferred, the power of dissemination is different. By vertical transfer of the resistance gene, whatever its origin, will be transmitted to the following generations. In the case of horizontal transfer, the resistance gene moves to neighboring bacteria and therefore the range of resistance can be much greater.


Get Set or Get Distracted? Disentangling Content-Priming and Attention-Catching Effects of Background Lure Stimuli on Identifying Targets in Two Simultaneously Presented Series.
In order to study the changing relevance of stimulus features in time and space, we used a task with rapid serial presentation of two stimulus streams where two targets ("T1" and "T2") had to be distinguished from background stimuli and where the difficult T2 distinction was impeded by background stimuli presented before T1 that resemble T2 ("lures"). Such lures might actually have dual characteristics: Their capturing attention might interfere with target identification, whereas their similarity to T2 might result in positive priming. To test this idea here, T2 was a blue digit among black letters, and lures resembled T2 either by alphanumeric category (black digits) or by salience (blue letters). Same-category lures were expected to prime T2 identification whereas salient lures would impede T2 identification. Results confirmed these predictions, yet the precise pattern of results did not fit our conceptual framework. To account for this pattern, we speculate that lures serve to confuse participants about the order of events, and the major factor distinguishing color lures and digit lures is their confusability with T2. Mechanisms of effects were additionally explored by measuring event-related EEG potentials. Consistent with the assumption that they attract more attention, color lures evoked larger N2pc than digit lures and affected the ensuing T1-evoked N2pc. T2-evoked N2pc was indistinguishably reduced by all kinds of preceding lures, though. Lure-evoked mesio-frontal negativity increased from first to third lures both with digit and color lures and, thereby, might have reflected expectancy for T1.


Comparison of pathologic stage in patients receiving esophagectomy with and without preoperative chemoradiation therapy for esophageal SCC.
The prognostic value for the post-chemoradiation therapy (CRT) pathologic stage is uncertain. The purpose of this study was to compare the pathologic stage in patients undergoing esophagectomy with and without preoperative CRT for esophageal squamous cell carcinoma (ESCC). This study retrospectively reviewed the data from 2151 patients with ESCC who underwent esophagectomy with or without preoperative CRT between 2008 and 2011 in Taiwan. Patients were divided into 2 groups. Group A consisted of patients treated with primary surgery without prior treatments (n=1301), and group B consisted of patients receiving preoperative CRT followed by esophagectomy (n=850). In group A, 679 patients received surgery alone, 92 received postoperative chemotherapy, 416 received postoperative chemoradiation therapy, and 114 received postoperative radiation therapy. In group A, the 3-year survival rates by pathologic stage were 82.2% for stage 0, 67.6% for stage I, 50.7% for stage II, 21.5% for stage III, and 14.8% for stage IV (P<.001). In group B, the 3-year survival rates of post-CRT pathologic stages 0, I, II, III, and IV were 59.4%, 46.0%, 40.3%, 19.1%, and 8.2%, respectively (P<.001). In multivariate analysis, the pathologic T, N, and M were all independent prognostic factors in both group A (esophagectomy alone) and B (CRT plus esophagectomy). The current, 7th edition of the esophageal TNM staging system could adequately stratify prognostic groups in patients with squamous cell carcinoma who were treated with preoperative CRT and esophagectomy.


Ultra-flattened and low dispersion in engineered microfibers with highly efficient nonlinearity reduction.
We propose an engineered microfiber with nano-scale slots that produce ultra-flattened and low dispersion of ±10 ps/(nm · km) over a 340 nm wavelength range. It is comparable with the results in photonic crystal fibers and planar slot waveguides, but can be hardly realized in conventional circular microfibers. By confining the light in a low nonlinearity air slot, the nonlinear coefficient can be greatly reduced. With the unique geometry and excellent performance, the slot microfiber offers large potential in miniature fiber devices for high-speed telecom applications.


Rapid neutrophil destruction following phagocytosis of Staphylococcus aureus.
Mechanisms underlying the enhanced virulence phenotype of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are incompletely defined, but presumably include evasion of killing by human polymorphonuclear leukocytes (PMNs or neutrophils). To better understand this phenomenon, we investigated the basis of rapid PMN lysis after phagocytosis of USA300, a prominent CA-MRSA strain. Survival of USA300 clinical isolates after phagocytosis ultimately resulted in neutrophil lysis. PMNs containing ingested USA300 underwent morphological changes consistent with apoptosis, but lysed rapidly thereafter (within 6 h), whereas cells undergoing FAS-mediated apoptosis or phagocytosis-induced cell death remained intact. Phagosome membranes remained intact until the point of PMN destruction, suggesting lysis was not caused by escape of S. aureus from phagosomes or the cytolytic action of pore-forming toxins. Microarray analysis of the PMN transcriptome after phagocytosis of representative community-associated S. aureus and healthcare-associated MRSA strains revealed changes unique to community-associated S. aureus strains, such as upregulation of transcripts involved in regulation of calcium homeostasis. Collectively, the data suggest that neutrophil destruction after phagocytosis of USA300 is in part a form of programmed necrosis rather than direct lysis by S. aureus pore-forming toxins. We propose that the ability of CA-MRSA strains to induce programmed necrosis of neutrophils is a component of enhanced virulence.


Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link.
Traumatic brain injury (TBI) and Alzheimer's disease (AD) are devastating neurological disorders, whose complex relationship is not completely understood. Cerebrovascular pathology, a key element in both conditions, could represent a mechanistic link between Aβ/tau deposition after TBI and the development of post concussive syndrome, dementia and chronic traumatic encephalopathy (CTE). In addition to debilitating acute effects, TBI-induced neurovascular injuries accelerate amyloid β (Aβ) production and perivascular accumulation, arterial stiffness, tau hyperphosphorylation and tau/Aβ-induced blood brain barrier damage, giving rise to a deleterious feed-forward loop. We postulate that TBI can initiate cerebrovascular pathology, which is causally involved in the development of multiple forms of neurodegeneration including AD-like dementias. In this review, we will explore how novel biomarkers, animal and human studies with a focus on cerebrovascular dysfunction are contributing to the understanding of the consequences of TBI on the development of AD-like pathology.


Transposon Express, a software application to report the identity of insertions obtained by comprehensive transposon mutagenesis of sequenced genomes: analysis of the preference for in vitro Tn5 transposition into GC-rich DNA.
Comprehensive mutant libraries can be readily constructed by transposon mutagenesis. To systematically mutagenise the genome of the Gram-positive bacterium Streptomyces coelicolor A3(2), we have employed high-throughput shuttle transposon mutagenesis of a cosmid library prepared in Escherichia coli. The location of transposon insertions is determined using automated procedures for cosmid isolation and DNA sequencing. However, a major bottleneck was the subsequent analysis of DNA sequence files. To overcome this limitation, a software application, Transposon Express, was written to allow the rapid location of transposon insertions in a sequenced genome (available at http://www.swan.ac.uk/genetics/dyson/InstallTE). Transposon Express determines the identity both of a disrupted open reading frame (ORF), and the short target site duplication created by transposition. Transposon Express also reports the orientation of the transposon and can therefore predict transcriptional coupling between an upstream promoter and a promoter-less reporter gene carried by the transposon. Analysis of a large dataset of independent insertions created using a Tn5-based transposon revealed an insertional preference for GC-rich streptomycete DNA compared to E.coli vector DNA. In addition to demonstrating the value of Transposon Express as a generic tool supporting genome-wide transposon mutagenesis programs, these data provide insight into target site selection by Tn5.


Pomegranate extract inhibits migration and invasion of oral cancer cells by downregulating matrix metalloproteinase-2/9 and epithelial-mesenchymal transition.
Discovering drug candidates for the modulation of metastasis is of great importance in inhibiting oral cancer malignancy. Although most pomegranate extract applications aim at the antiproliferation of cancer cells, its antimetastatic effects remain unclear, especially for oral cancer cells. The aim of this study is to evaluate the change of two main metastasis characters, migration and invasion of oral cancer cells. Further, we want to explore the molecular mechanisms of action of pomegranate extract (POMx) at low cytotoxic concentration. We found that POMx ranged from 0 to 50 μg/mL showing low cytotoxicity to oral cancer cells. In the case of oral cancer HSC-3 and Ca9-22 cells, POMx inhibits wound healing migration, transwell migration, and matrix gel invasion. Mechanistically, POMx downregulates matrix metalloproteinase (MMP)-2 and MMP-9 activities and expressions as well as epithelial-mesenchymal transition (EMT) signaling. POMx upregulates extracellular signal-regulated kinases 1/2 (ERK1/2), but not c-Jun N-terminal kinase (JNK) and p38 expression. Addition of ERK1/2 inhibitor (PD98059) significantly recovered the POMx-suppressed transwell migration and MMP-2/-9 activities in HSC-3 cells. Taken together, these findings suggest to further test low cytotoxic concentrations of POMx as a potential antimetastatic therapy against oral cancer cells.


Meta-analysis of proton pump inhibitors induced risk of community-acquired pneumonia.
Proton pump inhibitors (PPIs), one of the most widely used medications, are commonly used to suppress several acid-related upper gastrointestinal disorders. Acid-suppressing medication use could be associated with increased risk of community-acquired pneumonia (CAP), although the results of clinical studies have been conflicting. A comprehensive search of MEDLINE, EMBASE and Cochrane library and Database of Systematic Reviews from the earliest available online year of indexing up to October 2018. We performed a systematic review and meta-analysis of observational studies to evaluate the risk of PPI use on CAP outcomes. Included study location, design, population, the prevalence of CAP, comparison group and other confounders. We calculated pooled odds ratio (OR) using a random-effects meta-analysis. Of the 2577 studies screening, 11 papers were included in the systematic review and 7 studies with 65 590 CAP cases were included in the random-effects meta-analysis. In current PPI users, pooled OR for CAP was 1.86 (95% confidence interval (CI), 1.30-2.66), and in the case of recent users, OR for CAP was 1.66 (95% CI, 1.22-2.25). In the subgroup analysis of CAP, significance association is also observed in both high-dose and low-dose PPI therapy. When stratified by duration of exposure, 3-6 months PPIs users group was associated with increased risk of developing CAP (OR, 2.05; 95% CI, 1.22-3.45). There was a statistically significant association between the PPI users and the rate of hospitalization (OR, 2.59; 95% CI, 1.83-3.66). We found possible evidence linking PPI use to an increased risk of CAP. More randomized controlled studies are warranted to clarify an understanding of the association between PPI use and risk of CAP because observational studies cannot clarify whether the observed epidemiologic association is a causal effect or a result of unmeasured/residual confounding.


Is universal coverage via social health insurance financially feasible in Swaziland?
The Government of Swaziland decided to explore the feasibility of social health insurance (SHI) in order to enhance universal access to health services. We assess the financial feasibility of a possible SHI scheme in Swaziland. The SHI scenario presented is one that mobilises resources additional to the maintained Ministry of Health and Social Welfare (MOHSW) budget. It is designed to increase prepayment, enhance overall health financing equity, finance quality improvements in health care, and eventually cover the entire population. The financial feasibility assessment consists of calculating and projecting revenues and expenditures of the SHI scheme from 2008 to 2018. SimIns, a health insurance simulation software, was used. Quantitative data from government and other sources and qualitative data from discussions with health financing stakeholders were gathered. Policy assumptions were jointly developed with and agreed upon by a MOHSW team. SHI would take up an increasing proportion of total health expenditure over the simulation period and become the dominant health financing mechanism. In principle, and on the basis of the assumed policy variables, universal coverage could be reached within 6 years through the implementation of an SHI scheme based on a mix of contributory and tax financing. Contribution rates for formal sector employees would amount to 7% of salaries and the Ministry of Health and Social Welfare budget would need to be maintained. Government health expenditure including social health insurance would increase from 6% in 2008 to 11% in 2018.


Fluxes through plant metabolic networks: measurements, predictions, insights and challenges.
Although the flows of material through metabolic networks are central to cell function, they are not easy to measure other than at the level of inputs and outputs. This is particularly true in plant cells, where the network spans multiple subcellular compartments and where the network may function either heterotrophically or photoautotrophically. For many years, kinetic modelling of pathways provided the only method for describing the operation of fragments of the network. However, more recently, it has become possible to map the fluxes in central carbon metabolism using the stable isotope labelling techniques of metabolic flux analysis (MFA), and to predict intracellular fluxes using constraints-based modelling procedures such as flux balance analysis (FBA). These approaches were originally developed for the analysis of microbial metabolism, but over the last decade, they have been adapted for the more demanding analysis of plant metabolic networks. Here, the principal features of MFA and FBA as applied to plants are outlined, followed by a discussion of the insights that have been gained into plant metabolic networks through the application of these time-consuming and non-trivial methods. The discussion focuses on how a system-wide view of plant metabolism has increased our understanding of network structure, metabolic perturbations and the provision of reducing power and energy for cell function. Current methodological challenges that limit the scope of plant MFA are discussed and particular emphasis is placed on the importance of developing methods for cell-specific MFA.


Proteomic analysis of a noninvasive human model of acute inflammation and its resolution: the twenty-one day gingivitis model.
The 21-day experimental gingivitis model, an established noninvasive model of inflammation in response to increasing bacterial accumulation in humans, is designed to enable the study of both the induction and resolution of inflammation. Here, we have analyzed gingival crevicular fluid, an oral fluid comprising a serum transudate and tissue exudates, by LC-MS/MS using Fourier transform ion cyclotron resonance mass spectrometry and iTRAQ isobaric mass tags, to establish meta-proteomic profiles of inflammation-induced changes in proteins in healthy young volunteers. Across the course of experimentally induced gingivitis, we identified 16 bacterial and 186 human proteins. Although abundances of the bacterial proteins identified did not vary temporally, Fusobacterium outer membrane proteins were detected. Fusobacterium species have previously been associated with periodontal health or disease. The human proteins identified spanned a wide range of compartments (both extracellular and intracellular) and functions, including serum proteins, proteins displaying antibacterial properties, and proteins with functions associated with cellular transcription, DNA binding, the cytoskeleton, cell adhesion, and cilia. PolySNAP3 clustering software was used in a multilayered analytical approach. Clusters of proteins that associated with changes to the clinical parameters included neuronal and synapse associated proteins.


Branched-chain amino acid supplemented diet during maternal food restriction prevents developmental hypertension in adult rat offspring.
Maternal food restriction is known to cause developmental hypertension in offspring. We have previously shown that maternal high-protein diet can reverse fetal programming of hypertension and that branched-chain amino acid (BCAA) concentrations in maternal and fetal plasma were increased by maternal high-protein intake. Then, we hypothesized that isocaloric supplementation with BCAA to a maternal food restriction can reverse the adverse outcome. Pregnant rats were divided into four groups at 7.5 days postcoitum: normally nourished (NN) and 70% undernourished (UN) groups with and without BCAA supplementation (NN-standard diet (SD), NN-BCAA, UN-SD and UN-BCAA groups). Compared with pups in the NN groups, those in the UN-SD group had significantly increased systolic blood pressure (SBP) at 8 and 16 weeks of age (P < 0.05). However, the elevation of SBP was not observed in offspring in the UN-BCAA group. Offspring glomeruli number of the UN groups was significantly lower (P < 0.05) than that of the NN groups, independent of BCAA supplementation. Angiotensin II receptor type 2 (ATR2) mRNA and protein expression in the kidney was significantly augmented in the UN-BCAA group at 30 weeks of age. In conclusion, BCAA supplementation during maternal food restriction prevents developmental hypertension together with increased ATR2 expression in adult offspring kidney.


Adjuvant Chemotherapy for Patients with Stage III Colon Cancer: Results from a CDC-NPCR Patterns of Care Study.
To evaluate adjuvant chemotherapy use for Stage III colon cancer. This analysis included 973 patients with surgically treated stage III colon cancer. Socioeconomic information from the 2000 census was linked to patients' residential census tracts. Vital status through 12/31/02 was obtained from medical records and linkage to state vital statistics files and the National Death Index. Adjuvant chemotherapy was received by 67%. Treatment varied by state of residence, with Colorado, Rhode Island and New York residents more likely to receive chemotherapy than Louisiana residents. Older age, increasing comorbidities, divorced/widowed marital status, and residence in lower education areas or non-working class neighborhoods were associated with lower chemotherapy use. Survival varied by state but after adjustment for sex, sociodemographic and health factors, was significantly higher only for California and Rhode Island. Older age and lower educational attainment were associated with lower survival. Chemotherapy was protective for all comorbidity groups. Although adjuvant chemotherapy for Stage III colon cancer improves survival, some patients did not receive standard of care, demonstrating the need for cancer treatment surveillance. Interstate differences likely resulted from differences in local practice patterns, acceptance of treatment, and access.


Tolvaptan and Kidney Pain in Patients With Autosomal Dominant Polycystic Kidney Disease: Secondary Analysis From a Randomized Controlled Trial.
Kidney pain is a common complication in patients with autosomal dominant polycystic kidney disease (ADPKD), and data from the TEMPO 3:4 trial suggested that tolvaptan, a vasopressin V2 receptor antagonist, may have a positive effect on kidney pain in this patient group. Because pain is difficult to measure, the incidence of kidney pain leading to objective medical interventions was used in the present study to assess pain. Secondary analysis from a randomized controlled trial. Patients with ADPKD with preserved kidney function. Tolvaptan or placebo. Kidney pain events defined by objective medical interventions. Kidney pain events were recorded and independently adjudicated. Incidence of a first kidney pain event was assessed overall and categorized into 5 subgroups according to severity. Of 1,445 participating patients (48.4% women; mean age, 39±7 [SD] years; mean estimated glomerular filtration rate, 81±22mL/min/1.73m2; median total kidney volume, 1,692 [IQR, 750-7,555] mL), 50.9% reported a history of kidney pain at baseline. History of urinary tract infections, kidney stones, or hematuria (all P<0.001) and female sex (P<0.001) were significantly associated with history of kidney pain. Tolvaptan use resulted in a significantly lower incidence of kidney pain events when compared to placebo: 10.1% versus 16.8% (P<0.001), with a risk reduction of 36% (HR, 0.64; 95% CI, 0.48-0.86). The reduction in pain event incidence by tolvaptan was found in all groups irrespective of pain severity and was independent of predisposing factors (P for interaction > 0.05). The effect of tolvaptan was explained at least in part by a decrease in incidence of urinary tract infections, kidney stones, and hematuria when compared to placebo. Trial has specific inclusion criteria for total kidney volume and kidney function. Tolvaptan decreased the incidence of kidney pain events independent of patient characteristics predisposing for kidney pain and possibly in part due to reductions in ADPKD-related complications.


Exploring the impact of COVID-19 on the movement behaviors of children and youth: A scoping review of evidence after the first year.
The objective of this scoping review was to summarize systematically the available literature investigating the relationships between the coronavirus disease 2019 (COVID-19) pandemic and movement behaviors (physical activity, sedentary behavior, and sleep) of school-aged children (aged 5-11 years) and youth (aged 12-17 years) in the first year of the COVID-19 outbreak. Searches for published literature were conducted across 6 databases on 2 separate search dates (November 25, 2020, and January 27, 2021). Results were screened and extracted by 2 reviewers (DCP and KR) independently, using Covidence. Basic numeric analysis and content analysis were undertaken to present thematically the findings of included studies according to the associated impact on each movement behavior. A total of 1486 records were extracted from database searches; of those, 150 met inclusion criteria and were included for analysis. Of 150 articles, 110 were empirical studies examining physical activity (n = 77), sedentary behavior/screen time (n = 58), and sleep (n = 55). Results consistently reported declines in physical-activity time, increases in screen time and total sedentary behavior, shifts to later bed and wake times, and increases in sleep duration. The reported impacts on movement behaviors were greater for youth than for children. The COVID-19 pandemic is related to changes in the quantity and nature of physical activity, sedentary behavior, and sleep among children and youth. There is an urgent need for policy makers, practitioners, and researchers to develop solutions for attenuating adverse changes in physical activity and screen time among children and youth.


Assessing Health Consequences of Vitamin D Fortification Utilizing a Societal Experiment Design: Methodological Lessons Learned from the D-Tect Project.
By utilizing historical changes in Danish legislation related to mandatory vitamin D fortification of margarine, which was implemented in the mid 1930s and abruptly abandoned in June 1985, the studies in the D-tect project investigated the effects of vitamin D on health outcomes in individuals, who during gestation were exposed or unexposed to extra vitamin D from fortified margarine. This paper reviews and narratively summarizes the analytic approaches alongside the results of the societal fortification experiment studies from the D-tect project and addresses the challenges in designing societal experiment studies and evaluating their results. The latter are discussed as lessons learned that may be useful for designers of similar studies, expected to be extensively utilized while researching the health consequences of the COVID-19 pandemic by comparing individuals born before and after the epidemic. In the D-tect project, 16 articles based on the societal fortification experiment were published analyzing 10 different outcomes and using different statistical approaches. Lessons learned included the detail of the analysis of the historical information on the exposure, availability and validity of the outcome data, variety of analytical approaches, and specifics concerning vitamin D effect evaluation, such as consideration of the influence of sunshine or season. In conclusion, the D-tect project clearly demonstrated the cost-effectiveness and research potential of natural- or societal-experiment-based studies.


Lefties get it "right" when hearing tool sounds.
Our ability to manipulate and understand the use of a wide range of tools is a feature that sets humans apart from other animals. In right-handers, we previously reported that hearing hand-manipulated tool sounds preferentially activates a left hemisphere network of motor-related brain regions hypothesized to be related to handedness. Using functional magnetic resonance imaging, we compared cortical activation in strongly right-handed versus left-handed listeners categorizing tool sounds relative to animal vocalizations. Here we show that tool sounds preferentially evoke activity predominantly in the hemisphere "opposite" the dominant hand, in specific high-level motor-related and multisensory cortical regions, as determined by a separate task involving pantomiming tool-use gestures. This organization presumably reflects the idea that we typically learn the "meaning" of tool sounds in the context of using them with our dominant hand, such that the networks underlying motor imagery or action schemas may be recruited to facilitate recognition.


Summary of the recommendations on sexual dysfunctions in men.
There are few published guidelines for the management of sexual dysfunctions in men and women, despite the prevalence and lack of attention to these problems. Disorders of sexual function in men include erectile dysfunction, orgasm/ejaculation disorders, priapism, and Peyronie's disease. To provide evidence-based and expert-opinion consensus guidelines for the clinical management of men's sexual dysfunctions. An International Consultation in collaboration with major urological and sexual medicine societies assembled over 200 multidisciplinary experts from 60 countries into 17 consultation committees. Committee members established the scope and objectives for each chapter. Following intensive review of available data and publications, committees developed evidence-based guidelines in each area. New algorithms and guidelines for assessment and treatment of men's sexual dysfunction were developed. The Oxford system of evidence-based review was systematically applied. Expert opinion was based on systematic grading of the medical literature, in addition to cultural and ethical considerations. Recommendations and guidelines for men's sexual dysfunction are presented. These guidelines were developed as evidence-based, patient-centered, and multidisciplinary in focus. For the clinical assessment and diagnosis of ED, a basic evaluation was recommended for all patients, with optional and specialized testing reserved for special cases. A new treatment algorithm is proposed. This algorithm provides a clinically relevant guideline for managing ED in the large majority of men. New treatment guidelines and algorithms are provided for men's orgasm and ejaculation disorders, including premature ejaculation, retrograde and delayed ejaculation. Finally, expert opinion-based guidelines for the clinical management of priapism and Peyronie's disease are provided. Additional research is needed to validate and extend these guidelines. Nonetheless, this summary encompasses the recommendations concerning men's sexual dysfunctions presented at the 2nd International Consultation on Sexual Medicine in Paris, France, June 28-July 1, 2003.


Genome-wide analysis of disease progression in age-related macular degeneration.
Family- and population-based genetic studies have successfully identified multiple disease-susceptibility loci for Age-related macular degeneration (AMD), one of the first batch and most successful examples of genome-wide association study. However, most genetic studies to date have focused on case-control studies of late AMD (choroidal neovascularization or geographic atrophy). The genetic influences on disease progression are largely unexplored. We assembled unique resources to perform a genome-wide bivariate time-to-event analysis to test for association of time-to-late-AMD with ∼9 million variants on 2721 Caucasians from a large multi-center randomized clinical trial, the Age-Related Eye Disease Study. To our knowledge, this is the first genome-wide association study of disease progression (bivariate survival outcome) in AMD genetic studies, thus providing novel insights to AMD genetics. We used a robust Cox proportional hazards model to appropriately account for between-eye correlation when analyzing the progression time in the two eyes of each participant. We identified four previously reported susceptibility loci showing genome-wide significant association with AMD progression: ARMS2-HTRA1 (P = 8.1 × 10-43), CFH (P = 3.5 × 10-37), C2-CFB-SKIV2L (P = 8.1 × 10-10) and C3 (P = 1.2 × 10-9). Furthermore, we detected association of rs58978565 near TNR (P = 2.3 × 10-8), rs28368872 near ATF7IP2 (P = 2.9 × 10-8) and rs142450006 near MMP9 (P = 0.0006) with progression to choroidal neovascularization but not geographic atrophy. Secondary analysis limited to 34 reported risk variants revealed that LIPC and CTRB2-CTRB1 were also associated with AMD progression (P < 0.0015). Our genome-wide analysis thus expands the genetics in both development and progression of AMD and should assist in early identification of high risk individuals.


Higher serum 25(OH)D concentration is associated with lower risk of chronic otitis media with effusion: a case-control study.
Vitamin D supplementation and higher 25(OH)-vitamin D concentration are associated with reduced risk of acute respiratory infection. This study examined whether there is a similar association between higher serum 25(OH)D concentration and lower risk of chronic otitis media with effusion (COME). In a case-control study, serum 25(OH)D concentration in children referred for tympanostomy tube placement for COME (n = 178) was compared to that of healthy children randomly sampled from primary care practices (n = 179). Subjects aged three and four years were recruited in Auckland, New Zealand between May 2011 and November 2013. Blood samples were collected from the children, and their guardians were interviewed. Odds ratios were calculated using logistic regression. In a multivariable analysis, higher serum 25(OH)D concentration was associated with a lower risk of COME (OR: 0.86 per 10 nmol/L; 95% CI 0.77-0.97) after adjusting for age, sex, deprivation index, ethnicity, tobacco smoke exposure, duration of breastfeeding and season of blood sampling. Further adjustment for eight additional risk factors did not change the result. This finding supports further investigation into whether the risk of COME could be reduced by increasing serum 25(OH)D concentration through increased sun exposure, higher dietary intake or vitamin D supplementation.


Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol.
Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3-74.0 mg/dL); in 14,573 patients (77.0%), both determinations were ≥70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2-111.0 mg/dL). In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [CI]: 0.52-0.90) and 1.11 (95% CI: 0.83-1.49), with treatment-lipoprotein(a) interaction on MACE (Pinteraction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43. In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).


Reconciliation and Health Systems Performance in Northern, Indigenous and Rural Communities.
This commentary calls for a broader conceptualization of the healthcare system and proposes a health systems performance framework that will guide reconciliation and health system improvements in northern, Indigenous and rural communities. Reconciliation provides an opportunity to develop more reciprocal approaches to performance framework and indicator development in Indigenous and northern regions. An enhanced performance framework will inform management that is underpinned by policies and actionable strategies that build on evidence and Indigenous knowledge to inform health systems improvements. Performance measurement systems rooted in reconciliation and based on Indigenous values enable us to have a deeper understanding of system drivers and the legislation and policy levers that perpetuate health inequities.


An obesity-associated gut microbiome with increased capacity for energy harvest.
The worldwide obesity epidemic is stimulating efforts to identify host and environmental factors that affect energy balance. Comparisons of the distal gut microbiota of genetically obese mice and their lean littermates, as well as those of obese and lean human volunteers have revealed that obesity is associated with changes in the relative abundance of the two dominant bacterial divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through metagenomic and biochemical analyses that these changes affect the metabolic potential of the mouse gut microbiota. Our results indicate that the obese microbiome has an increased capacity to harvest energy from the diet. Furthermore, this trait is transmissible: colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota'. These results identify the gut microbiota as an additional contributing factor to the pathophysiology of obesity.


Devriesea agamarum associated cheilitis in a North African spiny-tailed lizard (Uromastyx acanthinura) in Spain.
An 11-year-old, male North African spiny-tailed lizard (Uromastyx acanthinura) was presented with hyperkeratotic cheilitis. Based on clinical examination, histology and microbiological testing, Devriesea agamarum was identified as the causative agent of the dermal disorder. Moreover, an abundant culture of D. agamarum was obtained following sampling of the oral cavity. Cheilitis was present for three years in the spiny-tailed lizard and during the first year of that period the lizard was housed together with an ocellated lizard (Timon lepidus), an Algerian orange-tailed skink (Eumeces algeriensis) and a female U. acanthinura. The latter lizard showed signs of chronic dermatitis and had deceased approximately 2.5 years prior to initial presentation of the male dab lizard because of renal failure. The other cohabiting lizards showed no dermal lesions and D. agamarum could not be demonstrated following dermal, cloacal and oral sampling. Recurrence of the bacterial skin infection was observed following a first antimicrobial treatment. This was considered to result from failure to eliminate the bacterium from the treated dab lizard or re-infection from the environment or asymptomatic carriers. A second treatment, including disinfection of the enclosure with house-hold bleach 0.1%, weekly mechanical debridement of the crusty lesion and treatment with ceftazidime at 20 mg/kg intramuscularly every 72 hours for 57 days resulted in resolution of the skin lesions, elimination of D. agamarum from the oral cavity based on repetitive microbiological sampling and no recurrence of the lesions during a 31 month follow up period. The present case is the first report of devrieseasis in Spain and highlights the importance of a multidirectional diagnostic and therapeutic approach towards controlling devrieseasis in captive lizard collections. Several disease aspects such as persistency are discussed in the light of the contemporary available literature.


Potential Protective Mechanisms of S-equol, a Metabolite of Soy Isoflavone by the Gut Microbiome, on Cognitive Decline and Dementia.
S-equol, a metabolite of soy isoflavone daidzein transformed by the gut microbiome, is the most biologically potent among all soy isoflavones and their metabolites. Soy isoflavones are phytoestrogens and exert their actions through estrogen receptor-β. Epidemiological studies in East Asia, where soy isoflavones are regularly consumed, show that dietary isoflavone intake is inversely associated with cognitive decline and dementia; however, randomized controlled trials of soy isoflavones in Western countries did not generally show their cognitive benefit. The discrepant results may be attributed to S-equol production capability; after consuming soy isoflavones, 40-70% of East Asians produce S-equol, whereas 20-30% of Westerners do. Recent observational and clinical studies in Japan show that S-equol but not soy isoflavones is inversely associated with multiple vascular pathologies, contributing to cognitive impairment and dementia, including arterial stiffness and white matter lesion volume. S-equol has better permeability to the blood-brain barrier than soy isoflavones, although their affinity to estrogen receptor-β is similar. S-equol is also the most potent antioxidant among all known soy isoflavones. Although S-equol is available as a dietary supplement, no long-term trials in humans have examined the effect of S-equol supplementation on arterial stiffness, cerebrovascular disease, cognitive decline, or dementia.


A method for assessing links between objectively measured food store scores and store & neighborhood favorability.
Worldwide, interest in research on methods to define access to healthy food at the local level has grown, given its central connection to carrying out a healthy lifestyle. Within this research domain, papers have examined the spatial element of food access, or individual perceptions about the food environment. To date, however, no studies have provided a method for linking a validated, objective measure of the food environment with qualitative data on how people access healthy food in their community. In this study, we present a methodology for linking scores from a modified Nutrition Environment Measures Survey in Stores (conducted at every store in our study site of Flint, Michigan) with perceptions of the acceptability of food stores and shopping locations drawn from seven focus groups (n = 53). Spatial analysis revealed distinct patterns in visiting and avoidance of certain store types. Chain stores tended to be rated more highly, while stores in neighborhoods with more African-American or poor residents were rated less favorably and avoided more frequently. Notably, many people avoided shopping in their own neighborhoods; participants traveled an average of 3.38 miles to shop for groceries, and 60% bypassed their nearest grocery store when shopping. The utility of our work is threefold. First, we provide a methodology for linking perceived and objective definitions of food access among a small sample that could be replicated in cities across the globe. Second, we show links between perceptions of food access and objectively measured food store scores to uncover inequalities in access in our sample to illustrate potential connections. Third, we advocate for the use of such data in informing the development of a platforms that aim to make the process of accessing healthy food easier via non-food retail based interventions. Future work can replicate our methods to both uncover patterns in distinct food environments and aid in advocacy around how to best intervene in the food environment in various locales.


Adiponectin, chemerin, cytokines, and dipeptidyl peptidase 4 are released from human adipose tissue in a depot-dependent manner: an in vitro system including human serum albumin.
Adipose tissue (AT) contributes to metabolic dysfunction through imbalanced production of adipokines, including cytokines. Visceral AT in particular is associated with metabolic disorders, indicating a specific secretory status. The relative significance of different human AT depots in adipokine release is not fully known. Further, previous in vitro systems usually included medium containing bovine serum albumin (BSA), which may induce cytokine release. Our aim was to compare release of a number of adipokines/cytokines - all implicated in insulin resistance - from human subcutaneous and visceral AT in a short-term incubation system minimizing cytokine induction and including repeated measurements during 24 h. A prerequisite was to evaluate a potential alternative to BSA in the incubation medium. Subcutaneous and/or visceral AT from 17 patients (age 20-68 years; BMI 22.6-56.7 kg/m2) undergoing elective surgery was incubated for 2, 4, 6, 8, and 24 h in medium with or without 1% BSA or human serum albumin (HSA). Medium concentrations of adiponectin, chemerin, nine cytokines, dipeptidyl peptidase 4 (DPP4), and omentin were analyzed by multiplex immunoassay or ELISA. Adipocyte size, AT macrophage density, and medium concentrations of endotoxin were determined. Cytokine release was induced by BSA but not by HSA. In evaluation of the final incubation protocol including 1% HSA, and as expected, adiponectin release was higher from subcutaneous biopsies of nonobese than of obese subjects and inversely associated with adipocyte size; omentin was released almost exclusively from visceral AT. Exploratory incubations revealed more abundant release of chemerin, cytokines (except IL-6), and DPP4 from the visceral depot, while adiponectin release was higher from subcutaneous than visceral AT. Release was linear for a maximum of 2-6 h. Macrophage density was higher in visceral than subcutaneous AT. Levels of endotoxin in the medium were negligible. Adiponectin, chemerin, many cytokines, and DPP4 are released from human AT in a depot-dependent manner. These results highlight functional differences between visceral and subcutaneous AT, and a mechanistic link between regional fat accumulation and metabolic disorders. Supplementation of human AT incubation medium with HSA rather than BSA is recommended to minimize induction of cytokine release.


Empirically Derived Dietary Patterns Using Robust Profile Clustering in the Hispanic Community Health Study/Study of Latinos.
Latent class models (LCMs) have been used in exploring dietary behaviors over a wide set of foods and beverages in a given population, but are prone to overgeneralize these habits in the presence of variation by subpopulations. This study aimed to highlight unique dietary consumption differences by both study site and ethnic background of Hispanic/Latino populations in the United States, that otherwise might be missed in a traditional LCM of the overall population. This was achieved using a new model-based clustering method, referred to as robust profile clustering (RPC). A total of 11,320 individuals aged 18-74 y from the Hispanic Community Health Study/Study of Latinos (2008-2011) with complete diet data were classified into 9 subpopulations, defined by study site (Bronx, Chicago, Miami, San Diego) and ethnic background. At baseline, dietary intake was ascertained using a food propensity questionnaire. Dietary patterns were derived from 132 food groups using the RPC method to identify patterns of the general Hispanic/Latino population and those specific to an identified subpopulation. Dietary patterns derived from the RPC were compared to those identified from an LCM. The LCM identified 48 shared consumption behaviors of foods and beverages across the entire cohort, whereas significant consumption differences in subpopulations were identified in the RPC model for these same foods. Several foods were common within study site (e.g., chicken, orange juice, milk), ethnic background (e.g., papayas, plantain, coffee), or both (e.g., rice, tomatoes, seafood). Post hoc testing revealed an improved model fit in the RPC model [Deviance Information Criterion DICRPC = 2.3 × 104, DICLCM = 9.5 × 106]. Dietary pattern behaviors of Hispanics/Latinos in the United States tend to align by ethnic background for some foods and by location for other foods. Consideration of both factors is imperative to better understand their contributions to population health and developing targeted nutrition intervention studies.


Disseminating evidence-based psychological treatments for eating disorders.
The research-practice gap is of concern in the treatment of eating disorders. Despite the existence of empirically supported treatments, few receive them. The barriers to wider dissemination and implementation of evidence-based treatment include clinician attitudes towards such treatments and the lack of sufficient numbers of suitably trained therapists to provide treatment. In this review we discuss these barriers in the context of the wider issue of the dissemination and implementation of psychological treatments and review the research with regard to the treatment of eating disorders. Particular emphasis is placed on examining recent efforts to expand the availability and reach of treatments by making treatment delivery and training more scalable. We highlight promising developments and areas where further research is needed.


In vivo nuclear transport kinetics in Saccharomyces cerevisiae: a role for heat shock protein 70 during targeting and translocation.
The transport of proteins into the nucleus is a receptor-mediated process that is likely to involve between 50-100 gene products, including many that comprise the nuclear pore complex. We have developed an assay in Saccharomyces cerevisiae for the nuclear transport of green fluorescent protein fused to the SV-40 large T antigen nuclear localization signal (NLS-GFP). This assay allows the measurement of relative NLS-GFP nuclear import rates in wild-type and mutant cells under various physiological conditions. Probably the best understood component of the nuclear transport apparatus is Srp1p, the NLS receptor, which binds NLS-cargo in the cytoplasm and accompanies it into the nucleus. When compared to SRP1+ cells, NLS-GFP import rates in temperature-sensitive srp1-31 cells were slower and showed a lower temperature optimum. The in vivo transport defect of the srp1-31 cells was correlated with the purified protein's thermal sensitivity, as assayed by in vitro NLS peptide binding. We show that the kinetics of NLS-directed nuclear transport in wild-type cells is stimulated by the elevated expression of SSA1, which encodes a cytoplasmic heat shock protein 70 (Hsp70). Elevated Hsp70 levels are sufficient to suppress the NLS-GFP import defects in srp1-31 and nup82-3 cells. NUP82 encodes a protein that functions within the nuclear pore complex subsequent to docking. These results provide genetic evidence that Hsp70 acts during both targeting and translocation phases of nuclear transport, possibly as a molecular chaperone to promote the formation and stability of the Srp1p-NLS-cargo complex.


The effect of nasogastric tubes on swallowing function in persons with dysphagia following stroke.
To determine whether the use of a nasogastric tube influences swallowing function in stroke patients with dysphagia. Before-after trial. Primary care center. A total of 22 patients with stroke (12 men, 10 women; mean age, 69.7 y; range, 19-85 y) participated in the study. Time from onset of stroke to time of assessment averaged 20.3 days (range, 14-38 d). All participants continued to use a nasogastric tube for nutrition supply and had either minor or no aspiration of barium on videofluoroscopic examination of swallowing (VFES). The swallowing function was evaluated by VFES with thin and thick bariums (5 mL each) as a contrast medium. The oral transit, swallowing trigger, and pharyngeal transit times were measured and compared before and after the removal of the nasogastric tube. The patients were also observed for changes in velopharyngeal closure, pharyngeal contraction, epiglottic tilt, valleculae stasis, pyriform sinus stasis, penetration, and aspiration. Transit times were reduced by 0.2 to 0.6 seconds after removal of the nasogastric tube, but the reduction was not statistically significant. These transit times were slightly longer with thick barium than with thin barium, but were without statistical significance. Similarly, most of the patients had no change in nontemporal assessment of swallowing function after the tube was removed. The placement of a nasogastric tube did not affect temporal and nontemporal measurement of swallowing in stroke patients with dysphagia with or without minor aspiration.


Relation of pulse pressure to long-distance gait speed in community-dwelling older adults: findings from the LIFE-P study.
Reduced gait speed is associated with falls, late-life disability, hospitalization/institutionalization and cardiovascular morbidity and mortality. Aging is also accompanied by a widening of pulse pressure (PP) that contributes to ventricular-vascular uncoupling. The purpose of this study was to test the hypothesis that PP is associated with long-distance gait speed in community-dwelling older adults in the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study. Brachial blood pressure and 400-meter gait speed (average speed maintained over a 400-meter walk at "usual" pace) were assessed in 424 older adults between the ages of 70-89 yrs at risk for mobility disability (mean age=77 yrs; 31% male). PP was calculated as systolic blood pressure (BP) - diastolic BP. Patients with a history of heart failure and stroke (n=42) were excluded leaving 382 participants for final analysis. When categorized into tertiles of PP, participants within the highest PP tertile had significantly slower gait speed than those within the lowest PP tertile (p<0.05). Following stepwise multiple regression, PP was significantly and inversely associated with 400-meter gait speed (p<0.05). Other significant predictors of gait speed included: handgrip strength, body weight, age and history of diabetes mellitus (p<0.05). Mean arterial pressure, systolic BP and diastolic BP were not predictors of gait speed. Pulse pressure is associated long-distance gait speed in community-dwelling older adults. Vascular senescence and altered ventricular-vascular coupling may be associated with the deterioration of mobility and physical function in older adults.


In Vivo Visible Light-Triggered Drug Release From an Implanted Depot.
Controlling chemistry in space and time has offered scientists and engineers powerful tools for research and technology. For example, on-demand photo-triggered activation of neurotransmitters has revolutionized neuroscience. Non-invasive control of the availability of bioactive molecules in living organisms will undoubtedly lead to major advances; however, this requires the development of photosystems that efficiently respond to regions of the electromagnetic spectrum that innocuously penetrate tissue. To this end, we have developed a polymer that photochemically degrades upon absorption of one photon of visible light and demonstrated its potential for medical applications. Particles formulated from this polymer release molecular cargo in vitro and in vivo upon irradiation with blue visible light through a photoexpansile swelling mechanism.


Metabolic fingerprinting in disease diagnosis: biomedical applications of infrared and Raman spectroscopy.
The ability to diagnose the early onset of disease, rapidly, non-invasively and unequivocally has multiple benefits. These include the early intervention of therapeutic strategies leading to a reduction in morbidity and mortality, and the releasing of economic resources within overburdened health care systems. Some of the routine clinical tests currently in use are known to be unsuitable or unreliable. In addition, these often rely on single disease markers which are inappropriate when multiple factors are involved. Many diseases are a result of metabolic disorders, therefore it is logical to measure metabolism directly. One of the strategies employed by the emergent science of metabolomics is metabolic fingerprinting; which involves rapid, high-throughput global analysis to discriminate between samples of different biological status or origin. This review focuses on a selective number of recent studies where metabolic fingerprinting has been forwarded as a potential tool for disease diagnosis using infrared and Raman spectroscopies.


Clinical epidemiology of malaria in the highlands of western Kenya.
Malaria in the highlands of Kenya is traditionally regarded as unstable and limited by low temperature. Brief warm periods may facilitate malaria transmission and are therefore able to generate epidemic conditions in immunologically naive human populations living at high altitudes. The adult:child ratio (ACR) of malaria admissions is a simple tool we have used to assess the degree of functional immunity in the catchment population of a health facility. Examples of ACR are collected from inpatient admission data at facilities with a range of malaria endemicities in Kenya. Two decades of inpatient malaria admission data from three health facilities in a high-altitude area of western Kenya do not support the canonical view of unstable transmission. The malaria of the region is best described as seasonal and meso-endemic. We discuss the implications for malaria control options in the Kenyan highlands.


Measuring consonant identification in nonsense syllables, words, and sentences.
Sensorineural hearing loss (SNHL) produces deficits in speech comprehension in noise that primarily are due to impairments in identifying consonants. Here, we describe the California Syllable Test (CaST) that quantifies the identification of common American English consonants. In experiment I, 16 young subjects with normal hearing identified 720 consonant-vowel-consonant (CVC) syllables in three test sessions. Consonants were identified slightly more accurately in words than nonsense syllables, and small interactions were found between the processing of initial and final consonants. Consonant-identification performance correlated strongly with sentence reception thresholds (SeRTs) measured with both the Hearing in Noise Test and QuickSIN (Etymotic Research; Elk Grove Village, Illinois). At SeRTs, subjects with normal hearing could identify 32.5% of consonants in isolated CVCs. In experiment II, a patient with moderate SNHL showed large elevations in consonant-identification thresholds and smaller elevations in SeRTs. At SeRT levels, the patient could identify only 12.5% of consonants in isolated CVCs, indicating that sentence comprehension relied disproportionately on vowel cues and semantic constraints. Consonant-profile analysis revealed disproportional impairments in identifying consonants dependent on high-frequency acoustic cues. Consonant confusion analysis revealed a reorganization of consonant per ception. The CaST is a promising tool for evaluating consonant-specific processing deficits in patients with hearing impairment.


Breastfeeding or breast milk for procedural pain in neonates.
Physiological changes brought about by pain may contribute to the development of morbidity in neonates. Clinical studies have shown reduction in the changes in physiological parameters and pain score measurements following pre-emptive analgesic administration in situations where the neonate is experiencing pain or stress. Nonpharmacological measures (such as holding, swaddling, breastfeeding) and pharmacological measures (such as acetaminophen, sucrose and opioids) have been used for this purpose. The primary objective of this review was to evaluate the effectiveness of breastfeeding or supplemental breast milk in reducing procedural pain in neonates. The secondary objective was to conduct subgroup analyses based on the type of control intervention, type of painful procedure, gestational age and the amount of supplemental breast milk given. A literature search was performed using MEDLINE (1966 - Feb 2006), EMBASE (1980 - Feb 2006), CINAHL (1982 - Feb 2006), Cochrane Central Register of Controlled Trials (Issue 4, 2005 of Cochrane Library), abstracts from the annual meetings of the Society for Pediatric Research (1994 - 2006) and major pediatric pain conference proceedings. No language restrictions were applied. Randomized or quasi-randomized controlled trials of breastfeeding or supplemental breast milk versus no treatment/other measures in neonates were eligible for inclusion in this review. The study must have reported on either physiologic markers of pain or validated pain scores. The methodological quality of the trials was assessed using the information provided in the studies and by personal communication with the authors. Data on relevant outcomes were extracted and the effect size was estimated and reported as relative risk (RR), risk difference (RD) and weighted mean difference (MD) as appropriate. Eleven eligible studies were identified. Marked heterogeneity in terms of control intervention and pain assessment measures were noted among the studies. Neonates in the breastfeeding group had statistically significantly less increase in the heart rate, reduced proportion of crying time and reduced duration of crying compared to swaddled group or pacifier group. Neonates in the breastfeeding group had a significant reduction in duration of crying compared to fasting (no intervention) group, but there was no significant difference when compared to glucose group. Premature Infant Pain Profile scores were significantly different between the breastfeeding group when compared to placebo group and the group positioned in mother's arms. However, these scores were not statistically significantly different in the breastfeeding group when compared to the no treatment group and the glucose group. Douleur Aigue Nouveau-ne scores were significantly different in the breastfeeding group when compared to the placebo group and the group positioned in mother's arms, but not when compared to the glucose group. Neonates in the supplemental breast milk group had significantly less increase in the heart rate and Neonatal Facial Coding Score compared to the placebo group. The differences in the duration of crying time and oxygen saturation change between supplemental breast milk group and the placebo group were not statistically significant. Neonates in the supplemental breast milk group had significantly higher increase in the heart rate changes and duration of crying time compared to glucose/sucrose group. No study was identified that has evaluated safety/effectiveness of repeated administration of breastfeeding or supplemental breast milk for pain relief. If available, breastfeeding or breast milk should be used to alleviate procedural pain in neonates undergoing a single painful procedure compared to placebo, positioning or no intervention. Administration of glucose/sucrose had similar effectiveness as breastfeeding for reducing pain. The effectiveness of breast milk for repeated painful procedures is not established and further research is needed. These studies should include various control interventions including glucose/ sucrose and should target preterm neonates.


Organization of visual cortex in the northern quoll, Dasyurus hallucatus: evidence for a homologue of the second visual area in marsupials.
Two visual areas, V1 and V2 (first and second visual areas), appear to be present in the posterior neocortex of all eutherian mammals investigated so far. However, previous studies have not established whether an area homologous to V2 also exists in metatherian mammals (marsupials). Using electrophysiological techniques, we mapped the visual receptive fields of neurons in the striate and peristriate cortices of the northern quoll, an Australian marsupial. We found that neurons in a 2-mm-wide strip of cortex rostrolateral to V1 form a single, relatively simple representation of the complete contralateral hemifield. This area resembles V2 of eutherians in several respects: (i) neurons in the medial half of the peristriate area represent the lower visual quadrant, whereas those in the lateral half represent the upper visual quadrant; (ii) the vertical meridian of the visual field is represented adjacent to V1, while the visual field periphery is represented along the lateral and rostrolateral borders of the peristriate area; (iii) there is a marked anisotropy in the representation, with a larger magnification factor parallel to the V1 border than perpendicular to this border; and (iv) receptive fields of multiunit clusters in the peristriate cortex are much larger than those of cells in V1 at comparable eccentricities. The cortex immediately rostral and lateral to V2 did not respond to visual stimulation under our recording conditions. These results suggest that V1 and V2 together form a 'core' of homologous visual areas, likely to exist in all therian mammals.


Co-activation of the L2 during L1 auditory processing: An ERP cross-modal priming study.
Several studies have shown that unbalanced bilinguals activate both of their languages simultaneously during L2 processing; however, evidence for L2 activation while participants are tested exclusively in their L1 has been more tenuous. Here, we investigate whether bilingual participants implicitly activate the label for a picture in their two languages, and whether labels activated in L2 can prime activation of cross-linguistically related L1 lexical targets. We tested highly proficient early Spanish-Basque bilinguals on an ERP cross-modal priming task conducted only in their L1, Spanish. Participants activated prime picture labels in both Spanish and Basque. More importantly, participants activated Basque translations of Spanish auditory targets, even in a Spanish experimental environment with no reference to Basque. Results provide strong evidence for non-selective bilingual lexical access, showing co-activation extending to lexical levels beyond phonological overlap. Our results add to the growing body of evidence for the interconnective nature of bilingual language activation.


Approaches for predicting long-term sickness absence. Re: Schouten et al. "Screening manual and office workers for risk of long-term sickness absence: cut-off points for the Work Ability Index".
We read with much interest the article of Schouten et al (1) on identifying workers with a high risk for future long-term sickness absence using the Work Ability Index (WAI). The ability to identify high-risk workers might facilitate targeted interventions for such workers and, consequently, can reduce sickness absence levels and improve workers' health. Earlier studies by both Tamela et al (2), Kant et al (3), and Lexis et al (4) have demonstrated that such an approach, based on the identification of high-risk workers and a subsequent intervention, can be effectively applied in practice to reduce sickness absence significantly. The reason for our letter on Schouten et al's article is twofold. First, by including workers already on sick leave in a study predicting long-term sick leave will result in an overestimation of the predictive properties of the instrument and biased predictors, especially when also the outcome of interest is included as a factor in the prediction model. Second, we object to the use of the term "screening" when subjects with the condition screened for are included in the study. Reinforced by the inclusion of sickness absence in the prediction model, including workers already on sick leave will shift the focus of the study findings towards the prediction of (re)current sickness absence and workers with a below-average return-to-work rate, rather than the identification of workers at high risk for the onset of future long-term sickness absence. The possibilities for prevention will shift from pure secondary prevention to a mix of secondary and tertiary prevention. As a consequence, the predictors of the model presented in the Schouten et al article can be used as a basis for tailoring neither preventive measures nor interventions. Moreover, including the outcome (sickness absence) as a predictor in the model, especially in a mixed population including workers with and without the condition (on sick leave), will result in biased predictors and an overestimation of the predictive value. A methodological approach of related issues is provided in the works of Glymour et al (5) and Hamilton et al (6). This phenomenon is even more clearly illustrated by the predictive properties of the workability index, as described by Alavinia et al (7, page 328), which reported that "when adjusted for individual characteristics, lifestyle factors, and work characteristics, two dimensions of the WAI were significant predictors for both moderate and long durations of sickness absence: (i) the presence of sickness absence in the past 12 months prior to the medical examination and (ii) experienced limitations due to health problems." So, when applied to the study by Schouten et al (1), this means that most of the predictive value would be related to the factors "sickness absence in the past 12 months". In addition, we object to the use of the term "screening" in the Schouten et al study as it includes workers with the intended outcome (long-term sickness absence). One can identify three separate aims to study the longitudinal association between risk factors and subsequent long-term sickness absence: (i) to establish causal risk factors for long-term sickness absence, often to find clues for primary preventive strategies (beyond the scope here); (ii) to identify high-risk workers who are still at work and might benefit from an intervention before sickness absence occurs (secondary prevention); and (iii) to identify workers on sick leave who might suffer a below-average return-to-work rate or have a high risk for the recurrence of (long-term) sickness absence and might benefit from intensification or optimization of the return-to-work process (tertiary prevention). In this light, one needs to separate screening instruments from predictive instruments and reserve the term "screening" for the situation as defined by Wilson and Junger (8, page 7): "The object of screening for disease is to discover those among the apparently well who are in fact suffering from disease" (ie, situations of secondary prevention). This means that, when applying this definition on long-term sickness absence under the precondition that the individuals are still at work, screening enables the identification of high-risk individuals in the early "stages" of a "disease" that can progress into long-term sickness absence. In the case of the Schouten et al study, the population at risk, as derived from their predictive instrument, consists of workers with and without sickness absence, and as such excludes the use of the term "screening" in this case. To conclude, we have substantiated that, in addition to correct usage of the term "screening", careful selection of the study population, predictors and most importantly the aim of the predictive model are essential in the process of developing predictive instruments aimed at identifying workers at high risk of long-term sickness absence. Two fundamentally different approaches are possible. One approach aims at identifying workers on sick leave with either a below-average chance to return to work an/or a high risk for a successive episode of long-term sickness absence. From a methodological and practical point of view, such an instrument should be developed and validated among workers already on sick leave. A second approach aims at identifying workers who are still at work but at high risk for future long-term sickness absence. To develop and validate such an instrument, a study sample where workers already on sick leave are excluded is a prerequisite. Such instruments fit in a pro-active approach of preventing future sickness absence, where an early intervention can be offered to those workers with an increased risk for future sickness absence.


Nanomaterials-based electrochemical immunosensors for proteins.
For this special issue on 90 years of polarography, the following personal account describes how my early research in electrochemistry and polarography in the laboratory of Prof. Petr Zuman led to a major research effort in the determination of proteins for cancer detection and monitoring. It reviews the very recent history of nanoparticle labels and multiplexed detection in protein immunosensors. It then describes our journey of discovery that has led to ultrasensitive protein immunosensors achieved by combining nanostructured electrodes with particles labeled with up to ½ million enzymes that can detect down to as little as 1 fg mL(-1) protein in diluted serum. Our most mature multiple protein detection system is a microfluidic device with eight sensors coated with 5-nm gold nanoparticles that uses off-line protein detection with heavily labeled magnetic particles. This approach has led to reliable sub pg mL(-1) detection limits for multiple proteins, provides excellent correlation with referee ELISA methods, and is currently being used for validation of panels of biomarkers for oral and prostate cancer. The article ends with a section on future perspectives.


Reliability, validity and responsiveness of the cross-culturally adapted Italian version of the core outcome measures index (COMI) for the neck.
Evaluation of the psychometric properties of a cross-culturally adapted questionnaire, the Core Outcome Measurement Index for neck pain (COMI-neck). The COMI-neck was cross-culturally adapted for the Italian language using established procedures. The following psychometric properties of the instrument were then assessed in patients with chronic neck pain undergoing rehabilitation: test-retest reliability (intraclass correlation coefficient, ICC); construct validity by comparing COMI-neck with the Neck Pain and Disability Scale, a numerical pain rating scale, and the EuroQol-Five Dimension (Pearson's correlations); and responsiveness by means of Standardized Response Mean (SRM), unpaired t tests, and Receiver Operating Characteristics (ROC) curves. The questionnaire was completed by 103 subjects. The COMI-neck summary score displayed no relevant floor or ceiling effects. Test-retest reliability was excellent (ICC = 0.87). With one exception (symptom-specific well-being), the individual COMI items and the COMI summary score correlated to the expected extent with the scores of the reference questionnaires (r = 0.40-0.80). The mean change scores for the Italian COMI-neck differed significantly between patients with a good global outcome and those with a poor outcome (p = 0.002); SRM for the good outcome group was 1.23, and for the poor outcome group 0.40. ROC analysis revealed an area under the curve of 0.73 (95% CI: 0.62-0.85). This study provides evidence that the Italian version of the COMI-neck is a valid and responsive questionnaire in the population of patients examined. Its use is recommended for clinical and research purposes.


Transcriptional dissection of human limbal niche compartments by massive parallel sequencing.
Corneal epithelium is maintained throughout life by well-orchestrated proliferation of limbal epithelial stem cells (LESCs), followed by migration and maturation centripetally towards the ocular surface. Disturbance of LESCs can potentially lead to a blinding condition, which can be reversed by reconstitution of a functional LESC pool. The current clinical procedures are effective to some degree, however, deeper knowledge of the molecular interplay within the limbal niche is necessary to achieve a fully satisfactory patient outcome. The present study was thus undertaken to carry out a comprehensive transcriptome analysis of four distinct human limbal compartments, including basal limbal crypts (BLCs), superficial limbal crypts (SLCs), cornea, and the supporting stroma, with the aid of laser capture microdissection and deep RNA sequencing. The tissue harvest pipeline was rigorously optimized so that the exposure to cold ischemia would be less than five minutes. The global gene ontology analysis confirmed existence of primitive cells in BLCs, migratory and activated cells in SLCs, and differentiated cells in cornea. Interestingly, many significantly upregulated genes in SLCs mapped to processes involved in regulation of vasculature, such as sFLT1. In contrast, BLCs exhibited many genes mapping to neurogenic processes and processes related to cell development. The primitive nature of BLCs was, furthermore, confirmed by the KEGG pathway analysis, and some potential regulators of LESCs were revealed, such as Lrig1 and SOX9. The analysis also yielded comprehensive lists of uniquely expressed genes in both BLCs and cornea, which may be useful to identify possible biomarkers. In conclusion, the current investigation provides new insight into the relationship between distinct cell populations within the limbal niche, identifies candidates to be verified for novel biological functions, and yields a wealth of information for prospective data mining.


Enhanced oxide-ion conductivity of solid-state electrolyte mesocrystals.
Oxide ion-conducting porous films were produced on a substrate by evaporation-induced self-assembly of rare earth-doped CeO2 (REDC) nanocubes 4-5 nm in size and subsequent mild calcination at 400 °C. Mesocrystalline structures comprising iso-oriented REDC nanocubes were formed by ordered assembly based on strict attachment of their {100} faces. Enhanced oxide-ion conductivities in a temperature range of 250-350 °C were observed on the mesocrystalline films consisting of Sm-doped CeO2 (SDC) nanocubes. The specific electrical properties of the mesocrystalline films are ascribed to improved surface-ion conduction due to a large specific surface area and a high crystallographic connectivity of SDC nanocubes.


Multilocus mapping of the X-linked hypophosphatemic rickets gene.
X-linked hypophosphatemic rickets (HYP), the most common form of familial hypophosphatemic (vitamin D-resistant) rickets, is an X-linked dominant disorder characterized by decreased renal tubular phosphate reabsorption and consequent hypophosphatemia. Despite the application of a wide variety of biochemical and cell biology techniques, controversy exists regarding whether a primary renal abnormality underlies the abnormal phosphate transport or if this defect is secondary to the effects of a hormonal/metabolic factor. Thus localization of the HYP gene and its ultimate cloning may be necessary to elucidate the pathophysiology of the disorder. In order to map the human HYP gene we investigated several new polymorphic probes for linkage to HYP and constructed a map of markers around the gene. The database used to ascertain linkage and perform mapping included 5 large HYP kindreds, 40 Centre d'Etudie Polymorphisms Humain reference pedigrees, and 19 kindreds which had been obtained for other disease linkage studies. Two point LOD scores (odds of linkage, log10) indicate that the probes DXS365, DXS257, DXS451, and DXS41 are tightly linked to the HYP locus. Indeed, there were no cross-overs between DXS365 and HYP with a peak LOD score of 13.98 [recombination fraction (theta) = 0.00]. Moreover, multipoint analysis reveals a probable locus order of: Xtel-DXS315-DXS43-DXS257-HYP-DXS41-DXS4 51-Xcen. The likelihood of HYP occurring between DXS257 and DXS41 is 407:1 over the next most likely position. DXS365 is located between DXS41 and DXS43 but could not be located with respect to HYP and DXS257. Regardless, we have located the HYP gene between the flanking markers DXS257 (telomeric) and DXS41 (centromeric) which are 3.5 centiMorgans apart. Thus, the results of this study will facilitate attempts to further localize and eventually clone the gene.


Molecular detection of benzimidazole resistance in Haemonchus contortus using real-time PCR and pyrosequencing.
Benzimidazoles (BZ) are widely used to treat parasitic nematode infections of humans and animals, but resistance is widespread in veterinary parasites. Several polymorphisms in beta-tubulin genes have been associated with BZ-resistance. In the present study, we investigated beta-tubulin isotype 1 sequences of 18 Haemonchus contortus isolates with varying levels of resistance to thiabendazole. The only polymorphism whose frequency was significantly increased in the resistant isolates was TTC to TAC at codon 200. Real-time PCR (using DNA from 100 third-stage larvae, L3s) and pyrosequencing (from DNA from 1000-10 000 L3s) were used to measure allele frequencies at codon 200 of these isolates, producing similar results; drug sensitivity decreased with increasing TAC frequency. Pyrosequencing was also used to measure allele frequencies at positions 167 and 198. We showed that such measurements are sufficient to assess the BZ-resistance status of most H. contortus isolates. The concordance between real-time PCR and pyrosequencing results carried out in different laboratories indicated that these tools are suitable for the routine diagnosis of BZ-resistance in H. contortus. The molecular methods were more sensitive than the 'egg hatch test', and less time-consuming than current in vivo- or in vitro-anthelmintic resistance detection methods. Thus, they provide a realistic option for routine molecular resistance testing on farms.


Conformational gating of long distance electron transfer through wire-like bridges in donor-bridge-acceptor molecules.
A series of five donor-bridge-acceptor (DBA) molecules in which the donor is tetracene, the acceptor is pyromellitimide, and the bridge molecules are oligo-p-phenylenevinylenes (OPV) of increasing length has been shown to undergo electron transfer (ET) by means of two mechanisms. When the bridge is short, strongly distance dependent superexchange dynamics dominates, whereas when the bridge is longer, bridge-assisted hopping dynamics prevails. The latter mechanism results in relatively soft distance dependence for ET in which the OPV oligomers act effectively as molecular wires. We now report studies on the critical influence that bridge dynamics have on electron transfer through these oligomers. The temperature dependence of the charge separation (CS) rates in all five molecules does not appear to obey the predictions of standard ET theories based upon the Condon approximation. All five molecules show behavior consistent with CS being "gated" by torsional motion between the tetracene donor and the first bridge phenyl ring. This is based on the near equivalence of the CS activation energies measured for all five molecules with the frequency of a known vibrational mode in 5-phenyltetracene. In the molecule containing a trans-stilbene bridge, a competition occurs between the tetracene-phenyl torsional motion and one that occurs between the vinyl group and the phenyls linked to it. This results in complex temperature-dependent CS that exhibits both activated and negatively activated regimes. The charge recombination (CR) reactions within the molecules which have the two shortest bridges, namely phenyl and trans-stilbene, show a weaker dependence on these molecular motions. The three molecules with the longest bridges all display complex temperature dependencies in both their rates of CS and CR, most likely because of the complex torsional motions, which arise from the multiple phenyl-vinyl linkages. The data show that long-distance electron transfer and therefore wire-like behavior within conjugated bridge molecules depend critically on these low-frequency torsional motions. Molecular device designs that utilize such bridges will need to address these issues.


Cell fate determination during tooth development and regeneration.
Teeth arise from sequential and reciprocal interactions between the oral epithelium and the underlying cranial neural crest-derived mesenchyme. Their formation involves a precisely orchestrated series of molecular and morphogenetic events, and gives us the opportunity to discover and understand the nature of the signals that direct cell fates and patterning. For that reason, it is important to elucidate how signaling factors work together in a defined number of cells to generate the diverse and precise patterned structures of the mature functional teeth. Over the last decade, substantial research efforts have been directed toward elucidating the molecular mechanisms that control cell fate decisions during tooth development. These efforts have contributed toward the increased knowledge on dental stem cells, and observation of the molecular similarities that exist between tooth development and regeneration.


Clinical and Immunologic Features of Ultra-Short Celiac Disease.
The clinical effects of gluten-sensitive enteropathy with villous atrophy limited to the duodenal bulb (D1) have not been delineated in adults with celiac disease. We investigated the sensitivity of D1 biopsy analysis in the detection of celiac disease, the number and sites of biopsies required to detect ultra-short celiac disease (USCD, villous atrophy limited to D1), and the clinical phenotype of USCD. We performed a prospective study of 1378 patients (mean age, 50.3 y; 62% female) who underwent endoscopy at a tertiary medical center in the United Kingdom from 2008 through 2014; routine duodenal biopsy specimens were collected from D1 and the second part of the duodenum (D2). Quadrantic D1 biopsy specimens were collected from 171 consecutive patients with a high suspicion of celiac disease (mean age, 46.5 y; 64% female). Clinical data from patients diagnosed with USCD, based on biopsy analysis, were compared with those from patients with conventional celiac disease (CCD) (villous atrophy beyond D1) and individuals without celiac disease (controls). The number of intraepithelial lymphocytes (IELs) and immune phenotypes were compared between D1 vs D2 in patients with celiac disease. Of the 1378 patients assessed, 268 (19.4%) were diagnosed with celiac disease; 9.7% of these patients had villous atrophy confined to D1 (USCD; P < .0001). Collection of a single additional biopsy specimen from any D1 site increased the sensitivity of celiac disease detection by 9.3%-10.8% (P < .0001). Patients with USCD were younger (P = .03), had lower titers of tissue transglutaminase antibody (P = .001), and less frequently presented with diarrhea (P = .001) than patients with CCD. Higher proportions of patients with CCD had ferritin deficiency (P = .007) or folate deficiency (P = .003) than patients with USCD or controls. Patients with celiac disease had a median of 50 IELs/100 enterocytes in D1 and a median of 48 IELs/100 enterocytes (P = .7) in D2. The phenotype of IELs from patients with D1 celiac disease was indistinguishable from those of patients with D2 celiac disease. Collection of a single additional biopsy specimen from any site in the D1 intestine increases the sensitivity of detection for celiac disease. Patients with USCD may have early stage or limited celiac disease, with a mild clinical phenotype and infrequent nutritional deficiencies.


A Rare Case of Sarcomatoid Carcinoma of the Lung with Spine Metastasis, Including a Literature Review.
BACKGROUND Sarcomatoid carcinoma is a rare, aggressive, malignant cancer composed of sarcoma and sarcoma-like components, and can occur in different organs such as the thyroid gland, bone, skin, breast, pancreas, liver, urinary tract, and lung. Pulmonary sarcomatoid carcinoma accounts for only a small percentage of lung cancers and has histological variants that include pleomorphic carcinoma, giant cell carcinoma, spindle cell carcinoma, carcinosarcoma, and pulmonary blastoma. CASE REPORT Here, we present a case of sarcomatoid carcinoma in a 63-year-old HIV-positive Hispanic male who presented with back pain, dry cough, and weight loss. A CT scan of his chest showed an ovoid mass in the lower lobe of the left lung, and an MRI of the spine showed a left lateral paraspinal soft tissue mass causing central canal stenosis and mild cord compression. The patient underwent laminectomy and resection of the spinal mass. A transthoracic needle biopsy of the lung and spinal masses had similar histopathology, and were indicative of sarcomatoid carcinoma. CONCLUSIONS We report a rare case of sarcomatoid carcinoma involving both the lung and spinal cord in the same patient. Sarcomatoid carcinomas of the lung have poor prognosis and are aggressive cancers. Moreover, our case also had the co-occurrence of HIV and sarcomatoid carcinoma.


Transmissive quasi-optical Ronchi phase grating for terahertz frequencies.
A transmissive, square-wave Ronchi phase grating has been fabricated from the dielectric polytetrafluoroethylene to diffract an ~0.7 THz beam quasi-optically. When illuminated by a coherent, cw terahertz (THz) source, the spot separation of the ±1 diffractive orders and the diffraction efficiency were measured as a function of THz frequency and rotation angle. The grating performance depends sensitively on the refractive index, whose value can be measured with an accuracy limited by the fabrication precision. The use of these gratings for polarization-insensitive quasi-optical imaging and phased arrays is discussed.


MexEF-OprN efflux pump exports the Pseudomonas quinolone signal (PQS) precursor HHQ (4-hydroxy-2-heptylquinoline).
Bacterial cells have evolved the capacity to communicate between each other via small diffusible chemical signals termed autoinducers. Pseudomonas aeruginosa is an opportunistic pathogen involved, among others, in cystic fibrosis complications. Virulence of P. aeruginosa relies on its ability to produce a number of autoinducers, including 4-hydroxy-2-alkylquinolines (HAQ). In a cell density-dependent manner, accumulated signals induce the expression of multiple targets, especially virulence factors. This phenomenon, called quorum sensing, promotes bacterial capacity to cause disease. Furthermore, P. aeruginosa possesses many multidrug efflux pumps conferring adaptive resistance to antibiotics. Activity of some of these efflux pumps also influences quorum sensing. The present study demonstrates that the MexEF-OprN efflux pump modulates quorum sensing through secretion of a signalling molecule belonging to the HAQ family. Moreover, activation of MexEF-OprN reduces virulence factor expression and swarming motility. Since MexEF-OprN can be activated in infected hosts even in the absence of antibiotic selective pressure, it could promote establishment of chronic infections in the lungs of people suffering from cystic fibrosis, thus diminishing the immune response to virulence factors. Therapeutic drugs that affect multidrug efflux pumps and HAQ-mediated quorum sensing would be valuable tools to shut down bacterial virulence.