Mortality and morbidity in suspected acute myocardial infarction in relation to ambulance transport.
In 681 patients admitted to the coronary care unit (CCU) at Sahlgrenska hospital between 1 May 1983 and 31 May 1984, due to suspected acute myocardial infarction (MI), the hospital mortality and morbidity were related to whether the patients were transferred to hospital by ambulance or not. In the ambulance group acute MI developed in 48% (during the first 3 days in hospital) compared with 41% in the non-ambulance group (P = 0.10). The overall mortality rate was 10.4% in the ambulance group versus 3.8% in the non-ambulance group (P = 0.001). Corresponding figures for MI patients were 19.3% versus 9.1% (P = 0.02). In all, patients referred by ambulance had larger infarcts according to maximum serum enzyme activity and a higher incidence of congestive heart failure. Similar findings were observed when MI patients were analysed separately. On the other hand, the incidence of ventricular fibrillation, requirement for lidocaine, and the course of pain was fairly similar in the two groups. In a multivariate analysis, infarct size was the major independent predictor for early mortality rate. We conclude that patients who call for an ambulance due to suspected acute MI appear to have a different early mortality and morbidity pattern compared to those who do not. The most obvious observation was a higher early mortality. These patients therefore might be the most suitable candidates for early intervention studies.


A rare case of large mediastinal germ cell tumor detected by echocardiography.
We describe a rare case of a large mediastinal germ cell tumor detected by modified views of transthoracic echocardiography. CT scanning and histological findings after tumor resection confirmed diagnosis. This case demonstrates the clinical importance of echocardiography in diagnosis of extra-cardiac masses.


Functional and Morphologic Changes of Meibomian Glands in an Asymptomatic Adult Population.
The aim of the study was to understand natural changes of meibomian glands (MG) that occur with aging in the absence of any ocular pathology or ocular discomfort symptoms, to differentiate between "age normal" and pathologic or dysfunctional changes of the MG. A total of 185 subjects (109 females) with no pre-existing ocular and systemic abnormalities were recruited and divided into four age groups: 25 to 34, 35 to 44, 45 to 54, and 55 to 66 years. At a single visit, the following MG measures were collected: meibum quality (MQ) and MG expressibility (MGE) of the lower lid, and MG drop-out score (meiboscale) using infrared meibography of the upper and lower lids. Assessments of anterior eye, tear function variables, noninvasive and invasive tear breakup time (TBUT), corneal integrity, and lid wiper epitheliopathy were also performed during the visit. An Ocular Surface Disease Index (OSDI) questionnaire was used to record dry eye symptoms. Meibum lipids samples were collected and analyzed. A majority of the study population (61%) was asymptomatic. There was a significant worsening in the MQ (P< 0.048), MGE (P < 0.03), and meiboscale (P < 0.01) with increasing age. Significant increase was observed in anterior blepharitis (P < 0.001) and telangiectasia (P< 0.02) with aging. Interestingly, tear osmolarity decreased significantly (P < 0.001), while tear meniscus height (P < 0.001) and invasive TBUT (P = 0.02) increased with increase in age. There was no significant association between MG variables and sex, ocular discomfort symptoms, or meibum lipids classes. Progressive MG loss occurs normally with age accompanied by reduced quality and quantity of the meibum produced. However, clinical presentation of ocular discomfort symptoms is stalled without corresponding disruption to tear function.


Cost-effectiveness Analysis in R Using a Multi-state Modeling Survival Analysis Framework: A Tutorial.
This tutorial provides a step-by-step guide to performing cost-effectiveness analysis using a multi-state modeling approach. Alongside the tutorial, we provide easy-to-use functions in the statistics package R. We argue that this multi-state modeling approach using a package such as R has advantages over approaches where models are built in a spreadsheet package. In particular, using a syntax-based approach means there is a written record of what was done and the calculations are transparent. Reproducing the analysis is straightforward as the syntax just needs to be run again. The approach can be thought of as an alternative way to build a Markov decision-analytic model, which also has the option to use a state-arrival extended approach. In the state-arrival extended multi-state model, a covariate that represents patients' history is included, allowing the Markov property to be tested. We illustrate the building of multi-state survival models, making predictions from the models and assessing fits. We then proceed to perform a cost-effectiveness analysis, including deterministic and probabilistic sensitivity analyses. Finally, we show how to create 2 common methods of visualizing the results-namely, cost-effectiveness planes and cost-effectiveness acceptability curves. The analysis is implemented entirely within R. It is based on adaptions to functions in the existing R package mstate to accommodate parametric multi-state modeling that facilitates extrapolation of survival curves.


Development of an Instrument for the Assessment of Health-Related Multi-sectoral Resource Use in Europe: The PECUNIA RUM.
Measuring objective resource-use quantities is important for generating valid cost estimates in economic evaluations. In the absence of acknowledged guidelines, measurement methods are often chosen based on practicality rather than methodological evidence. Furthermore, few resource-use measurement (RUM) instruments focus on the measurement of resource use in multiple societal sectors and their development process is rarely described. Thorn and colleagues proposed a stepwise approach to the development of RUM instruments, which has been used for developing cost questionnaires for specific trials. However, it remains unclear how this approach can be translated into practice and whether it is applicable to the development of generic self-reported RUM instruments and instruments measuring resource use in multiple sectors. This study provides a detailed description of the practical application of this stepwise approach to the development of a multi-sectoral RUM instrument developed within the ProgrammE in Costing, resource use measurement and outcome valuation for Use in multi-sectoral National and International health economic evaluAtions (PECUNIA) project. For the development of the PECUNIA RUM, the methodological approach was based on best practice guidelines. The process included six steps, including the definition of the instrument attributes, identification of cost-driving elements in each sector, review of methodological literature and development of a harmonized cross-sectorial approach, development of questionnaire modules and their subsequent harmonization. The selected development approach was, overall, applicable to the development of the PECUNIA RUM. However, due to the complexity of the development of a multi-sectoral RUM instrument, additional steps such as establishing a uniform methodological basis, harmonization of questionnaire modules and involvement of a broader range of stakeholders (healthcare professionals, sector-specific experts, health economists) were needed. This is the first study that transparently describes the development process of a generic multi-sectoral RUM instrument in health economics and provides insights into the methodological aspects and overall validity of its development process.


Natural history of neuroendocrine enteropancreatic tumors.
Neuroendocrine enteropancreatic tumors (NEEPTs) include tumors developing from the pancreatic islets and the duodenal loop, and those developing from gut serotonin-secreting cells (mid-gut carcinoids). When functioning, they are rare tumors with frequently inconsistant clinical and biological characteristics. Provocative dynamic tests are very useful. Their natural history, with the exception of insulinomas and mid-gut carcinoids, is still incompletely known due to their rarity, relatively recent description, slow evolution and the absence of definitive reliable markers for prognosis. The following factors affect the natural history of NEEPTs. (1) Inclusion or not within the spectrum of multiple endocrine neoplasia type-1 (MEN1), such an integration often dramatically modifies the management strategy. In patients with MEN1, NEEPTs are often multiple, diffusely spread in the duodenopancreatic area and of small size. Definite cure by surgery is then very scarce. Mid-gut carcinoid tumors are the most protean NEEPTs. In contrast to appendiceal carcinoids, usually with a benign course, mid-gut carcinoids have a more malignant course and are very common indeed: local transmural invasion, early metastasis to lymph nodes and/or liver, and symptoms from hormone oversecretion. Carcinoid syndrome is usually well controlled by long-acting somatostatin analogs. (2) Disease spreading, i.e. liver and bone metastases, are the major causes of death in patients with NEEPTs. Liver metastases (LMs) are synchronous in about 75% of the patients with LMs but may develop during follow-up (about 25% of the patients with LMs were without LMs at the initial evaluation). Development of bone metastases has a very poor prognosis accompanying LM progression.


Association of Pre-End-Stage Renal Disease Hemoglobin with Early Dialysis Outcomes.
Incident hemodialysis patients have a high mortality risk within the first months after dialysis initiation. Pre-end-stage renal disease (ESRD) factors like anemia management may impact early post-ESRD outcomes. Therefore, we evaluated the impact of pre-ESRD hemoglobin (Hgb) and pre-ESRD Hgb slope on post-ESRD mortality and hospitalization outcomes. The study included 31,472 veterans transitioning to ESRD. Using Cox and negative binomial regression models, we evaluated the association of pre-ESRD Hgb and Hgb slope with 12-month post-ESRD all-cause and cardiovascular mortality and hospitalization rates using 4 levels of hierarchical multivariable adjustment, including erythropoietin use and kidney decline in slope models. The cohort was 2% female, 30% African-American, and on average 68 ± 11 years old. Compared to Hgb 10-< 11 g/dL, both low (< 10 g/dL) and high (≥12 g/dL) levels were associated with higher all-cause mortality after full adjustment (HR 1.25 [95% CI 1.15-1.35] and 1.09 [95% CI 1.02-1.18], respectively). Similarly, Hgb exhibited a U-shaped association with CV mortality, while only lower Hgb was associated with a higher hospitalization rate. Neither an annual pre-ESRD decline in Hgb nor increase was associated with higher post-ESRD mortality risk after adjustment for kidney decline. However, we observed a modest J-shaped association between pre-ESRD Hgb slope and post-ESRD hospitalization rate. Lower and higher pre-ESRD Hgb levels are associated with a higher risk of early post-ESRD mortality, while there was no association between the pre-ESRD slope and mortality. An increase in pre-ESRD Hgb slope was associated with higher risk of post-ESRD hospitalization. Additional studies aimed at anemia management prior to ESRD transition are warranted.


The impact of postoperative complications on the administration of adjuvant therapy following pancreaticoduodenectomy for adenocarcinoma.
The impact of postoperative complications on the administration of adjuvant therapy following pancreaticoduodenectomy (PD) for adenocarcinoma is still unclear. A retrospective review of all patients undergoing PD at our institution between 1995 and 2011 was performed. Clinicopathological data, including Clavien-Dindo complication grade, time to adjuvant therapy (TTA), and survival, were analyzed. A total of 1,144 patients underwent PD for adenocarcinoma between 1995 and 2011. The overall complication rate was 49.1 % and clinically severe complications (≥IIIb) occurred in 4.2 %. Overall, 621 patients (54.3 %) were known to have received adjuvant therapy. The median TTA was 60 days. Although the presence of a complication was associated with a delay in TTA (p = 0.002), the grade of complication was not (p = 0.112). On multivariate analysis, only age > 68 years (p < 0.001) and length of stay >9 days (p = 0.002) correlated with no adjuvant therapy. Patients with postoperative complications were more likely to receive single adjuvant chemotherapy or radiation therapy (31.4 %) than were patients without complications (17.1 %; p < 0.001). Patients without a complication had a longer median survival compared with patients who experienced complications (19.5 vs. 16.1 months; p = 0.001). Patients without complications who received adjuvant therapy had longer median survival than patients with complications who received no adjuvant therapy (22.5 vs. 10.7 months; p < 0.001). Multivariate analysis demonstrated that complications [hazard ratio (HR) 1.16; p = 0.023] and adjuvant therapy (HR 0.67; p < 0.001) were related to survival. Complications and no adjuvant therapy are common following PD for adenocarcinoma. Postoperative complications delay TTA and reduce the likelihood of multimodality adjuvant therapy. Identifying patients at increased risk for complications and those unlikely to receive adjuvant therapy warrants further investigation as they may benefit from a neoadjuvant approach.


Evaluation of Parallel Coordinates: Overview, Categorization and Guidelines for Future Research.
The parallel coordinates technique is widely used for the analysis of multivariate data. During recent decades significant research efforts have been devoted to exploring the applicability of the technique and to expand upon it, resulting in a variety of extensions. Of these many research activities, a surprisingly small number concerns user-centred evaluations investigating actual use and usability issues for different tasks, data and domains. The result is a clear lack of convincing evidence to support and guide uptake by users as well as future research directions. To address these issues this paper contributes a thorough literature survey of what has been done in the area of user-centred evaluation of parallel coordinates. These evaluations are divided into four categories based on characterization of use, derived from the survey. Based on the data from the survey and the categorization combined with the authors' experience of working with parallel coordinates, a set of guidelines for future research directions is proposed.


COX-derived prostanoid pathways in gastrointestinal cancer development and progression: novel targets for prevention and intervention.
Arachidonic acid metabolism through cyclooxygenase (COX) pathways leads to the generation of biologically active eicosanoids. Eicosanoid expression levels vary during development and progression of gastrointestinal (GI) malignancies. COX-2 is the major COX-isoform responsible for G.I. cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic NSAID use reduces the risk of cancer development, while both incidence and risk of death due to G.I. cancers were significantly reduced by daily aspirin intake. A number of randomized controlled trials (APC trial, Prevention of Sporadic Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective COX-2 inhibitors. However, chronic use of selective COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signaling have been investigated in cancer development/progression. PGE(2), which binds to both EP and PPAR receptors, is the major prostanoid implicated in the carcinogenesis of G.I. cancers. The role of TXA(2) in G.I. cancers has also been examined, although further studies are required to uncover its role in carcinogenesis. Other prostanoids investigated include PGD(2) and its metabolite 15d-PGJ2, PGF(1α) and PGI(2). Targeting these prostanoids in G.I. cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-tumor reactivity. A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I. cancers. In this review, we will discuss the role of the COX-derived prostanoids in G.I. cancer development and progression. Targeting these downstream prostanoids for chemoprevention and/or treatment of G.I. cancers will also be discussed. Finally, we will highlight the latest pre-clinical technologies as well as avenues for future investigation in this highly topical research field.


Glycoprotein asporin as a novel player in tumour microenvironment and cancer progression.
Small leucine rich proteoglycans (SLRPs), major non-collagen components of the extracellular matrix (ECM), have multiple biological roles with diverse effects. Asporin, a member of the SLRPs class I, competes with other molecules in binding to collagen and affects its mineralization. Its role in cancer is only now being elucidated. The PubMed online database was used to search relevant reviews and original articles. Furthermore, altered asporin expression was analysed in publicly available genome-wide expression data at the Gene Expression Omnibus database. Polymorphisms in the N-terminal polyaspartate domain, which binds calcium, are associated with osteoarthritis and prostate cancer. Asporin also promotes the progression of scirrhous gastric cancer where it is required for coordinated invasion by cancer associated fibroblasts and cancer cells. Besides the enhanced expression of asporin observed in multiple cancer types, such as breast, prostate, gastric, pancreas and colon cancer, tumour suppressive effects of asporin were described in triple-negative breast cancer. We also discuss a number of factors modulating asporin expression in different cell types relevant for alterations toing the tumour microenvironment. The apparent contradicting tumour promoting and suppressive effects of asporin require further investigation. Deciphering the role of asporin and other SLRPs in tumour-stroma interactions is needed for a better understanding of cancer progression and potentially also for novel tumour microenvironment based therapies.


Neuroanatomical and neuropsychological correlates of the cerebellum in children with attention-deficit/hyperactivity disorder--combined type.
Studies of healthy individuals and those with cerebellar damage have implicated the cerebellum in a variety of cognitive and behavioral processes. Decreased cerebellar volume has been found in children with attention-deficit/hyperactivity disorder (ADHD) and differentially related to behavioral outcomes. The present study investigated whether smaller cerebellar vermis volume was present in children with ADHD-combined type (ADHD-C) compared with controls and whether volume related to parent- and teacher-reported levels of ADHD symptomatology. T1-weighted magnetic resonance images and parent- and teacher-reported ADHD symptoms were acquired for 32 children diagnosed with ADHD-C and 15 typically developing controls. Participants were right-handed, had no comorbid diagnoses of learning disabilities, conduct disorder, or affective/mood disorder, and were 9 to 15 years of age. Participants with ADHD-C showed significantly smaller volume in the posterior inferior vermis compared with controls. No statistically significant differences were observed for cerebral volume, anterior vermis volume, posterior superior volume, or total cerebellar volume. Regression analyses indicated that a significant amount of the variance in parent-reported Behavior Assessment System for Children, Second Edition, Hyperactivity and Attention and Conners Restless/Impulsive ratings was explained by volume of the posterior inferior vermis. Consistent with previous studies, children with ADHD had smaller volume in the posterior inferior vermis. New findings emerged with smaller volume of the posterior inferior vermis predicting a significant amount of the variance in parent-reported hyperactivity, attention, and restlessness/impulsivity. Thus, symptoms of hyperactivity and inattention in ADHD may be partly explained by smaller volume of the cerebellar vermis and its connections within the cerebrum.


Treatment of a thoracic dural-pleural fistula with a vascularized omental flap: a case report.
Case report. To report an unusual case of pseudomeningocele with dural-pleural fistula formation and spinal cord herniation after anterior thoracic decompression, as well as a unique surgical method for treating this complication. Thoracic pseudomeningocele with fistula formation is a rare but serious complication of spinal surgery. The negative pressure environment created in the pleural space can complicate management and result in dural-plural fistula formation. We report on the use of a vascularized omental flap to treat this complication after failure of more traditional techniques. A 76-year-old man presented with complaints of myeloradiculopathy, including weakness of lower extremities, with gait and bowel and bladder dysfunction after 2 previous decompressions at the T6-T7 level. Revision surgery was complicated by a dural-plural fistula and spinal cord herniation with neurological deterioration requiring reoperation. Treatment with vascularized omental flap successfully treated the fistula, and the patient had resolution of all symptoms with the exception of some lower extremity neuropathic pain. Postoperative imaging showed excellent decompression of the spinal canal and a small, stable pseudomeningocele without evidence of cerebrospinal fluid hypotension or active dural-pleural fistula. Treatment of thoracic psuedomeningoceles and fistulas can be difficult due to the unique negative intrathoracic pressure environment that complicates closure using traditional methods. Alternative treatment options may be necessary when more traditional techniques fail. Our report highlights one such option, a vascularized omental flap, which was used to successfully treat the patient.


On measuring the acoustic state changes in lipid membranes using fluorescent probes.
Ultrasound is increasingly being used to modulate the properties of biological membranes for applications in drug delivery and neuromodulation. While various studies have investigated the mechanical aspects of the interaction such as acoustic absorption and membrane deformation, it is not clear how these effects transduce into biological functions, for example, changes in the permeability or the enzymatic activity of the membrane. A critical aspect of the activity of an enzyme is the thermal fluctuations of its solvation or hydration shell. Thermal fluctuations are also known to be directly related to membrane permeability. Here solvation shell changes of lipid membranes subject to an acoustic impulse were investigated using a fluorescence probe, Laurdan. Laurdan was embedded in multi-lamellar lipid vesicles in water, which were exposed to broadband pressure impulses of the order of 1 MPa peak amplitude and 10 µs pulse duration. An instrument was developed to monitor changes in the emission spectrum of the dye at two wavelengths with sub-microsecond temporal resolution. The experiments show that changes in the emission spectrum, and hence the fluctuations of the solvation shell, are related to the changes in the thermodynamic state of the membrane and correlated with the compression and rarefaction of the incident sound wave. The results suggest that acoustic fields affect the state of a lipid membrane and therefore can potentially modulate the kinetics of channels and enzymes embedded in the membrane.


Water-soluble precursors of beef flavour. Part II: Effect of post-mortem conditioning.
Changes in glycolytic metabolites, nucleotide degradation products, free amino acids and other amino compounds were monitored in beef muscle (M. longissimus lumborum), stored for 21days at 4°C, in order to evaluate how post-mortem conditioning may affect flavour formation in beef. The major effects observed in sugar-related substances were the dephosphorylation of the phosphates of glucose, fructose and mannose, to yield their free sugars, as well as the breakdown of inosine 5'-monophosphate, to give a sixfold increase in ribose. Total reducing sugars increased by only 15% during conditioning, while glycogen levels remained unchanged from 2days post-slaughter. Free amino acids increased during conditioning, particularly between days 7 and 14. Phenylalanine, methionine, lysine, leucine and isoleucine were the amino acids showing the greatest increase with conditioning time, with methionine, in particular, showing a sevenfold increase during the conditioning period. The effects of these precursor changes on cooked beef flavour are discussed.


[Life in imperial Rome: new data from recent excavations in Suburbium].
One of the goals of the anthropological research of the Anthropological Service of the Archaeological Superintendence of Rome is to reconstruct the hygienic-environmental living conditions of the ancient populations in Imperial Age. We considered some not specific pointers of stress in four necropolis, that are excavated in the last years in the Suburbium. In particular Harris's lines, porotic hyperostosis and enamel hypoplasia are been considered. Two shape of research have been lead: (a) an analysis of the frequencies of the three factors on the data from a single necropolis and (b) a comparison between enamel hypoplasia and porotic hyperostosis. The distributions of such alterations indicates the presence of light stresses.


Hyponatremia in Cirrhosis: An Update.
Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and portal hypertension leads to splanchnic vasodilation, and this leads to the activation of compensatory mechanisms such as renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and antidiuretic hormone (ADH) to ameliorate low circulatory volume. The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume, resulting in the development of ascites. These compensatory mechanisms lead to impairment of the kidneys to eliminate solute-free water in decompensated cirrhosis. Nonosmotic secretion of antidiuretic hormone (ADH), also known as arginine vasopressin, further worsens excess water retention and thereby hyponatremia. The management of hyponatremia in this setting is a challenge as conventional therapies for hyponatremia including fluid restriction and correction of hypokalemia are frequently inefficacious. In this review, we discuss the pathophysiology, complications, and various treatment modalities, including albumin infusion, selective vasopressin receptor antagonists, or hypertonic saline for patients with severe hyponatremia and those awaiting liver transplantation.


Impact of Powdery Mildew and Leaf Rust on Milling and Baking Quality of Soft Red Winter Wheat.
Changes in milling and baking quality (especially flour yield) of soft red winter wheat can have a large economic impact on flour mills. To determine the relationship between early-season powdery mildew and late-season leaf rust on flour yield, flour protein, alkaline water retention capacity, and kernel texture (softness equivalent), a study was conducted over 2 years at Kinston and Plymouth, NC. Different levels of powdery mildew and leaf rust developed on three winter wheat cultivars that varied in levels of disease resistance, the presence of seed treatment, and the presence and timing of foliar fungicide application. In Kinston and Plymouth in 1989-90, where leaf rust occurred early, the softness equivalent score was lower in wheat grown from seed treated with triadimenol. The following year, when the leaf rust epidemic increased later, foliar fungicide application reduced disease and resulted in lower softness equivalent scores in both Plymouth and Kinston for cv. Saluda and in Kinston for cv. Coker 983. A regression model was developed to describe the relationship between the log of the area under the disease progress curves and adjusted flour yield (AFY). The AFY of Saluda was reduced in the presence of powdery mildew such that %AFY = 103.96 - 0.92 (log AUMPC).


Endothelial function is impaired in HIV-infected patients with lipodystrophy.
Data supporting a link between body-fat distribution changes and cardiovascular disease risk in HIV-infected patients are scarce and contradictory. We evaluated endothelial dysfunction, an early event in the development of atherosclerosis, and pro-atherosclerotic plasma biomarkers in HIV-infected patients with lipodystrophy. HIV-infected patients with and without lipodystrophy were prospectively enrolled. Endothelial function was measured through flow-mediated dilatation (FMD) of the brachial artery. Plasma levels of several biomarkers of inflammation, endothelial activation and coagulation associated with adipose tissue and endothelial dysfunction were determined. The study included 110 patients, 55 of them with lipodystrophy. FMD was significantly lower in patients with lipodystrophy than in those without lipodystrophy (median [IQR] 3.1% [0.4-8.9] versus 6.3% [3.3-10.7]; P=0.004). Patients with isolated lipoatrophy exhibited the lowest FMD (2.6% [0-6.6]; P(Kruskal-Wallis)=0.02). Lipodystrophy was associated with significantly higher plasma levels of interleukin 6 (IL-6) and plasminogen activator inhibitor 1 (PAI-1) and lower levels of adiponectin; severe lipodystrophy was associated with higher concentrations of vascular cell adhesion molecule 1 (sVCAM-1). There was an inverse correlation between FMD and IL-6 (Spearman's rho =-0.26; P=0.007). In a multivariate regression model with the lowest quartile of FMD as the dependent variable and lipodystrophy, traditional cardiovascular risk factors, 10-year Framingham risk score, pro-atherosclerotic biomarkers and HIV-related variables as predictors, the only independent predictor of endothelial dysfunction was lipodystrophy (odds ratio 5.22, 95% confidence interval 1.76-15.46; P=0.003). Lipodystrophy is associated with endothelial dysfunction, independently of the presence of traditional cardiovascular risk factors. This finding and the accompanying profile of pro-atherosclerotic biomarkers support an increased cardiovascular risk in HIV-infected patients with lipodystrophy.


Mucoid-to-nonmucoid conversion in alginate-producing Pseudomonas aeruginosa often results from spontaneous mutations in algT, encoding a putative alternate sigma factor, and shows evidence for autoregulation.
The mucoid phenotype is common among strains of Pseudomonas aeruginosa that cause chronic pulmonary infections in patients with cystic fibrosis and is due to overproduction of an exopolysaccharide called alginate. However, the mucoid phenotype is unstable in vitro, especially when the cells are incubated under low oxygen tension. Spontaneous conversion to the nonmucoid form is typically due to mutations (previously called algS) that are closely linked to the alginate regulatory gene algT, located at 68 min on the chromosome. Our sequence analysis of algT showed that its 22-kDa gene product shares homology with several alternate sigma factors in bacteria, suggesting that AlgT (also known as AlgU) interacts directly with RNA polymerase core to activate the promoters of alginate genes. AlgT showed striking sequence similarity (79%) to sigma E of Escherichia coli, an alternate sigma factor involved in high-temperature gene expression. Our analysis of the molecular basis for spontaneous conversion from mucoid to nonmucoid, in the cystic fibrosis isolate FRD, revealed that nonmucoid conversion was often due to one of two distinct missense mutations in algT that occurred at codons 18 and 29. RNase protection assays showed that spontaneous nonmucoid strains with the algT18 and algT29 alleles have a four- to fivefold reduction in the accumulation of algT transcripts compared with the wild-type mucoid strain. Likewise, a plasmid-borne algT-cat transcriptional fusion was about 3-fold less active in the algT18 and algT29 backgrounds compared with the mucoid wild-type strain, and it was 20-fold less active in an algT::Tn501 background. These data indicate that algT is autoregulated. The spontaneous algT missense alleles also caused about fivefold-reduced expression of the adjacent negative regulator, algN (also known as mucB). Transcripts of algN were essentially absent in the algT::Tn501 strain. Thus, algT regulates the algTN cluster, and the two genes may be cotranscribed. A primer extension analysis showed that algT transcription starts 54 bp upstream of the start of translation. Although the algT promoter showed little similarity to promoters recognized by the vegetative sigma factor, it was similar to the algR promoter. This finding suggests that AlgT may function as a sigma factor to activate its own promoter and those of other alginate genes. The primer extension analysis also showed that algT transcripts were readily detectable in the typical nonmucoid strain PAO1, which was in contrast to a weak signal seen in the algT18 mutant of FRD. A plasmid-borne algT gene in PAO1 resulted in both the mucoid phenotype and high levels of algT transcripts, further supporting the hypothesis that AlgT controls its own gene expression and expression of genes of the alginate regulon.


Tumor necrosis factor stimulates fibroblast growth factor 23 levels in chronic kidney disease and non-renal inflammation.
Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis, and its early rise in patients with chronic kidney disease is independently associated with all-cause mortality. Since inflammation is characteristic of chronic kidney disease and associates with increased plasma FGF23 we examined whether inflammation directly stimulates FGF23. In a population-based cohort, plasma tumor necrosis factor (TNF) was the only inflammatory cytokine that independently and positively correlated with plasma FGF23. Mouse models of chronic kidney disease showed signs of renal inflammation, renal FGF23 expression and elevated systemic FGF23 levels. Renal FGF23 expression coincided with expression of the orphan nuclear receptor Nurr1 regulating FGF23 in other organs. Antibody-mediated neutralization of TNF normalized plasma FGF23 and suppressed ectopic renal Fgf23 expression. Conversely, TNF administration to control mice increased plasma FGF23 without altering plasma phosphate. Moreover, in Il10-deficient mice with inflammatory bowel disease and normal kidney function, plasma FGF23 was elevated and normalized upon TNF neutralization. Thus, the inflammatory cytokine TNF contributes to elevated systemic FGF23 levels and also triggers ectopic renal Fgf23 expression in animal models of chronic kidney disease.


A review of quantitative structure-property relationships for the fate of ionizable organic chemicals in water matrices and identification of knowledge gaps.
Many organic chemicals are ionizable by nature. After use and release into the environment, various fate processes determine their concentrations, and hence exposure to aquatic organisms. In the absence of suitable data, such fate processes can be estimated using Quantitative Structure-Property Relationships (QSPRs). In this review we compiled available QSPRs from the open literature and assessed their applicability towards ionizable organic chemicals. Using quantitative and qualitative criteria we selected the 'best' QSPRs for sorption, (a)biotic degradation, and bioconcentration. The results indicate that many suitable QSPRs exist, but some critical knowledge gaps remain. Specifically, future focus should be directed towards the development of QSPR models for biodegradation in wastewater and sediment systems, direct photolysis and reaction with singlet oxygen, as well as additional reactive intermediates. Adequate QSPRs for bioconcentration in fish exist, but more accurate assessments can be achieved using pharmacologically based toxicokinetic (PBTK) models. No adequate QSPRs exist for bioconcentration in non-fish species. Due to the high variability of chemical and biological species as well as environmental conditions in QSPR datasets, accurate predictions for specific systems and inter-dataset conversions are problematic, for which standardization is needed. For all QSPR endpoints, additional data requirements involve supplementing the current chemical space covered and accurately characterizing the test systems used.


Low-grade B-Cell lymphomas with plasmacytic differentiation lack PAX5 gene rearrangements.
The chromosomal translocation t(9;14)(p13;q32) has been reported in association with lymphoplasmacytic lymphoma (LPL). Although this translocation involving the paired homeobox-5 (PAX5) gene at chromosome band 9p13 and the immunoglobulin heavy chain (IgH) gene at 14q32 has been described in approximately 50% of LPL cases, the actual number of cases studied is quite small. Many of the initial cases associated with t(9;14)(p13;q32) were actually low-grade B-cell lymphomas with plasmacytic differentiation other than LPL. Thus, we analyzed a series of low-grade B-cell lymphomas for PAX5 gene rearrangements. We searched records from the Department of Pathology, Stanford University Medical Center for low-grade B-cell lymphomas, with an emphasis on plasmacytic differentiation, that had available paraffin blocks or frozen tissue. We identified 37 cases, including 13 LPL, 18 marginal zone lymphomas (nodal, extranodal, splenic, and alpha-heavy chain disease), and 6 small lymphocytic lymphomas. A novel dual-color break-apart bacterial artificial chromosome probe was designed to flank the PAX5 gene, spanning previously described PAX5 breakpoints, and samples were analyzed by interphase fluorescence in situ hybridization. All cases failed to demonstrate a PAX5 translocation, indicating that t(9;14)(p13;q32) and other PAX5 translocations are uncommon events in low-grade B-cell lymphomas with plasmacytic differentiation. This study also confirms recent reports that found an absence of PAX5 rearrangements in LPL, suggesting the reassessment of PAX5 rearrangements in LPL.


Enhancing cognitive and social-emotional development through a simple-to-administer mindfulness-based school program for elementary school children: a randomized controlled trial.
The authors hypothesized that a social and emotional learning (SEL) program involving mindfulness and caring for others, designed for elementary school students, would enhance cognitive control, reduce stress, promote well-being and prosociality, and produce positive school outcomes. To test this hypothesis, 4 classes of combined 4th and 5th graders (N = 99) were randomly assigned to receive the SEL with mindfulness program versus a regular social responsibility program. Measures assessed executive functions (EFs), stress physiology via salivary cortisol, well-being (self-reports), prosociality and peer acceptance (peer reports), and math grades. Relative to children in the social responsibility program, children who received the SEL program with mindfulness (a) improved more in their cognitive control and stress physiology; (b) reported greater empathy, perspective-taking, emotional control, optimism, school self-concept, and mindfulness, (c) showed greater decreases in self-reported symptoms of depression and peer-rated aggression, (d) were rated by peers as more prosocial, and (e) increased in peer acceptance (or sociometric popularity). The results of this investigation suggest the promise of this SEL intervention and address a lacuna in the scientific literature-identifying strategies not only to ameliorate children's problems but also to cultivate their well-being and thriving. Directions for future research are discussed.


COP I domains required for coatomer integrity, and novel interactions with ARF and ARF-GAP.
We performed a systematic mapping of interaction domains on COP I subunits to gain novel insights into the architecture of coatomer. Using the two-hybrid system, we characterize the domain structure of the alpha-, beta'-, epsilon-COP and beta-, gamma-, delta-, zeta-COP coatomer subcomplexes and identify links between them that contribute to coatomer integrity. Our results demonstrate that the domain organization of the beta-, gamma-, delta-, zeta-COP subcomplex and AP adaptor complexes is related. Through in vivo analysis of alpha-COP truncation mutants, we characterize distinct functional domains on alpha-COP. Its N-terminal WD40 domain is dispensable for yeast cell viability and overall coatomer function, but is required for KKXX-dependent trafficking. The last approximately 170 amino acids of alpha-COP are also non-essential for cell viability, but required for epsilon-COP incorporation into coatomer and maintainance of normal epsilon-COP levels. Further, we demonstrate novel direct interactions of coatomer subunits with regulatory proteins: beta'- and gamma-COP interact with the ARF-GTP-activating protein (GAP) Glo3p, but not Gcs1p, and beta- and epsilon-COP interact with ARF-GTP. Glo3p also interacts with intact coatomer in vitro.


Structural analyses of gp45 sliding clamp interactions during assembly of the bacteriophage T4 DNA polymerase holoenzyme. I. Conformational changes within the gp44/62-gp45-ATP complex during clamp loading.
A multisubunit ring-shaped protein complex is used to tether the polymerase to the DNA at the primer-template junction in most DNA replication systems. This "sliding clamp" interacts with the polymerase, completely encircles the DNA duplex, and is assembled onto the DNA by a specific clamp loading complex in an ATP-driven process. Site-specific mutagenesis has been used to introduce single cysteine residues as reactive sites for adduct formation within each of the three subunits of the bacteriophage T4-coded sliding clamp complex (gp45). Two such mutants, gp45S19C and gp45K81C, are reacted with the cysteine-specific photoactivable cross-linker TFPAM-3 and used to track the changes in the relative positioning of the gp45 subunits with one another and with the other components of the clamp loading complex (gp44/62) in the various stages of the loading process. Cross-linking interactions performed in the presence of nucleotide cofactors show that ATP binding and hydrolysis, interaction with primer-template DNA, and release of ADP all result in significant conformational changes within the clamp loading cycle. A structural model is presented to account for the observed rearrangements of intersubunit contacts within the complex during the loading process.


[Hypertensive vasculopathy as a causative factor of normal pressure hydrocephalus--a clinical analysis (author's transl)].
Eighteen subjects, who were diagnosed as idiopathic normal pressure hydrocephalus in our outer patient clinic, were undergone with CT scan, metrizamide CT cisternography (CTC), radioisotope cisternography (RIC), and they were classified into 3 groups in accordance with ischemic score which had been proposed by Hachinski. Ventriculoperitoneal shunt was performed in 17 subjects, but improvement of the symptoms were obtained only in five. Dementia, gait disturbance and urinary incontinence were common features among the ones who had clinical improvement after shunt and the ones who had not, but systemic arterial hypertension and focal ischemic signs were more frequently found in formers than in latters. The subjects with low ischemic score were classified into Group 1, and the one with high ischemic score were classified into Group 2 and the other one with moderate score were into Group 3. The subjects who had clinical improvement postoperatively were exclusively found in Group 2 and 3. If the degree of ischemic score has good correlation with actual existence of cerebral ischemic lesions, we might suspect from our data that systemic arterial hypertension and ischemic lesion of the cerebrum might be basic pathologies which develop an idiopathic normal pressure hydrocephalus.


Three-Dimensional Growth of Prostate Cancer Cells Exposed to Simulated Microgravity.
Prostate cancer metastasis has an enormous impact on the mortality of cancer patients. Factors involved in cancer progression and metastasis are known to be key players in microgravity (µg)-driven three-dimensional (3D) cancer spheroid formation. We investigated PC-3 prostate cancer cells for 30 min, 2, 4 and 24 h on the random positioning machine (RPM), a device simulating µg on Earth. After a 24 h RPM-exposure, the cells could be divided into two groups: one grew as 3D multicellular spheroids (MCS), the other one as adherent monolayer (AD). No signs of apoptosis were visible. Among others, we focused on cytokines involved in the events of metastasis and MCS formation. After 24 h of exposure, in the MCS group we measured an increase in ACTB, MSN, COL1A1, LAMA3, FN1, TIMP1, FLT1, EGFR1, IL1A, IL6, CXCL8, and HIF1A mRNA expression, and in the AD group an elevation of LAMA3, COL1A1, FN1, MMP9, VEGFA, IL6, and CXCL8 mRNAs compared to samples subjected to 1 g conditions. Significant downregulations in AD cells were detected in the mRNA levels of TUBB, KRT8, IL1B, IL7, PIK3CB, AKT1 and MTOR after 24 h. The release of collagen-1α1 and fibronectin protein in the supernatant was decreased, whereas the secretion of IL-6 was elevated in 24 h RPM samples. The secretion of IL-1α, IL-1β, IL-7, IL-2, IL-8, IL-17, TNF-α, laminin, MMP-2, TIMP-1, osteopontin and EGF was not significantly altered after 24 h compared to 1 g conditions. The release of soluble factors was significantly reduced after 2 h (IL-1α, IL-2, IL-7, IL-8, IL-17, TNF-α, collagen-1α1, MMP-2, osteopontin) and elevated after 4 h (IL-1β, IL-2, IL-6, IL-7, IL-8, TNF-α, laminin) in RPM samples. Taken together, simulated µg induced 3D growth of PC-3 cancer cells combined with a differential expression of the cytokines IL-1α, IL-1β, IL-6 and IL-8, supporting their involvement in growth and progression of prostate cancer cells.


Detection of human brain cancer infiltration ex vivo and in vivo using quantitative optical coherence tomography.
More complete brain cancer resection can prolong survival and delay recurrence. However, it is challenging to distinguish cancer from noncancer tissues intraoperatively, especially at the transitional, infiltrative zones. This is especially critical in eloquent regions (for example, speech and motor areas). This study tested the feasibility of label-free, quantitative optical coherence tomography (OCT) for differentiating cancer from noncancer in human brain tissues. Fresh ex vivo human brain tissues were obtained from 32 patients with grade II to IV brain cancer and 5 patients with noncancer brain pathologies. On the basis of volumetric OCT imaging data, pathologically confirmed brain cancer tissues (both high- and low-grade) had significantly lower optical attenuation values at both cancer core and infiltrated zones when compared with noncancer white matter, and OCT achieved high sensitivity and specificity at an attenuation threshold of 5.5 mm(-1) for brain cancer patients. We also used this attenuation threshold to confirm the intraoperative feasibility of performing in vivo OCT-guided surgery using a murine model harboring human brain cancer. Our OCT system was capable of processing and displaying a color-coded optical property map in real time at a rate of 110 to 215 frames per second, or 1.2 to 2.4 s for an 8- to 16-mm(3) tissue volume, thus providing direct visual cues for cancer versus noncancer areas. Our study demonstrates the translational and practical potential of OCT in differentiating cancer from noncancer tissue. Its intraoperative use may facilitate safe and extensive resection of infiltrative brain cancers and consequently lead to improved outcomes when compared with current clinical standards.


The attenuated spline reconstruction technique for single photon emission computed tomography.
We present the attenuated spline reconstruction technique (aSRT) which provides an innovative algorithm for single photon emission computed tomography (SPECT) image reconstruction. aSRT is based on an analytic formula of the inverse attenuated Radon transform. It involves the computation of the Hilbert transforms of the linear attenuation function and of two sinusoidal functions of the so-called attenuated sinogram These computations are achieved by employing the attenuation information provided by computed tomography (CT) scans and by utilizing custom-made cubic spline interpolation. The purpose of this work is: (i) to present the mathematics of aSRT, (ii) to reconstruct simulated and real SPECT/CT data using aSRT and (iii) to evaluate aSRT by comparing it to filtered backprojection (FBP) and to ordered subsets expectation minimization (OSEM) reconstruction algorithms. Simulation studies were performed by using an image quality phantom and an appropriate attenuation map. Reconstructed images were generated for 45, 90 and 180 views over 360 degrees with 20 realizations and involved Poisson noise of three different levels (NL), namely 100% (NL1), 50% (NL2) and 10% (NL3) of the total counts, respectively. Moreover, real attenuated SPECT sinograms were reconstructed from a real study of a Jaszczak phantom, as well as from a real clinical myocardial SPECT/CT study. Comparisons between aSRT, FBP and OSEM reconstructions were performed using contrast, bias and image roughness. The results suggest that aSRT can efficiently produce accurate attenuation-corrected reconstructions for simulated and real phantoms, as well as for clinical data. In particular, in the case of the clinical myocardial study, aSRT produced reconstructions with higher cold contrast than both FBP and OSEM. aSRT, by incorporating the attenuation correction within itself, may provide an improved alternative to FBP. This is particularly promising for 'cold' regions as those occurring in myocardial ischaemia.


Therapy of human transitional cell carcinoma of the bladder by oral administration of the epidermal growth factor receptor protein tyrosine kinase inhibitor 4,5-dianilinophthalimide.
Epidermal growth factor receptor (EGF-R), a transmembrane glycoprotein that mediates the mitogenic response of cells to epidermal growth factor, is highly expressed on malignant human bladder cancer cells. The 4,5-dianilinophthalimides represent a novel class of inhibitors of the EGF-R family of tyrosine kinase with selectivity at the enzymatic and cellular levels. Two compounds of this class, CGP 54211 and CGP 53353, inhibited tyrosine kinase activity of the EGF-R in five different human transitional cell carcinoma lines. The compounds also produced cytostasis in vitro. Highly metastatic human 253J B-V cells were implanted in the bladder wall of nude mice. The daily oral administration of CGP 54211 inhibited the level of EGF-R phosphorylation in this tumor; necrosis and inhibition of tumor growth paralleled this inhibition.


Context dependence of mutational effects in a protein: the crystal structures of the V35I, I47V and V35I/I47V gene V protein core mutants.
The basis for the context dependence of the effects of core mutations on protein stability was investigated by comparing the structures of three gene V protein mutants with that of the wild-type protein. We previously examined a "swapped" mutant in which core residues Val35 and Ile47 were simply reversed so that the mutant had no hydrophobicity change from the native protein. The swapped mutant was destabilized by 3 kcal/mol per gene V protein dimer relative to the wild-type protein, demonstrating that factors other than hydrophobicity must make substantial contributions to the effects of mutations on the stability of the protein. Here we have determined the structure of this swapped mutant (V35I/I47V) as well as those of the two constituent mutants (V35I and I47V). We find that the structures of the mutant proteins are very similar to that of the wild-type protein except for the necessary addition or deletion of methylene groups and for slight positional shifts of atoms around each mutated residue. The structure of the double mutant is a composite of the structures of the two single mutants. In the mutant structures, the V35I mutation fills a cavity that exists in the wild-type protein and the I47V mutation creates a new cavity. The structures of the mutants indicate further that the reason the V35I and I47V mutations do not have opposite effects on stability is that the cavity in the wild-type protein filled by the V35I mutation is not optimally shaped for accommodating the additional methylene group of the isoleucine. These results support the concepts that the details of core packing have substantial influence on the effects of core mutations on protein stability and that these packing effects are major determinants of the context dependence of core mutation effects on stability.


The safety and efficacy of fractional photothermolysis for the correction of striae distensae.
Improving the appearance of striae distensae, particularly striae alba, has remained a challenge due to the limited availability of effective and low-risk treatment options. Fractional photothermolysis, a novel concept in skin rejuvenation, has been reported to be effective in the treatment of facial rhytides, acne scars, and surgical scars, but its use in the treatment of striae has not been well studied. To determine the safety and efficacy of fractional photothermolysis treatment on striae alba and striae rubra. Twenty female patients with striae rubra or striae alba on their abdomen, thighs, or buttocks were enrolled in the study. Lesions were randomized to receive treatment, with site-matched normal control areas. Patients received a total of 6 treatments using a 1550-nm, erbium-doped fiber laser with 2 to 3 weeks of elapsed time between treatments. Clinical response to treatment was assessed at each visit, and at 1-month, 2-month, and 3-month follow-up intervals by the patient and investigator. A comparison evaluation of 8 patients examining photographs of striae at baseline and at the 3-month follow-up evaluation which was assessed by 4 independent dermatologists using the quartile grading scale. The independent evaluators' assessments of improvement from photographs of 8 randomly selected patients showed an overall improvement of 26% to 50% in 63% (5/8) of patients. A less than 25% improvement in dyschromia was noted in 50% (4/8) of patients. An improvement in texture of 26% to 50% was observed in 50% (4/8) of patients. The clinical responses were independent of age, gender, and skin phototype. The treatments were tolerated well by all patients with a majority of patients experiencing transient posttreatment erythema and edema. Fractional photothermolysis can be effectively and safely used in the treatment of striae rubra and striae alba.


Metal dependence and branched RNA cocrystal structures of the RNA lariat debranching enzyme Dbr1.
Intron lariats are circular, branched RNAs (bRNAs) produced during pre-mRNA splicing. Their unusual chemical and topological properties arise from branch-point nucleotides harboring vicinal 2',5'- and 3',5'-phosphodiester linkages. The 2',5'-bonds must be hydrolyzed by the RNA debranching enzyme Dbr1 before spliced introns can be degraded or processed into small nucleolar RNA and microRNA derived from intronic RNA. Here, we measure the activity of Dbr1 from Entamoeba histolytica by using a synthetic, dark-quenched bRNA substrate that fluoresces upon hydrolysis. Purified enzyme contains nearly stoichiometric equivalents of Fe and Zn per polypeptide and demonstrates turnover rates of ∼3 s-1 Similar rates are observed when apo-Dbr1 is reconstituted with Fe(II)+Zn(II) under aerobic conditions. Under anaerobic conditions, a rate of ∼4.0 s-1 is observed when apoenzyme is reconstituted with Fe(II). In contrast, apo-Dbr1 reconstituted with Mn(II) or Fe(II) under aerobic conditions is inactive. Diffraction data from crystals of purified enzyme using X-rays tuned to the Fe absorption edge show Fe partitions primarily to the β-pocket and Zn to the α-pocket. Structures of the catalytic mutant H91A in complex with 7-mer and 16-mer synthetic bRNAs reveal bona fide RNA branchpoints in the Dbr1 active site. A bridging hydroxide is in optimal position for nucleophilic attack of the scissile phosphate. The results clarify uncertainties regarding structure/function relationships in Dbr1 enzymes, and the fluorogenic probe permits high-throughput screening for inhibitors that may hold promise as treatments for retroviral infections and neurodegenerative disease.


Stroke in Parkinson's disease.
The association between Parkinson's disease (PD) and stroke remains completely understood. We aimed to investigate stroke risk and post-stroke outcomes in patients with PD. The retrospective cohort study included 1303 patients aged ≥ 40 years with new-diagnosed PD and 5212 non-PD adults were selected by frequency matching with age and sex in 2000-05. Both two groups were followed up until the end of 2013. Another nested stroke cohort study of 17 678 patients with stroke hospitalization in 2002-09 was conducted to compare the admission outcome in patients with and without PD history. We collected patients' characteristics and medical conditions in the present two studies from claims data of Taiwan's National Health Insurance. Incidences and risks of stroke in people with and without PD during the follow-up period were calculated by adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) in the Cox proportional hazard model. Complications and mortality during the stroke admission associated with PD were analysed by calculating adjusted odds ratios (ORs) and 95% CIs in the logistic regressions. Incidences of stroke for people with and without PD were 19.8 and 9.93 per 1000 person-years, respectively, with corresponding HR of 1.96 (95% CI 1.67-2.30). History of PD was associated with post-stroke gastrointestinal bleeding (OR 1.25, 95% CI 1.05-1.49), epilepsy (OR 1.64, 95% CI 1.32-2.04), pneumonia (OR 1.34, 95% CI 1.20-1.49), urinary tract infection (OR 1.33, 95% CI 1.21-1.45) and mortality (OR 1.35, 95% CI 1.13-1.62). PD increases stroke risk and influences post-stroke outcomes.


The effect of different dietary sugars and honey on longevity and fecundity in two hyperparasitoid wasps.
In nature adult insects, such as parasitic wasps or 'parasitoids' often depend on supplemental nutritional sources, such as sugars and other carbohydrates, to maximize their life-expectancy and reproductive potential. These food resources are commonly obtained from animal secretions or plant exudates, including honeydew, fruit juices and both floral and extra-floral nectar. In addition to exogenous sources of nutrition, adult parasitoids obtain endogenous sources from their hosts through 'host-feeding' behavior, whereby blood is imbibed from the host. Resources obtained from the host contain lipids, proteins and sugars that are assumed to enhance longevity and/or fecundity. Here we conducted an experiment exploring the effects of naturally occurring sugars on longevity and fecundity in the solitary hyperparasitoids, Lysibia nana and Gelis agilis. Although both species are closely related, L. nana does not host-feed whereas G. agilis does. In a separate experiment, we compared reproduction and longevity in G. agilis reared on either honey, a honey-sugar 'mimic', and glucose. Reproductive success and longevity in both hyperparasitoids varied significantly when fed on different sugars. However, only mannose- and water-fed wasps performed significantly more poorly than wasps fed on four other sugar types. G. agilis females fed honey produced twice as many progeny as those reared on the honey-sugar mimic or on glucose, whereas female longevity was only reduced on the mimic mixture. This result shows not only that host feeding influences reproductive success in G. agilis, but also that non-sugar constituents in honey do. The importance of non-sugar nutrients in honey on parasitoid reproduction is discussed.


Experimental comparison of proton CT and dual energy x-ray CT for relative stopping power estimation in proton therapy.
Proton computed tomography (pCT) has been proposed as an alternative to x-ray computed tomography (CT) for acquiring relative to water stopping power (RSP) maps used for proton treatment planning dose calculations. In parallel, it has been shown that dual energy x-ray CT (DECT) improves RSP accuracy when compared to conventional single energy x-ray CT. This study aimed at directly comparing the RSP accuracy of both modalities using phantoms scanned at an advanced prototype pCT scanner and a state-of-the-art DECT scanner. Two phantoms containing 13 tissue-mimicking inserts of known RSP were scanned at the pCT phase II prototype and a latest generation dual-source DECT scanner (Siemens SOMATOM Definition FORCE). RSP accuracy was compared by mean absolute percent error (MAPE) over all inserts. A highly realistic Monte Carlo (MC) simulation was used to gain insight on pCT image artifacts which degraded MAPE. MAPE was 0.55% for pCT and 0.67% for DECT. The realistic MC simulation agreed well with pCT measurements ([Formula: see text]). Both simulation and experimental results showed ring artifacts in pCT images which degraded the MAPE compared to an ideal pCT simulation ([Formula: see text]). Using the realistic simulation, we could identify sources of artifacts, which are attributed to the interfaces in the five-stage plastic scintillator energy detector and calibration curve interpolation regions. Secondary artifacts stemming from the proton tracker geometry were also identified. The pCT prototype scanner outperformed a state-of-the-art DECT scanner in terms of RSP accuracy (MAPE) for plastic tissue mimicking inserts. Since artifacts tended to concentrate in the inserts, their mitigation may lead to further improvements in the reported pCT accuracy.


The association between self-reported lifestyle changes and health-related quality of life in coronary patients: the EUROASPIRE III survey.
Patients with coronary heart disease often suffer from an impaired health-related quality of life (HRQoL). A healthier lifestyle not only extends individuals' lengths of life but might also improve their HRQoL. The aim of this study was to explore the relation between self-reported lifestyle changes and HRQoL in European coronary patients. Data on 8745 coronary patients, from 22 countries, participating in the EUROASPIRE III survey (2006-2007) were used. These patients hospitalized for coronary artery bypass graft, percutaneous coronary intervention, acute myocardial infarction, or myocardial ischaemia were interviewed and examined at least 6 months and no later than 3 years after their hospital admission to gather information on their HRQoL, self-reported lifestyle changes, and risk factors. Significantly better HRQoL scores were found in ex-smokers compared to current smokers. Patients who made an attempt to increase their physical activity level had a better HRQoL compared to those who had not made an attempt. Furthermore dietary changes were associated with HRQoL, with better outcomes in patients who tried to reduce fat and salt intake and increase fish, fruit, and vegetable intake. The intention to change behaviour was not associated with HRQoL. Better HRQoL scores were found in those coronary patients who adopted a healthier lifestyle. The actual lifestyle changes - smoking cessation, increasing physical activity, and adopting a healthy diet - and not the intention to change are associated with better HRQoL outcomes.


Tail-cuff blood pressure measurement without external preheating in awake rats.
A new photoelectric sensor capable of detecting tail pulses even in unheated rats was tested for accuracy in indirect measurements of blood pressure. This sensor proved more sensitive than a Doppler ultrasonic flowmeter because it allowed detection not only of tail pulsations without preheating but also of peak oscillations usable for estimating mean arterial pressure. After blood pressures in anesthetized rats were elevated with norepinephrine or lowered with sodium nitroprusside, systolic pressures determined with the photoelectric sensor were almost identical with those recorded concurrently from femoral catheters (r = 0.939). Cuff pressure at peak oscillations in the tail correlated better with femoral mean pressure than with femoral diastolic pressure. However, similar comparisons in awake rats with chronically implanted carotid catheters showed that, although correlation between tail-cuff and carotid systolic pressures remained significant (r = 0.962), the correlation between peak tail oscillations and either mean or diastolic pressure was not. When systolic pressures were measured indirectly once a week for 7 weeks in unheated awake rats, normotensive rats could be easily distinguished from streptozotocin-diabetic and DOCA-salt hypertensive rats.


Quantitative cerebral blood flow imaging with extended-focus optical coherence microscopy.
Quantitative three-dimensional blood flow imaging is a valuable technique to investigate the physiology of the brain. Two-photon microscopy (2PM) allows quantification of the local blood flow velocity with micrometric resolution by performing repeated line scans, but prohibitively long measurement times would be required to apply this technique to full three-dimensional volumes. By multiplexing the image acquisition over depth, Fourier domain optical coherence tomography (FDOCT) enables quantification of blood flow velocities with a high volume acquisition rate, albeit at a relatively low spatial resolution. Extended-focus optical coherence microscopy (xfOCM) increases the lateral resolution without sacrificing depth of field and therefore combines the high volume acquisition rate of FDOCT with a resolution comparable to 2PM. Here, we demonstrate high-resolution quantitative imaging of the blood flow velocity vector's magnitude in the adult murine brain with xfOCM.


Resilience and human adaptability: who rises above adversity? 1990 Eleanor Clarke Slagle Lecture.
We work in a world of traumas and triumphs. Most of the persons we serve come to us out of necessity, struggling with the sequelae of disease and illness or the aftermath of natural or manmade disasters. We bring our expertise and compassion; they bring their bodies, minds, and compromised lives. Our worlds converge around a shared task; identifying and enhancing their capacities for daily living. We pursue problems of movement, perception, cognition, affect, and social capacity within the context of their roles and aspirations. Our contacts may be extensive, but often they are brief and only partially fulfilled. Our patients move on with varying degrees of functional ability--some with determination and buoyancy, others with little confidence that life is actually worth living. We remain, frequently knowing little about the factors that have influenced the outcome of our efforts. In spite of their compelling importance to our patients, our professional viability, and the health care system.


Inhibitory GTP-binding regulatory protein Gi3 can couple angiotensin II receptors to inhibition of adenylyl cyclase in hepatocytes.
Angiotensin II can inhibit hormone-stimulated adenylyl cyclase in intact hepatocytes or in hepatic membrane preparations. Because the response can be blocked by pertussis toxin, the object of the present study was to determine which of the known variants of Gi can couple angiotensin II receptors to inhibition of adenylyl cyclase. The potential candidates were identified by probing RNA isolated from rat hepatocytes with cDNAs specific for the alpha subunits of known toxin-sensitive guanine nucleotide-binding regulatory proteins (G proteins). Hepatocytes contained no detectable RNA for the Go or Gi1 alpha subunits and similar levels of RNA coding for the Gi2 and Gi3 alpha subunits. To determine whether Gi3 could couple angiotensin receptors to inhibition of cyclase, membranes were prepared from hepatocytes whose G proteins were fully ADP-ribosylated with pertussis toxin, and the Gi3 holoprotein purified from rabbit liver was reconstituted into the membranes. The nature of the Gi3 reconstituted into the membrane was assessed by immunoblotting with antibodies specific for the Gi alpha subunits. Reconstitution of 6-10 pmol of Gi3/mg of membrane protein into the toxin-treated membranes restored the ability of 10 nM angiotensin II to inhibit adenylyl cyclase. Because pertussis toxin has nonspecific effects, an assay was developed to measure the interaction of the angiotensin receptor with reconstituted G proteins in normal membranes. In the presence of Mg2+, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) caused a reduction of the affinity of the angiotensin II receptor for 125I-angiotensin II that was stable to washing and the detergents used to reconstitute G proteins into the membranes. Using this protocol to activate G proteins and "uncouple" receptors, the ability of the GDP-liganded form of Gi to restore high affinity binding was examined. Reconstitution of about 10-15 pmol of oligomeric Gi3/mg of membrane protein restored both the high affinity state of the angiotensin II receptor and the ability of GTP gamma S to shift the affinity to a lower state. The same shift in receptor affinity could be accomplished by reconstituting the Gi3 alpha subunit, resolved free of beta gamma subunits, into the membranes. Reconstitution of up to 50 pmol of Gs/mg of membrane protein had no effect on angiotensin II receptor affinity. The results suggest that a major form of Gi in hepatocytes is Gi3 and that it can couple angiotensin receptors to inhibition of adenylyl cyclase.


Management of neglected complex hangman's fracture by reforming the C2 pedicle: new innovative technique of motion preservation at the C1-2 joint in 2 cases.
Hangman's fracture, also known as traumatic spondylolisthesis of the axis, causes widening of the neural canal and thus a low rate of neurological deficits. This low rate is one of the reasons it is neglected and patients present with late neurological deficits. In an effort to preserve motion at the C1-2 joint, the authors devised a new technique of bilateral C2 pedicle reconstruction. They describe the first two cases in the literature of an old hangman's fracture with resorbed C2 pedicles due to chronic fracture, in which bilateral C2 pedicles were reconstructed. One of the two cases (case 2) is the first reported case of severe C2-3 spondyloptosis with C2 displaced up to the level of C4. Case 1 had a follow up of 21 months, while case 2 had a follow up of 12 months. Both patients experienced neurological improvement with evidence of fusion and artificial pedicle formation at last follow-up. Bilateral C2 pedicle reconstruction is a feasible technique that can be used with a good outcome in select patients.


A Difference-Education Intervention Equips First-Generation College Students to Thrive in the Face of Stressful College Situations.
A growing social psychological literature reveals that brief interventions can benefit disadvantaged students. We tested a key component of the theoretical assumption that interventions exert long-term effects because they initiate recursive processes. Focusing on how interventions alter students' responses to specific situations over time, we conducted a follow-up lab study with students who had participated in a difference-education intervention 2 years earlier. In the intervention, students learned how their social-class backgrounds mattered in college. The follow-up study assessed participants' behavioral and hormonal responses to stressful college situations. We found that difference-education participants discussed their backgrounds in a speech more frequently than control participants did, an indication that they retained the understanding of how their backgrounds mattered. Moreover, among first-generation students (i.e., students whose parents did not have 4-year degrees), those in the difference-education condition showed greater physiological thriving (i.e., anabolic-balance reactivity) than those in the control condition, which suggests that they experienced their working-class backgrounds as a strength.


A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal.
The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tumor biology, and prognostic factors. The classification suggested is based on a consensus conference held at the International Agency for Research on Cancer (IARC) in November 2017 and subsequent discussion with additional experts. The key feature of the new classification is a distinction between differentiated neuroendocrine tumors (NETs), also designated carcinoid tumors in some systems, and poorly differentiated NECs, as they both share common expression of neuroendocrine markers. This dichotomous morphological subdivision into NETs and NECs is supported by genetic evidence at specific anatomic sites as well as clinical, epidemiologic, histologic, and prognostic differences. In many organ systems, NETs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, and/or the presence of necrosis; NECs are considered high grade by definition. We believe this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.


Hepatic glucose uptake and disposition during short-term high-fat vs. high-fructose feeding.
In dogs consuming a high-fat and -fructose diet (52 and 17% of total energy, respectively) for 4 wk, hepatic glucose uptake (HGU) in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery is markedly blunted with reduction in glucokinase (GK) protein and glycogen synthase (GS) activity. The present study compared the impact of selective increases in dietary fat and fructose on liver glucose metabolism. Dogs consumed weight-maintaining chow (CTR) or hypercaloric high-fat (HFA) or high-fructose (HFR) diets diet for 4 wk before undergoing clamp studies with infusion of somatostatin and intraportal insulin (3-4 times basal) and glucagon (basal). The hepatic glucose load (HGL) was doubled during the clamp using peripheral vein (Pe) glucose infusion in the first 90 min (P1) and portal vein (4 mg·kg(-1)·min(-1)) plus Pe glucose infusion during the final 90 min (P2). During P2, HGU was 2.8 ± 0.2, 1.0 ± 0.2, and 0.8 ± 0.2 mg·kg(-1)·min(-1) in CTR, HFA, and HFR, respectively (P < 0.05 for HFA and HFR vs. CTR). Compared with CTR, hepatic GK protein and catalytic activity were reduced (P < 0.05) 35 and 56%, respectively, in HFA, and 53 and 74%, respectively, in HFR. Liver glycogen concentrations were 20 and 38% lower in HFA and HFR than CTR (P < 0.05). Hepatic Akt phosphorylation was decreased (P < 0.05) in HFA (21%) but not HFR. Thus, HFR impaired hepatic GK and glycogen more than HFA, whereas HFA reduced insulin signaling more than HFR. HFA and HFR effects were not additive, suggesting that they act via the same mechanism or their effects converge at a saturable step.


The integrated activities of IRF-2 (HiNF-M), CDP/cut (HiNF-D) and H4TF-2 (HiNF-P) regulate transcription of a cell cycle controlled human histone H4 gene: mechanistic differences between distinct H4 genes.
Maximal transcription of a prototypical cell cycle controlled histone H4 gene requires a proliferation-specific in vivo genomic protein/DNA interaction element, Site II. Three sequence-specific transcription factors interact with overlapping recognition motifs within Site II: interferon regulatory factor IRF-2 (HiNF-M), the putative H4 subtype-specific protein H4TF-2 (HiNF-P), and HiNF-D which represents a complex of the homeodomain protein CDP/cut, CDC2, cyclin A and pRB. However, natural sequence variation in the Site II sequences of different human H4 genes abolishes binding of specific trans-acting factors; the functional consequences of these variations have not been investigated. To address the precise contribution of H4 promoter factors to the level of H4 gene transcription, we performed a systematic mutational analysis of Site II transcriptional motifs. These mutants were tested for ability to bind each of the Site II cognate proteins, and subsequently evaluated for ability to confer H4 transcriptional activity using chimeric H4 promoter/CAT fusion constructs in different cell types. We also analyzed the effect of over-expressing IRF-2 on CAT reporter gene expression driven by mutant H4 promoters and assessed H4 transcriptional control in cells nullizygous for IRF-1 and IRF-2. Our results show that the recognition sequence for IRF-2 (HiNF-M) is the dominant component of Site II and modulates H4 gene transcription levels by 3 fold. However, the overlapping recognition sequences for IRF-2 (HiNF-M), H4TF-2 (HiNF-P) and CDP/cut (HiNF-D) together modulate H4 gene transcription levels by at least an order of magnitude. Thus, maximal activation of H4 gene transcription during the cell cycle in vivo requires the integrated activities of multiple transcription factors at Site II. We postulate that the composite organization of Site II supports responsiveness to multiple signalling pathways modulating the activities of H4 gene transcription factors during the cell cycle. Variations in Site II sequences among different H4 genes may accommodate differential regulation of H4 gene expression in cells and tissues with unique phenotypic properties.


Blood flow in hemodialysis catheters: a numerical simulation and microscopic analysis of in vivo-formed fibrin.
Although catheters with side holes allow high flow rate during hemodialysis, they also induce flow disturbances and create a critical hemodynamic environment that can favor fibrin deposition and thrombus formation. This study compared the blood flow and analyzed the influence of shear stress and shear rate in fibrin deposition and thrombus formation in nontunneled hemodialysis catheters with unobstructed side holes (unobstructed device) or with some side holes obstructed by blood thrombi (obstructed device). Computational fluid dynamics (CFD) was performed to simulate realistic blood flow under laminar and turbulent conditions. The results from the numerical simulations were compared with the fibrin distribution and thrombus architecture data obtained from scanning electron microscopy (SEM) and two photons laser scanning microscopy (TPLSM) on human thrombus formed in catheters removed from patients. CFD showed that regions of flow eddies and separation were mainly found in the venous holes region. TPLSM characterization of thrombi and fibrin structure in patient samples showed fibrin formations in accordance with simulated flux dynamics. Under laminar flow conditions, the wall shear stress close to border holes increased from 87.3±0.2 Pa in the unobstructed device to 176.2±0.5 Pa in the obstructed one. Under turbulent flow conditions, the shear stress increased by 47% when comparing the obstructed to the unobstructed catheter. The shear rates were generally higher than 5000/s and therefore sufficient to induce fibrin deposition. This findings were supported by SEM data documenting a preferential fibrin arrangement on side hole walls.


Intrinsically disordered protein threads through the bacterial outer-membrane porin OmpF.
Porins are β-barrel outer-membrane proteins through which small solutes and metabolites diffuse that are also exploited during cell death. We have studied how the bacteriocin colicin E9 (ColE9) assembles a cytotoxic translocon at the surface of Escherichia coli that incorporates the trimeric porin OmpF. Formation of the translocon involved ColE9's unstructured N-terminal domain threading in opposite directions through two OmpF subunits, capturing its target TolB on the other side of the membrane in a fixed orientation that triggers colicin import. Thus, an intrinsically disordered protein can tunnel through the narrow pores of an oligomeric porin to deliver an epitope signal to the cell to initiate cell death.


When "embedded" means "stuck": Moderating effects of job embeddedness in adverse work environments.
Job embeddedness is predominately assumed to benefit employees, work groups, and organizations (e.g., higher performance, social cohesion, and lower voluntary turnover). Challenging this assumption, we examined the potentially negative outcomes that may occur if employees are embedded in an adverse work environment-feeling "stuck," yet unable to exit a negative situation. More specifically, we considered two factors representing adverse work conditions: abusive supervision and job insecurity. Drawing from conservation of resources theory, we hypothesized that job embeddedness would moderate the relationship between these conditions and outcomes of voluntary turnover, physical health, emotional exhaustion, and sleep quality/quantity, such that employees embedded in more adverse environments would be less likely to quit, but would experience more negative personal outcomes. Results from two independent samples, one in Japan (N = 597) and one in the United States (N = 283), provide support for the hypothesized pattern of interaction effects, thereby highlighting a largely neglected "dark side" of job embeddedness. (PsycINFO Database Record


Economic evaluation of a community based exercise programme to prevent falls.
To assess the incremental costs and cost effectiveness of implementing a home based muscle strengthening and balance retraining programme that reduced falls and injuries in older women. An economic evaluation carried out within a randomised controlled trial with two years of follow up. Participants were individually prescribed an exercise programme (exercise group, n=116) or received usual care and social visits (control group, n=117). 17 general practices in Dunedin, New Zealand. Women aged 80 years and older living in the community and invited by their general practitioner to take part. Number of falls and injuries related to falls, costs of implementing the intervention, healthcare service costs resulting from falls and total healthcare service costs during the trial. Cost effectiveness was measured as the incremental cost of implementing the exercise programme per fall event prevented. 27% of total hospital costs during the trial were related to falls. However, there were no significant differences in health service costs between the two groups. Implementing the exercise programme for one and two years respectively cost $314 and $265 (1995 New Zealand dollars) per fall prevented, and $457 and $426 per fall resulting in a moderate or serious injury prevented. The costs resulting from falls make up a substantial proportion of the hospital costs for older people. Despite a reduction in falls as a result of this home exercise programme there was no significant reduction in healthcare costs. However, the results reported will provide information on the cost effectiveness of the programme for those making decisions on falls prevention strategies.


A new multimedia contaminant fate model for China: how important are environmental parameters in influencing chemical persistence and long-range transport potential?
We present a new multimedia chemical fate model (SESAMe) which was developed to assess chemical fate and behaviour across China. We apply the model to quantify the influence of environmental parameters on chemical overall persistence (POV) and long-range transport potential (LRTP) in China, which has extreme diversity in environmental conditions. Sobol sensitivity analysis was used to identify the relative importance of input parameters. Physicochemical properties were identified as more influential than environmental parameters on model output. Interactive effects of environmental parameters on POV and LRTP occur mainly in combination with chemical properties. Hypothetical chemicals and emission data were used to model POV and LRTP for neutral and acidic chemicals with different KOW/DOW, vapour pressure and pKa under different precipitation, wind speed, temperature and soil organic carbon contents (fOC). Generally for POV, precipitation was more influential than the other environmental parameters, whilst temperature and wind speed did not contribute significantly to POV variation; for LRTP, wind speed was more influential than the other environmental parameters, whilst the effects of other environmental parameters relied on specific chemical properties. fOC had a slight effect on POV and LRTP, and higher fOC always increased POV and decreased LRTP. Example case studies were performed on real test chemicals using SESAMe to explore the spatial variability of model output and how environmental properties affect POV and LRTP. Dibenzofuran released to multiple media had higher POV in northwest of Xinjiang, part of Gansu, northeast of Inner Mongolia, Heilongjiang and Jilin. Benzo[a]pyrene released to the air had higher LRTP in south Xinjiang and west Inner Mongolia, whilst acenaphthene had higher LRTP in Tibet and west Inner Mongolia. TCS released into water had higher LRTP in Yellow River and Yangtze River catchments. The initial case studies demonstrated that SESAMe performed well on comparing POV and LRTP of chemicals in different regions across China in order to potentially identify the most sensitive regions. This model should not only be used to estimate POV and LRTP for screening and risk assessments of chemicals, but could potentially be used to help design chemical monitoring programmes across China in the future.


Letting go: bacterial genome reduction solves the dilemma of adapting to predation mortality in a substrate-restricted environment.
Resource limitation and predation mortality are major determinants of microbial population dynamics, and optimization for either aspect is considered to imply a trade-off with respect to the other. Adaptation to these selective factors may, moreover, lead to disadvantages at rich growth conditions. We present an example of a concomitant evolutionary optimization to both, substrate limitation and predation in an aggregate-forming freshwater bacterial isolate, and we elucidate an underlying genomic mechanism. Bacteria were propagated in serial batch culture in a nutrient-restricted environment either with or without a bacterivorous flagellate. Strains isolated after 26 growth cycles of the predator-prey co-cultures formed as much total biomass as the ancestor at ancestral growth conditions, albeit largely reallocated to cell aggregates. A ~273 kbp genome fragment was lost in three strains that had independently evolved with predators. These strains had significantly higher growth yield on substrate-restricted media than others that were isolated from the same treatment before the excision event. Under predation pressure, the isolates with the deletion outcompeted both, the ancestor and the strains evolved without predators even at rich growth conditions. At the same time, genome reduction led to a growth disadvantage in the presence of benzoate due to the loss of the respective degradation pathway, suggesting that niche constriction might be the price for the bidirectional optimization.


S100B single nucleotide polymorphisms exhibit sex-specific associations with chronic pain in sickle cell disease in a largely African-American cohort.
Pain in sickle cell disease (SCD) is severe and multifaceted resulting in significant differences in its frequency and intensity among individuals. In this study, we examined the influence of S100B gene single nucleotide polymorphisms (SNP) on acute and chronic pain variability in SCD. Composite pain index (CPI) scores captured chronic pain. Painful crisis related emergency care utilization recorded acute pain incidence. Genotyping was performed using MassARRAY iPLEX platform. Regression analysis revealed associations of increased CPI with rs9722 A allele in additive (p = 0.005) and dominant (p = 0.005) models. Rs1051169 G allele on the other hand was associated with decreased CPI in additive (p = 0.001), and dominant (p = 0.005) models. Sex-specific analysis found that these associations were significant in females but not males in this cohort. Linkage analysis identified two haploblocks. Block 1 (rs9983698-rs9722) haplotype T-A was associated with increased CPI (p = 0.002) while block 2 (rs1051169-rs11911834) haplotype G-G was associated with decreased CPI (p = 0.001). Both haplotypic associations were only significant in females. No association of S100B SNPs with utilization reached statistical significance. S100B SNPs and haplotypes are associated with chronic pain in female, but not male, patients with SCD, implicating a potential role of S100B polymorphism in SCD pain heterogeneity in a sex-dependent manner.


Skull morphology affected by different sleep positions in infancy.
In infancy, prior to cranial suture and fontanel calcification, the craniofacial skeleton can be easily deformed by an externally exerted force. In this study, the relationship between the sleep position and skull morphology was investigated. A group of 81 cleft lip and/or palate infants without other systemic anomalies was first seen in the craniofacial center at approximately 1 month of age. The sleep position of each infant was recorded as supine, prone, or mixed type. The body and skull growth were longitudinally measured at 1, 3, and 6 months of age. Infants sleeping in the supine sleep position tended to have a wider head width, shorter head length, and a larger cephalic index by 6 months of age. The opposite phenomena were observed in the prone sleep group. The mixed sleep group tended to have head width, head length, and cephalic index between those of the supine sleep group and the prone sleep group. During the first 3 months of life, the sleep position could mold the skull primarily in the dimension of head width. In conclusion, the supine sleep position may promote brachycephaly and the prone sleep position dolichocephaly.


Impact of the social environment on occupational experience and performance among persons with unilateral neglect.
The purpose of this study was to gain an understanding of social environmental influences on occupational experience and performance over the course of rehabilitation of four persons with unilateral neglect. The Phenomenological Psychological Method (Karlsson, 1993) was used to gather and analyze qualitative data on four women over a 4-month period. Four women were interviewed five to seven times each and observed during their rehabilitation process. Analysis focused on how these persons with unilateral neglect experienced and responded to their interactions with others in their everyday lives. As perceived by the study participants, rehabilitation professionals and relatives demonstrated a sequence of strategies for dealing with and helping the women perform despite their unilateral neglect. The sequence of strategies reflects the changing experience of neglect over time. The strategies used by professionals and family members during the rehabilitation process enabled these women to reclaim and occupy the neglected half of the world. Moreover, the women with neglect learned to incorporate others as extensions of their bodies in order to compensate for their ongoing inability to directly experience the left half of the world. The results suggest that it is important for others (e.g., therapists, nurses, or relatives) to understand the client's changing experience of neglect and adjust their support and collaboration accordingly. Occupational therapy intervention for persons with neglect could potentially become more effective by systematically incorporating the kinds of strategies identified in this study. Moreover, therapists could consult with others to increase their understanding and effectiveness in interacting with persons who have unilateral neglect.


Basal localization of MT1-MMP is essential for epithelial cell morphogenesis in 3D collagen matrix.
The membrane-anchored collagenase membrane type 1 matrix metalloprotease (MT1-MMP) has been shown to play an essential role during epithelial tubulogenesis in 3D collagen matrices; however, its regulation during tubulogenesis is not understood. Here, we report that degradation of collagen in polarized epithelial cells is post-translationally regulated by changing the localization of MT1-MMP from the apical to the basal surface. MT1-MMP predominantly localizes at the apical surface in inert polarized epithelial cells, whereas treatment with HGF induced basal localization of MT1-MMP followed by collagen degradation. The basal localization of MT1-MMP requires the ectodomains of the enzyme because deletion of the MT-loop region or the hemopexin domain inhibited basal localization of the enzyme. TGFβ is a well-known inhibitor of tubulogenesis and our data indicate that its mechanism of inhibition is, at least in part, due to inhibition of MT1-MMP localization to the basal surface. Interestingly, however, the effect of TGFβ was found to be bi-phasic: at high doses it effectively inhibited basal localization of MT1-MMP, whereas at lower doses tubulogenesis and basal localization of MT1-MMP was promoted. Taken together, these data indicate that basal localization of MT1-MMP is a key factor promoting the degradation of extracellular matrix by polarized epithelial cells, and that this is an essential part of epithelial morphogenesis in 3D collagen.


Mechanisms of water infiltration into conical hydrophobic nanopores.
Fluid channels with inclined solid walls (e.g. cone- and slit-shaped pores) have wide and promising applications in micro- and nano-engineering and science. In this paper, we use molecular dynamics (MD) simulations to investigate the mechanisms of water infiltration (adsorption) into cone-shaped nanopores made of a hydrophobic graphene sheet. When the apex angle is relatively small, an external pressure is required to initiate infiltration and the pressure should keep increasing in order to further advance the water front inside the nanopore. By enlarging the apex angle, the pressure required for sustaining infiltration can be effectively lowered. When the apex angle is sufficiently large, under ambient condition water can spontaneously infiltrate to a certain depth of the nanopore, after which an external pressure is still required to infiltrate more water molecules. The unusual involvement of both spontaneous and pressure-assisted infiltration mechanisms in the case of blunt nanocones, as well as other unique nanofluid characteristics, is explained by the Young's relation enriched with the size effects of surface tension and contact angle in the nanoscale confinement.


Quantitative description of the far-lateral transcondylar transtubercular approach to the foramen magnum and clivus.
The purpose of this study was to evaluate the far-lateral transcondylar transtubercular approach (complete FLA) based on quantitative measurements of the exposure of the foramen magnum and petroclival area obtained after each successive step of this approach. The complete FLA was reproduced in eight specially prepared cadaveric heads (a total of 15 sides). The approach was divided into six steps: 1) C-1 hemilaminectomy and suboccipital craniectomy with unroofing of the sigmoid sinus (basic FLA); 2) partial resection of the occipital condyle (up to the hypoglossal canal); 3) removal of the jugular tuberculum; 4) mastoidectomy (limited to the labyrinth and the fallopian canal) and retraction of the sigmoid sinus; 5) resection of the lateral mass of C-1 with mobilization of the vertebral artery; and 6) resection of the remaining portion of the occipital condyle. After each successive step, a standard set of measurements was obtained using a frameless stereotactic device. The measurements were used to estimate two parameters: the size of the exposed petroclival area and the size of a spatial cone directed toward the anterior rim of the foramen magnum, which depicts the amount of surgical freedom available for manipulation of instruments. The initial basic FLA provided exposure of only 21 +/- 6% of the petroclival area that was exposed with the full, six-step maximally aggressive (complete) FLA. Likewise, only 18 +/- 9% of the final surgical freedom was obtained after the basic FLA was performed. Each subsequent step of the approach increased both petroclival exposure and surgical freedom. The most dramatic increase in petroclival exposure was noted after removal of the jugular tuberculum (71 +/- 12% of final exposure), whereas the least improvement in exposure occurred after the final step, which consisted of total condyle resection. The complete FLA provides wide and sufficient exposure of the foramen magnum and lower to middle clivus. The complete FLA consists of several steps, each of which contributes to increasing petroclival exposure and surgical freedom. However, the FLA may be limited to the less aggressive steps, while still achieving significant exposure and surgical freedom. The choice of complete or basic FLA thus depends on the underlying pathological condition and the degree of exposure required for effective surgical treatment.