What Is the Mid-term Failure Rate of Revision ACL Reconstruction? A Systematic Review.
When anterior cruciate ligament (ACL) reconstruction fails, a revision procedure may be performed to improve knee function, correct instability, and allow return to activities. The results of revision ACL reconstruction have been reported to produce good but inferior patient-reported and objective outcomes compared with primary ACL reconstruction, but the degree to which this is the case varies widely among published studies and may be influenced by heterogeneity of patients, techniques, and endpoints assessed. For those reasons, a systematic review may provide important insights. In a systematic review, we asked: (1) What is the proportion of revision ACL reconstruction cumulative failures defined as rerupture or objective failure using prespecified clinical criteria at mean followup of at least 5 years? (2) What are the most common complications of revision ACL reconstruction? A systematic review was performed by searching PubMed/Medline, EMBASE, and CENTRAL. We included studies that reported the clinical evaluation of revision ACL reconstruction with Lachman test, pivot shift test, side-to-side difference with KT-1000/2000 arthrometer, and with a mean followup of at least 5 years. We excluded studies that incompletely reported these outcomes, that reported only reruptures, or that were not in the English language. Extracted data included the number of graft reruptures and objective clinical failure, defined as a knee that met one of the following endpoints: Lachman test Grade II to III, pivot shift Grade II to III, KT-1000/2000 > 5-mm difference, or International Knee Documentation Committee Grade C or D. For each study, we determined the proportion of patients who had experienced a rupture of the revision ACL graft as well as the proportion of patients who met one or more of our clinical failure endpoints. Those proportions were summed for each study to generate a percentage of patients who met our definition of cumulative failure. Complications and reoperations were recorded but not pooled as a result of inconsistency of reporting and heterogeneity of populations across the included studies. Of the 663 screened studies, 15 articles were included in the systematic review. Because one study reported two separate groups of patients with different treatments, 16 case series were considered in the evaluation. The proportion of reruptures (range, 0%-25%) was > 5% in only four of 16 series and > 10% in only one of them. The objective clinical failures (range, 0%-82%) was > 5% in 15 of 16 series and > 10% in 12 of them. The proportion exceeded 20% in five of 16 series. The cumulative failures (range, 0%-83%) was > 5% in all except one series and > 10% in 12 of 16 series; five series had a cumulative failure proportion > 20%. The most frequent complications were knee stiffness and anterior knee pain, whereas reoperations were primarily débridement and meniscectomies. Considering rerupture alone as a failure endpoint in patients who have undergone revision ACL reconstruction likely underestimates the real failure rate, because the percentage of failures noticeably increases when objective criteria are also considered. Whether patient-reported and subjective scores evaluating knee function, level of activity, satisfaction, and pain might also contribute to the definition of failure may be the focus of future studies. Level IV, therapeutic study.


Frequency dependence of plethysmographic volume in healthy and asthmatic subjects.
In airway obstruction, thoracic gas volume derived from mouth pressure vs. plethysmographic volume changes (TGVm) is overestimated, whereas TGVes, derived from esophageal pressure vs. plethysmographic volume changes, is not (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 52: 939-954, 1982). The reason appears to be that mouth pressure swings are less than alveolar pressure swings. We measured TGVm and TGVes in six normal subjects and in nine asthmatic patients before and during bronchospasm, while panting at the same lung volume at 0.8 Hz (low), 2-2.5 Hz (medium), and 4.5-5 Hz (high). No difference was observed between TGVm and TGVes (P greater than 0.05) at any frequency (f) in normal subjects or asthmatics before bronchospasm. During bronchospasm, TGVm and TGVes were similar at low f. However, TGVm increased from 5.66 +/- 1.16 (SD) liters at low f to 6.50 +/- 1.71 liters at medium f (P less than 0.01), resulting in a TGVm 1.16 +/- 0.95 liters higher than TGVes (P less than 0.01). In three asthmatics during bronchospasm, mean TGVm-TGVes difference was 0.01 liter at low f, 0.26 liter at medium f, and 0.73 liter at high f. Surprisingly TGVes was in average 5% higher at low f than at medium or high f, both in normal subjects and asthmatics. A similar pattern was observed for TGVm, except in asthmatics during bronchospasm. We conclude that in airway obstruction overestimation of TGVm is frequency dependent and can be avoided by panting at low f. However, at this f TGV is 5% larger than at higher f, difference which is not related to airway obstruction.


Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase.
Full activation of protein kinase B (PKB)/Akt requires phosphorylation on Thr-308 and Ser-473 by 3-phosphoinositide-dependent kinase-1 (PDK1) and Ser-473 kinase (S473K), respectively. Although PDK1 has been well characterized, the identification of the S473K remains controversial. A major PKB Ser-473 kinase activity was purified from the membrane fraction of HEK293 cells and found to be DNA-dependent protein kinase (DNA-PK). DNA-PK co-localized and associated with PKB at the plasma membrane. In vitro, DNA-PK phosphorylated PKB on Ser-473, resulting in a approximately 10-fold enhancement of PKB activity. Knockdown of DNA-PK by small interfering RNA inhibited Ser-473 phosphorylation induced by insulin and pervanadate. DNA-PK-deficient glioblastoma cells did not respond to insulin at the level of Ser-473 phosphorylation; this effect was restored by complementation with the human PRKDC gene. We conclude that DNA-PK is a long sought after kinase responsible for the Ser-473 phosphorylation step in the activation of PKB.


The puzzling construction of the conidial outer layer of Aspergillus fumigatus.
If the mycelium of Aspergillus fumigatus is very short-lived in the laboratory, conidia can survive for years. This survival capacity and extreme resistance to environmental insults is a major biological characteristic of this fungal species. Moreover, conidia, which easily reach the host alveola, are the infective propagules. Earlier studies have shown the role of some molecules of the outer conidial layer in protecting the fungus against the host defense. The outer layer of the conidial cell wall, directly in contact with the host cells, consists of α-(1,3)-glucan, melanin, and proteinaceous rodlets. This study is focused on the global importance of this outer layer. Single and multiple mutants without one to three major components of the outer layer were constructed and studied. The results showed that the absence of the target molecules resulting from multiple gene deletions led to unexpected phenotypes without any logical additivity. Unexpected compensatory cell wall surface modifications were indeed observed, such as the synthesis of the mycelial virulence factor galactosaminogalactan, the increase in chitin and glycoprotein concentration or particular changes in permeability. However, sensitivity of the multiple mutants to killing by phagocytic host cells confirmed the major importance of melanin in protecting conidia.


Predictors of physical activity in older adults early in an emergency hospital admission: a prospective cohort study.
Reduced mobility may be responsible for functional decline and acute sarcopenia in older hospitalised patients. The drivers of reduced in-hospital mobility are poorly understood, especially during the early phase of acute hospitalisation. We investigated predictors of in-hospital activity during a 24-h period in the first 48 h of hospital admission in older adults. This was a secondary analysis of a prospective repeated measures cohort study. Participants aged 75 years or older were recruited within the first 24 h of admission. At recruitment, patients underwent a baseline assessment including measurements of pre-morbid functional mobility, cognition, frailty, falls efficacy, co-morbidity, acute illness severity, knee extension strength and grip strength, and consented to wear accelerometers to measure physical activity during the first 7 days (or until discharge if earlier). In-hospital physical activity was defined as the amount of upright time (standing or walking). To examine the predictors of physical activity, we limited the analysis to the first 24 h of recording to maximise the sample size as due to discharge from hospital there was daily attrition. We used a best subset analysis including all baseline measures. The optimal model was defined by having the lowest Bayesian information criterion in the best-subset analyses. The model specified a maximum of 5 covariates and used an exhaustive search. Seventy participants were recruited but eight were excluded from the final analysis due to lack of accelerometer data within the first 24 h after recruitment. Patients spent a median of 0.50 h (IQR: 0.21; 1.43) standing or walking. The optimal model selected the following covariates: functional mobility as measured by the de Morton Mobility Index and two measures of illness severity, the National Early Warning Score, and serum C-reactive protein. Physical activity, particularly in the acute phase of hospitalisation, is very low in older adults. The association between illness severity and physical activity may be explained by symptoms of acute illness being barriers to activity. Interdisciplinary approaches are required to identify early mobilisation opportunities.


Genetic divergence and admixture of ancestral genome groups in the sugarcane variety 'RB867515' (Saccharum spp).
We analyzed 80 plants of the sugarcane (Saccharum spp) variety 'RB867515' in order to investigate its diversity and genetic structure at the molecular level. Four simple sequence repeat (SSR) loci (UGSM51, SMC1237, SEGMS1069, and UGSM38) and five expressed sequence tag (EST)-SSR loci (ESTA68, ESTB92, ESTB145, ESTC66, and ESTC84) were used as molecular markers. The polymorphic loci rate was 66.6%. A total of 17 alleles and an average of 1.88 alleles/locus were detected. The number of alleles in the EST-SSR loci was lower than the number of alleles in the SSRs of non-expressed loci. The mean observed heterozygosity among the nine SSR loci was 0.3291. Genetic structure analysis showed that 'RB867515' contains alleles from three ancestral groups (K = 3), but there is little admixing of alleles in the same plant (from 0.8 to 17.3%); only 1.88% of the plants shared alleles from two or three groups. ESTB92, ESTC84, and UGSM38 were monomorphic, but there was evidence of polymorphism in ESTA68, ESTB145, ESTC66, UGSM51, SMC1237, and SEGMS1069, indicating that 'RB867515' has variability at the molecular level and the potential to be used as a parent in breeding programs. The molecular variability observed in 'RB867515' indicates that the clone terminology that is used to identify this cultivar is inconsistent with the original meaning of "clone", which is defined as a sample of genetically identical plants.


Influence of optical source characteristics on the measurement of polarization-mode dispersion of highly mode-coupled fibers.
A new theoretical analysis of the interferometric polarization-mode dispersion (PMD) measurement predicts, in the limit of large PMD, a new relationship to the highly mode-coupled principal states model. This theory is confirmed by computer simulation of the ratio of the mean differential group delay (DGD) to the interferometric PMD. Jones matrix eigenanalysis and wavelength scanning with extrema counting are shown to measure the mean DGD independently of the optical source spectrum, whereas interferometrically measured PMD is shown to depend on the optical source spectrum as well as on the characteristics of the fiber to be measured.


Fragmentation in the future of work: A horizon scan examining the impact of the changing nature of work on workers experiencing vulnerability.
The future of work is characterized by changes that could disrupt all aspects of the nature and availability of work. Our study aims to understand how the future of work could result in conditions, which contribute to vulnerability for different groups of workers. A horizon scan was conducted to systematically identify and synthesize diverse sources of evidence, including academic and gray literature and resources shared over social media. Evidence was synthesized, and trend categories were developed through iterative discussions among the research team. Nine trend categories were uncovered, which included the digital transformation of the economy, artificial intelligence (AI)/machine learning-enhanced automation, AI-enabled human resource management systems, skill requirements for the future of work; globalization 4.0, climate change and the green economy, Gen Zs and the work environment; populism and the future of work, and external shocks to accelerate the changing nature of work. The scan highlighted that some groups of workers may be more likely to experience conditions that contribute to vulnerability, including greater exposure to job displacement or wage depression. The future of work could also create opportunities for labor market engagement. The future of work represents an emerging public health concern. Exclusion from the future of work has the potential to widen existing social and health inequities. Thus, tailored supports that are resilient to changes in the nature and availability of work are required for workers facing vulnerability.


Learning phenotype densities conditional on many interacting predictors.
Estimating a phenotype distribution conditional on a set of discrete-valued predictors is a commonly encountered task. For example, interest may be in how the density of a quantitative trait varies with single nucleotide polymorphisms and patient characteristics. The subset of important predictors is not usually known in advance. This becomes more challenging with a high-dimensional predictor set when there is the possibility of interaction. We demonstrate a novel non-parametric Bayes method based on a tensor factorization of predictor-dependent weights for Gaussian kernels. The method uses multistage predictor selection for dimension reduction, providing succinct models for the phenotype distribution. The resulting conditional density morphs flexibly with the selected predictors. In a simulation study and an application to molecular epidemiology data, we demonstrate advantages over commonly used methods.


Complete Genome Sequence of the Quality Control Strain Staphylococcus aureus subsp. aureus ATCC 25923.
Staphylococcus aureus subsp. aureus ATCC 25923 is commonly used as a control strain for susceptibility testing to antibiotics and as a quality control strain for commercial products. We present the completed genome sequence for the strain, consisting of the chromosome and a 27.5-kb plasmid.


The opioid peptides. A role in hypertension?
This review is an attempt to highlight evidence that may implicate the endogenous opioid system in the pathogenesis of hypertension in humans. The evidence raised includes biochemical, physiological, pharmacological, and behavioral studies conducted in in vitro and in vivo systems, experimental models of hypertension, and humans with essential hypertension. While the compelling biochemical and pharmacological evidence in experimental animals clearly shows the presence of opioid peptides and their receptors in strategic sites of cardiovascular control and potent cardiovascular response to opioid peptides, opioid antagonists show no consistent blockade or reversal of hypertension in experimental animals or humans. One possible explanation for this phenomenon could be the vast redundancy in systems regulating blood pressure (i.e., the blockade of one system still leaves many other systems fully able to rapidly offset the eliminated system). Regarding the opioid system, the situation is much more complex, since some opioid receptors (mu-type) mediate pressor responses, while other receptors (kappa-type) mediate depressor responses. Therefore, nonselective opioid receptor antagonists (e.g., naloxone), which block both types of receptors, can be devoid of any cardiovascular activity, while a selective mu-receptor antagonist or a selective and potent kappa-receptor agonist may produce the desired antihypertensive effect. A combination of both actions (i.e., a drug that is both a mu-antagonist and a kappa-agonist) might be even more advantageous. Until such compounds are developed, this hypothesis will be hard to prove.


Promotion and acceleration of diabetic ulcer healing by arginine-glycine-aspartic acid (RGD) peptide matrix. RGD Study Group.
To determine the effectiveness and safety of arginine-glycine-aspartic acid (RGD) peptide matrix in the treatment of diabetic foot ulcers. This randomized placebo-controlled investigator- and patient-blinded prospective multicenter investigation was conducted at three institutional and three private U.S. clinics providing ambulatory care. Sixty-five diabetic patients with chronic full-thickness neurotrophic foot ulcers were enrolled. Six discontinued the study because of adverse events. RGD peptide matrix (Argidene Gel; formerly Telio-Derm Gel) was applied topically twice weekly for up to 10 weeks in patients who otherwise received standard care. Control group patients received topical saline as a placebo plus standard care. The primary method of assessment was the incidence and rate of ulcer closure. All patients enrolled were included in the data analysis. The percentage of patients whose ulcers healed completely in the RGD peptide matrix group (35%; 14 of 40 patients) was over fourfold greater (P = 0.02) than that in the placebo group (8%; 2 of 25 patients). By the study end point (either day of healing or week 10), 30 of 40 (75%) RGD peptide matrix patients had achieved > 50% ulcer closure compared with 12 of 25 (48%) placebo patients (P = 0.03). RGD peptide matrix also significantly (P = 0.03) increased the rate of ulcer closure over the 10 weeks of the study. RGD peptide matrix treatment promoted and accelerated the healing of chronic diabetic foot ulcers to a significant degree.


Impact of percutaneous pulmonary valve implantation procedural steps on leaflets histology and mechanical behaviour: An in vitro study.
Percutaneous pulmonary valve implantation (PPVI) using the bovine jugular vein Melody(®) valve (Medtronic Inc., Minneapolis, MN, USA) is safe and effective. However, post-procedural complications have been reported, the reasons for which are unclear. To assess the impact of PPVI procedural steps on valvular histology and leaflet mechanical behaviour. Three different valved stents (the Melody(®) valve and two homemade stents with bovine and porcine pericardium) were tested in vitro under four conditions: (1) control group; (2) crimping; (3) crimping plus inflation of low-pressure balloon; (4) condition III plus post-dilatation (high-pressure balloon). For each condition, valvular leaflets (and a venous wall sample for Melody(®) stents) were taken for histological analysis and mechanical uniaxial testing of the valve leaflets. Among the Melody(®) valves, the incidence of transverse fractures was significantly higher in traumatized samples compared with the control group (P<0.05), whereas the incidence and depth of transverse fractures were not statistically different between the four conditions for bovine and porcine pericardial leaflets. No significant modification of the mechanical behaviour of in vitro traumatized Melody(®) valvular leaflets was observed. Bovine and porcine pericardia became more elastic and less resilient after balloon expansion and post-dilatation (conditions III and IV), with a significant decrease in elastic modulus and stress at rupture. Valved stent implantation procedural steps induced histological lesions on Melody(®) valve leaflets. Conversely, bovine and porcine pericardial valved stents were not histologically altered by in vitro manipulations, although their mechanical properties were significantly modified. These data could explain some of the long-term complications observed with these substitutes.


Fatty acid biosynthesis revisited: structure elucidation and metabolic engineering.
Fatty acids are primary metabolites synthesized by complex, elegant, and essential biosynthetic machinery. Fatty acid synthases resemble an iterative assembly line, with an acyl carrier protein conveying the growing fatty acid to necessary enzymatic domains for modification. Each catalytic domain is a unique enzyme spanning a wide range of folds and structures. Although they harbor the same enzymatic activities, two different types of fatty acid synthase architectures are observed in nature. During recent years, strained petroleum supplies have driven interest in engineering organisms to either produce more fatty acids or specific high value products. Such efforts require a fundamental understanding of the enzymatic activities and regulation of fatty acid synthases. Despite more than one hundred years of research, we continue to learn new lessons about fatty acid synthases' many intricate structural and regulatory elements. In this review, we summarize each enzymatic domain and discuss efforts to engineer fatty acid synthases, providing some clues to important challenges and opportunities in the field.


Association of serum transforming growth factor β1 with left ventricular hypertrophy in children with primary hypertension.
The current study was designed to assess the association of serum transforming growth factor β1 (TGF-β1) with left ventricular hypertrophy (LVH) in children with primary hypertension. The present single-center prospective trial examined 182 patients diagnosed with primary hypertension in Children's Hospital, Capital Institute of Pediatrics, between January 2021 and September 2022. Clinical data were analyzed, and ambulatory blood pressure was assessed for 24 h. LVH, the commonest subclinical cardiac feature of hypertension, was assessed by echocardiography. According to left ventricular geometry, cases were assigned to the LVH (n = 44) and normal geometry (n = 138) groups. Serum TGF-β1 amounts were quantitated by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curves were established to analyze various variables for their predictive values in LVH. Among 182 children with primary hypertension, the concentrations of serum TGF-β1 were higher in stage 2 hypertension than in stage 1 (47.3 (38.8, 52.5) vs. 46.0 (38.6, 48.2) ng/L, Z = - 2.376; P = 0.018). Additionally, serum TGF-β1 content showed a positive correlation with BP levels (P < 0.05). TGF-β1 amounts were significantly elevated in the LVH group compared with the normal geometry group (51.7 (46.1, 54.9) vs. 46.1 (38.7, 48.1) ng/L, Z = - 4.324; P = 0.0000). Serum TGF-β1 content was positively associated with LVH (r = 0.321, P = 0.0000). Multivariable logistic regression analysis showed BMI (OR = 1.188, 95% CI 1.082-1.305; P = 0.0000) and elevated serum TGF-β1 content (OR = 1.063, 95% CI 1.016-1.113; P = 0.009) independently predicted LVH. A multivariable logistic regression model considering BMI and TGF-β1 content in LVH prediction was 0.771, with sensitivity and specificity of 72.7% and 70.3%, respectively. These data revealed an association of serum TGF-β1 with BP in children with primary hypertension. Serum TGF-β1 concentration was positively correlated with hypertensive cardiac damage. Serum TGF-β1 might constitute a valuable molecular marker for the prediction of LVH in children with primary hypertension. The combination of BMI and TGF-β1 has a certain diagnostic and predictive value for LVH in children with primary hypertension, which may provide a new reference index for early clinical identification of hypertensive cardiac damage. • Experimental and clinical data indicated TGF-β1 is involved in BP elevation. • TGF-β1 is positively correlated with LVMI and hypertrophy in adults. • Our current study reveals an association of serum TGF-β1 with BP in children with primary hypertension. • Elevated serum TGF-β1 level is positively associated with LVH in children with primary hypertension. • The combination of BMI and TGF-β1 has a certain diagnostic and predictive value for LVH in children with primary hypertension.


Developmental potential of embryonic cells in a nucleocytoplasmic hybrid formed using a goldfish haploid nucleus and loach egg cytoplasm.
In teleosts, viable nucleocytoplasmic hybrids, formed by combining a nucleus from one species with the egg cytoplasm of another, have been used as one of the methods for breed improvement in aquaculture, but have been little exploited for developmental biology studies. Here, we used an artificial androgenesis technique to form nucleocytoplasmic hybrids comprising a goldfish haploid nucleus and loach egg cytoplasm. These hybrids were used to investigate interactions between the nucleus and cytoplasm during embryonic development. Additionally, the developmental characteristics of embryonic cells of nucleocytoplasmic hybrids were examined in chimeras produced by transplantation of blastomeres into recipient loach or goldfish embryos. We found that the nucleocytoplasmic hybrids arrested at the dome stage of embryonic development and did not form any gastrula structures. The goosecoid (gsc) and no tail (ntl) genes were expressed normally before gastrulation in nucleocytoplasmic hybrids, similar to diploid loach. However, expression of the gsc and ntl genes was not maintained in nucleocytoplasmic hybrids. In chimeric embryos, blastomeres derived from nucleocytoplasmic hybrids were found to mix with the cells of recipient loach embryos at the gastrula stage. The transplanted blastomeres formed small clusters at the somitogenesis stage and, finally, small spots at the hatching stage. In contrast, when the blastomeres were transplanted into goldfish embryos, the transplanted blastomeres aggregated in the chimeric embryos. Thus, embryonic cells from nucleocytoplasmic hybrids that arrest before gastrulation could survive beyond the somitogenesis stage depending on the cytoplasmic environment in the recipient embryos.


Pharmacokinetics of fentanyl after intravenous administration in isoflurane-anesthetized red-tailed hawks (Buteo jamaicensis) and Hispaniolan Amazon parrots (Amazona ventralis).
OBJECTIVE To compare the disposition of fentanyl citrate after a single IV injection in isoflurane-anesthetized red-tailed hawks (Buteo jamaicensis) and Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS 6 adult red-tailed hawks and 6 adult Hispaniolan Amazon parrots. PROCEDURES Anesthesia was induced and maintained with isoflurane; intermittent positive-pressure ventilation was provided. The minimum alveolar concentration of isoflurane was determined for each bird by use of the bracketing method and a supramaximal electrical stimulus. Fentanyl (20 μg/kg) was administered IV. Arterial (red-tailed hawks) or jugular venous (Hispaniolan Amazon parrots) blood samples were obtained immediately before and 1, 2, 4, 8, 15, 30, 60, 120, 180, 240, and 480 minutes (red-tailed hawks) and 1, 5, 10, 15, 30, 60, 120, and 180 minutes (Hispaniolan Amazon parrots) after fentanyl administration. RESULTS A 3-compartment and a 2-compartment model best described fentanyl pharmacokinetics in red-tailed hawks and Hispaniolan Amazon parrots, respectively. Median apparent volume of the central compartment and volume of distribution at steady state were 222 mL/kg and 987 mL/kg, respectively, for the red-tailed hawks and 5,108 mL/kg and 13,079 mL/kg, respectively, for the Hispaniolan Amazon parrots. Median clearance and elimination half-life were 8.9 mL/min/kg and 90.22 minutes, respectively, for the red-tailed hawks and 198.8 mL/min/kg and 51.18 minutes, respectively, for the Hispaniolan Amazon parrots. CONCLUSIONS AND CLINICAL RELEVANCE Pharmacokinetic results for fentanyl in isoflurane-anesthetized red-tailed hawks and Hispaniolan Amazon parrots indicated large differences and should strongly discourage extrapolation of doses between these 2 species.


Comparison of long-term variability for standard and short-wavelength automated perimetry in stable glaucoma patients.
To quantify and compare, on a point-by-point basis, the long-term variability of standard and short-wavelength automated perimetry in a group of stable glaucoma patients. From a group of 53 glaucoma patients experienced in visual field testing, we identified one eye, randomly chosen, from each of 25 glaucoma patients whose condition was found to be stable, based on both standard and short-wavelength automated perimetry visual field criteria. On each of three visits during a period of up to 3 months, each patient performed one standard and one short-wavelength automated perimetry 24-2 visual field in a random order on a Humphrey visual field analyzer. The long-term variability (also referred to as test-retest variability) was defined as the SD of the three threshold decibel values at each test location. The long-term variability for each test point (mean +/- SD) was determined separately for both standard visual fields and short-wavelength automated perimetry. With all 52 test locations of the 24-2 field averaged, the global long-term variability, mean (+/- SD) for standard visual fields and short-wavelength automated perimetry was 2.37 +/- 2.03 dB (95% confidence interval, 2.26-2.48 dB) and 2.92 +/- 2.03 dB (95% confidence interval, 2.81-3.03 dB), respectively (P <.0001). In 16 of the 52 visual field locations, long-term variability on short-wavelength automated perimetry was significantly higher than long-term variability on standard visual fields. In addition, the long-term variability increased with greater distance from the point of fixation for both standard visual fields and short-wavelength automated perimetry. The long-term variability decreased closer to fixation, more for standard visual fields than for short-wavelength automated perimetry. In a group of stable glaucoma patients, mean long-term variability was 0.55 dB higher for short-wavelength automated perimetry than for standard visual fields. This needs to be taken into consideration when serial visual fields are evaluated for change.


Small- bowel mucosal changes and antibody responses after low- and moderate-dose gluten challenge in celiac disease.
Due to the restrictive nature of a gluten-free diet, celiac patients are looking for alternative therapies. While drug-development programs include gluten challenges, knowledge regarding the duration of gluten challenge and gluten dosage is insufficient.We challenged adult celiac patients with gluten with a view to assessing the amount needed to cause some small-bowel mucosal deterioration. Twenty-five celiac disease adults were challenged with low (1-3 g) or moderate (3-5g) doses of gluten daily for 12 weeks. Symptoms, small-bowel morphology, densities of CD3+ intraepithelial lymphocytes (IELs) and celiac serology were determined. Both moderate and low amounts of gluten induced small-bowel morphological damage in 67% of celiac patients. Moderate gluten doses also triggered mucosal inflammation and more gastrointestinal symptoms leading to premature withdrawals in seven cases. In 22% of those who developed significant small- intestinal damage, symptoms remained absent. Celiac antibodies seroconverted in 43% of the patients. Low amounts of gluten can also cause significant mucosal deterioration in the majority of the patients. As there are always some celiac disease patients who will not respond within these conditions, sample sizes must be sufficiently large to attain to statistical power in analysis.


Interferometric model for phase analysis in fiber couplers.
An interferometric model is proposed to estimate the phase differences in lossless, strongly coupled biconical fiber couplers. This approximate method is simpler than the traditional s-parameter network theory-based analysis technique and minimizes the number of unknowns. The phase difference between the transmitted and coupled light fields is directly related to the field interaction and can be estimated by employing the energy conservation and mode orthogonality principles. The maximum coupling coefficient and dependence of phase difference on coupling conditions can be analyzed for multiport single-mode fiber couplers.


Trends in infant bedding use: National Infant Sleep Position study, 1993-2010.
Use of potentially hazardous bedding, as defined by the American Academy of Pediatrics (eg, pillows, quilts, comforters, loose bedding), is a modifiable risk factor for sudden infant death syndrome and unintentional sleep-related suffocation. The proportion of US infants sleeping with these types of bedding is unknown. To investigate the US prevalence of and trends in bedding use, we analyzed 1993-2010 data from the National Infant Sleep Position study. Infants reported as being usually placed to sleep with blankets, quilts, pillows, and other similar materials under or covering them in the last 2 weeks were classified as bedding users. Logistic regression was used to describe characteristics associated with bedding use. From 1993 to 2010, bedding use declined but remained a widespread practice (moving average of 85.9% in 1993-1995 to 54.7% in 2008-2010). Prevalence was highest for infants of teen-aged mothers (83.5%) and lowest for infants born at term (55.6%). Bedding use was also frequently reported among infants sleeping in adult beds, on their sides, and on a shared surface. The rate of decline in bedding use was markedly less from 2001-2010 compared with 1993-2000. For 2007 to 2010, the strongest predictors (adjusted odds ratio: ≥1.5) of bedding use were young maternal age, non-white race and ethnicity, and not being college educated. Bedding use for infant sleep remains common despite recommendations against this practice. Understanding trends in bedding use is important for tailoring safe sleep interventions.


Tumor intrinsic subtype is reflected in cancer-adjacent tissue.
Overall survival of early-stage breast cancer patients is similar for those who undergo breast-conserving therapy (BCT) and mastectomy; however, 10% to 15% of women undergoing BCT suffer ipsilateral breast tumor recurrence. The risk of recurrence may vary with breast cancer subtype. Understanding the gene expression of the cancer-adjacent tissue and the stromal response to specific tumor subtypes is important for developing clinical strategies to reduce recurrence risk. We utilized two independent datasets to study gene expression data in cancer-adjacent tissue from invasive breast cancer patients. Complementary in vitro cocultures were used to study cell-cell communication between fibroblasts and specific breast cancer subtypes. Our results suggest that intrinsic tumor subtypes are reflected in histologically normal cancer-adjacent tissue. Gene expression of cancer-adjacent tissues shows that triple-negative (Claudin-low or basal-like) tumors exhibit increased expression of genes involved in inflammation and immune response. Although such changes could reflect distinct immune populations present in the microenvironment, altered immune response gene expression was also observed in cocultures in the absence of immune cell infiltrates, emphasizing that these inflammatory mediators are secreted by breast-specific cells. In addition, although triple-negative breast cancers are associated with upregulated immune response genes, luminal breast cancers are more commonly associated with estrogen-response pathways in adjacent tissues. Specific characteristics of breast cancers are reflected in the surrounding histologically normal tissue. This commonality between tumor and cancer-adjacent tissue may underlie second primaries and local recurrences. Biomarkers derived from cancer-adjacent tissue may be helpful in defining personalized surgical strategies or in predicting recurrence risk.


Exercise for vasomotor menopausal symptoms.
Evidence suggests that many perimenopausal and early postmenopausal women will experience menopausal symptoms; hot flushes are the most common. Symptoms caused by fluctuating levels of oestrogen may be alleviated by hormone therapy (HT), but a marked global decline in its use has resulted from concerns about the risks and benefits of HT. Consequently, many women are seeking alternatives. As large numbers of women are choosing not to take HT, it is increasingly important to identify evidence-based lifestyle modifications that have the potential to reduce vasomotor menopausal symptoms. To examine the effectiveness of any type of exercise intervention in the management of vasomotor symptoms in symptomatic perimenopausal and postmenopausal women. Searches of the following electronic bibliographic databases were performed to identify randomised controlled trials (RCTs): Cochrane Menstrual Disorders and Subfertility Group Specialised Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley Internet interface), MEDLINE (Ovid), EMBASE (Ovid), PsycINFO (Ovid), the Science Citation Index and the Social Science Citation Index (Web of Science), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (Ovid) and SPORTDiscus. Searches include findings up to 3 March 2014. RCTs in which any type of exercise intervention was compared with no treatment/control or other treatments in the management of menopausal vasomotor symptoms in symptomatic perimenopausal/postmenopausal women. Five studies were deemed eligible for inclusion. Two review authors independently selected the studies, and three review authors independently extracted the data. The primary review outcome was vasomotor symptoms, defined as hot flushes and/or night sweats. We combined data to calculate standardised mean differences (SMDs) with 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I(2) statistic. We assessed the overall quality of the evidence for main comparisons using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods. We included five RCTs (733 women) comparing exercise with no active treatment, exercise with yoga and exercise with HT. The evidence was of low quality: Limitations in study design were noted, along with inconsistency and imprecision. In the comparison of exercise versus no active treatment (three studies, n = 454 women), no evidence was found of a difference between groups in frequency or intensity of vasomotor symptoms (SMD -0.10, 95% CI -0.33 to 0.13, three RCTs, 454 women, I(2) = 30%, low-quality evidence). Nor was any evidence found of a difference between groups in the frequency or intensity of vasomotor symptoms when exercise was compared with yoga (SMD -0.03, 95% CI -0.45 to 0.38, two studies, n = 279 women, I(2) = 61%, low-quality evidence). It was not possible to include one of the trials in the meta-analyses; this trial compared three groups: exercise plus soy milk, soy milk only and control; results favoured exercise relative to the comparators, but study numbers were small. One trial compared exercise with HT, and the HT group reported significantly fewer flushes in 24 hours than the exercise group (mean difference 5.8, 95% CI 3.17 to 8.43, 14 participants). None of the trials found evidence of a difference between groups with respect to adverse effects, but data were very scanty. Evidence was insufficient to show whether exercise is an effective treatment for vasomotor menopausal symptoms. One small study suggested that HT is more effective than exercise. Evidence was insufficient to show the relative effectiveness of exercise when compared with HT or yoga.


The influence of occupational class and physical workload on working life expectancy among older employees.
Objective This study investigates the impact of physical workload factors and occupational class on working life expectancy (WLE) and working years lost (WYL) in a sample of older Finnish workers. Methods A 70% random sample of Finns in 2004 was linked to a job exposure matrix for physical workload factors and register information on occupational class and labor market status until 2014. Transitions between being at work, time-restricted work disability, unemployment, economic inactivity, disability retirement, retirement and death were estimated. A multistate Cox regression model with transition-specific covariates was used to estimate the WLE and WYL at age 50 up to 63 years for each occupational class and physical workload factor for men and women (N=415 105). Results At age 50, male and female manual workers had a WLE of 10.13 and 10.14 years, respectively. Among both genders, manual workers had one year shorter WLE at age 50 than upper non-manual employees. This difference was largely attributable to unemployment (men: 0.60, women: 0.66 years) and disability retirement (men: 0.28, women: 0.29 years). Self-employed persons had the highest WLE (11.08 years). Men and women exposed to four or five physical workload factors had about one year lower WLE than non-exposed workers. The difference was primarily attributable to ill-health-related reasons, including disability retirement (men: 0.45 years, women: 0.53 years) and time-restricted work disability (men: 0.23, women: 0.33 years). Conclusions Manual workers and those exposed to physical workload factors had the lowest WLE. The differences in WYL between exposure groups can primarily be explained by ill-health-based exit routes.


Genomic and clinical characterization of stromal infiltration markers in prostate cancer.
The progression of prostate cancer is a complex, multistep process that involves molecular alterations in cells of the tumor and the microenvironment, with associated interactions between the stroma and epithelium. Genomic expression analyses of stromal infiltration markers were performed to determine the significance thereof in prostate cancer. Genome-wide expression profiles of formalin-fixed, paraffin-embedded radical prostatectomy samples were evaluated from a prospective registry cohort (n = 5239) and 3 retrospective institutional cohorts (n = 1135). Two independent stromal gene expression signatures implied stromal infiltration. Cox proportional hazards regression defined the association between stromal infiltration expression and metastasis-free survival (MFS). Stromal expression scores were correlated with stromal signature genes and with other key stromal markers (CAV1, VIM, and TAGLN), basal activity, and CD3 and CD4 immune biomarkers (r > 0.5 for all). The top decile of stromal expression was associated with high genomic risk scores (Decipher ≥ 0.6) , high Cancer of the Prostate Risk Assessment-Postsurgical scores, Gleason 9 to 10 disease, and a higher risk for metastasis (hazard ratio, 2.35; 95% CI, 1.37-4.02; P = .001). A higher stromal infiltration score was also associated with decreased expression of DNA repair genes and higher radiation sensitivity genomic scores. Postoperative radiation therapy (RT) was associated with an MFS benefit for patients with high stromal scores, but not for patients with low stromal scores (Pinteraction = .02). Expression of stromal infiltration markers is correlated with prostate cancer aggressiveness/progression and may be predictive of a response to RT. Stromal infiltration markers should be studied and considered for incorporation into clinical prognostication and decision making.


City planning and population health: a global challenge.
Significant global health challenges are being confronted in the 21st century, prompting calls to rethink approaches to disease prevention. A key part of the solution is city planning that reduces non-communicable diseases and road trauma while also managing rapid urbanisation. This Series of papers considers the health impacts of city planning through transport mode choices. In this, the first paper, we identify eight integrated regional and local interventions that, when combined, encourage walking, cycling, and public transport use, while reducing private motor vehicle use. These interventions are destination accessibility, equitable distribution of employment across cities, managing demand by reducing the availability and increasing the cost of parking, designing pedestrian-friendly and cycling-friendly movement networks, achieving optimum levels of residential density, reducing distance to public transport, and enhancing the desirability of active travel modes (eg, creating safe attractive neighbourhoods and safe, affordable, and convenient public transport). Together, these interventions will create healthier and more sustainable compact cities that reduce the environmental, social, and behavioural risk factors that affect lifestyle choices, levels of traffic, environmental pollution, noise, and crime. The health sector, including health ministers, must lead in advocating for integrated multisector city planning that prioritises health, sustainability, and liveability outcomes, particularly in rapidly changing low-income and middle-income countries. We recommend establishing a set of indicators to benchmark and monitor progress towards achievement of more compact cities that promote health and reduce health inequities.


Investigation of Bovine Serum Albumin (BSA) Attachment onto Self-Assembled Monolayers (SAMs) Using Combinatorial Quartz Crystal Microbalance with Dissipation (QCM-D) and Spectroscopic Ellipsometry (SE).
Understanding protein adsorption kinetics to surfaces is of importance for various environmental and biomedical applications. Adsorption of bovine serum albumin to various self-assembled monolayer surfaces including neutral and charged hydrophilic and hydrophobic surfaces was investigated using in-situ combinatorial quartz crystal microbalance with dissipation and spectroscopic ellipsometry. Adsorption of bovine serum albumin varied as a function of surface properties, bovine serum albumin concentration and pH value. Charged surfaces exhibited a greater quantity of bovine serum albumin adsorption, a larger bovine serum albumin layer thickness, and increased density of bovine serum albumin protein compared to neutral surfaces at neutral pH value. The quantity of adsorbed bovine serum albumin protein increased with increasing bovine serum albumin concentration. After equilibrium sorption was reached at pH 7.0, desorption of bovine serum albumin occurred when pH was lowered to 2.0, which is below the isoelectric point of bovine serum albumin. Our data provide further evidence that combinatorial quartz crystal microbalance with dissipation and spectroscopic ellipsometry is a sensitive analytical tool to evaluate attachment and detachment of adsorbed proteins in systems with environmental implications.


Angle-resolved synchrotron photoemission and density functional theory on the iridium modified Si(1 1 1) surface.
The physical and electronic properties of the Ir modified Si(1 1 1) surface have been investigated with the help of angle resolved photoemission spectroscopy and density functional theory. The surface consists of Ir-ring clusters that form a [Formula: see text]reconstruction. A comparison between the measured and calculated band structure of the system reveals that the dispersions of the projected bulk states and the states originating from [Formula: see text] domains are heavily modified due to Umklapp scattering from the surface Brillouin zone. Density of states calculations show that Ir-ring clusters contribute to the states in the vicinity of the Fermi level.


When pain meets … pain-related choice behavior and pain perception in different goal conflict situations.
Individuals in pain often face the choice between avoiding pain and pursuing other equally valued goals. However, little is known about pain-related choice behavior and pain perception in goal conflict situations. Seventy-eight healthy volunteers performed a computerized task requiring repeated choices between incompatible options, differing in their effect on probability to receive painful stimulation and money. Depending on group assignment, participants chose between increased pain probability versus decreased money probability (avoidance-avoidance conflict situation); decreased pain probability versus increased money probability (approach-approach conflict situation); or decrease versus increase in both probabilities (double approach/avoidance conflict situation). During the choice task, participants rated painfulness, unpleasantness, threat, and fearfulness associated with the painful stimulation and how they felt. Longer choice latency and more choice switching were associated with higher retrospective ratings of conflict and of decision difficulty, and more equal importance placed on pain avoidance and earning money. Groups did not differ in choice behavior, pain stimulus ratings, or affect. Across groups, longer choice latencies were nonsignificantly associated with higher pain, unpleasantness, threat, and fearfulness. In the avoidance-avoidance group, more choice switching was associated with higher pain-related threat and fearfulness, and with more negative affect. These results of this study suggest that associations between choice behaviors, pain perception, and affect depend on conflict situation. We present a first experimental demonstration of the relationship between pain-related choice behaviors, pain, and affect in different goal conflict situations. This experimental approach allows us to examine these relationships in a controlled fashion. Better understanding of pain-related goal conflicts and their resolution may lead to more effective pain treatment.


Comparison of cranial facet joint violation rates between open and percutaneous pedicle screw placement using intraoperative 3-D CT (O-arm) computer navigation.
Retrospective study comparing cranial facet joint violation rates of open and percutaneous pedicle screws inserted using 3-dimensional image-guidance. To determine the rate of cranial facet joint violation in intraoperative computed tomography (CT) image-guided lumbar pedicle screw instrumentation and compare facet joint violation rates between CT image-guided open and percutaneous techniques. Facet joint violation by pedicle screws can potentially result in a higher rate of adjacent segment degeneration. Reported cranial facet joint violation rates range from 7% to 100%. Intraoperative image-guidance, which has enhanced pedicle screw placement accuracy, may aid in avoiding impingement of the cranial facet joints. We reviewed 188 cases of 3-dimensional image-guided lumbar pedicle screw instrumentation from November 2006 to December 2011. The cranial screws of each construct were graded by 3 reviewers according to the Seo classification (0 = no impingement; 1 = screw head in contact/suspected to be in contact with joint; 2 = screw clearly invaded the joint) on intraoperative axial CT images. If there was a difference in evaluation, a consensus was reached to arrive at a single grade. The χ2 test was used to determine significance between the open and percutaneous group (α = 0.05). A total of 370 screws (245 open, 125 percutaneous) were graded. Overall facet joint violation rate was 18.9% (grade 1 = 16.2%, grade 2 = 2.7%). Open technique (grade 1 = 22.4%, grade 2 = 4.1%) had a significantly higher violation rate than percutaneous technique (grade 1 = 4%, grade 2 = 0%) (P < 0.0001). There is a trend of an increasing likelihood of facet joint violation from L1 to L5. The use of intraoperative CT image-guidance in lumbar pedicle screw placement resulted in a facet joint violation rate at the lower end of the reported range in literature. The percutaneous technique has a significantly lower facet violation rate than the open technique. 4.


Perceived and objectively measured physical activity and sedentary time among South Asian women in the UK.
Limited self-report data suggest that South Asian (SA) women fail to meet physical activity (PA) recommendations. Recent research using objective measures reveals SA women living in the UK have higher PA levels than previously reported, and a pattern of under-reporting PA and sedentary time (ST). There is limited research on SA women's understanding and experiences of PA/ST, and the cultural contexts and conditions within which they occur. Therefore the aims of this mixed-methods study were to compare perceived PA and ST to objectively measured data and explore PA- and ST-specific contexts, experiences, and sources of PA and ST amongst SA women in the UK. 24 women were purposively sampled to participate in a semi-structured interview from a larger study of 140 women who wore an accelerometer for 7 days. Demographic and anthropometric data were also collected. Notable qualitative themes on contextualisation were of adequate PA as "keeping busy" or "being healthy", and of ST as "lazy" or "resting in old age". Few participants reported being sedentary, and most believed they were sufficiently physically active. Objectively measured PA/ST indicated that 66% women were less active than perceived (with regard to duration and intensity), with none able to estimate duration of ST. Findings suggest that overall, SA women have contextualisations of PA/ST that may not coincide with those of researchers, health professionals and policy makers, and lack awareness of the intensity of PA in which they engage and the health risks of high levels of ST. These findings highlight the need for objective measures of PA and ST in this population combined with in-depth qualitative assessments to provide more accurate assessments of these behaviours. This information can subsequently be used to develop health promotion messages and interventions focusing on increasing duration and/or intensity levels of daily activities (e.g., walking, housework) and reducing ST in this population.


Processing social participation: an event-related brain potential study.
We examined the electrophysiological correlates of the processing of social exclusion and inclusion by using a modified version of the Cyberball paradigm. Exclusion was found to be associated with a significant increase in the P3 complex. The frontal-central P3a was primarily related to the affective processing of rejection, whereas the late parietal P3b was associated with its perceived intensity. The expression of P3a and negative mood did also depend on the earlier experience; earlier inclusion affected the processing of exclusion, and vice versa. In conclusion, our data indicate that the complex process of social rejection can be tracked by using event-related brain potentials.


LEAD STUDIES : III. THE EFFECTS OF LEAD ON RED BLOOD CELLS. PART 3. A CHEMICAL EXPLANATION OF THE REACTION OF LEAD WITH RED BLOOD CELLS.
These three papers have developed the following facts, which suffice to explain completely the anemia of lead poisoning. In vitro, the exposure to a very small amount of lead greatly changes the surface of the red blood cells. Their permeability to water is so altered that they shrink and are incapable of swelling as much as normal cells. With this is associated a marked increase in the resistance to different osmotic surroundings-demonstrated by far less hemolysis than normal in salt solution of very low concentrations. The "leaded" cells, however, are relatively short lived, and hemolyze readily as the result of slight trauma. These observations can also be demonstrated in vivo as experiments with rabbits with acute lead poisoning show. In addition to these effects on permeability, lead alters the physical properties of red blood cells so that they lose their normal stickiness and are no longer agglutinated by the sera of different isoagglutinating groups. All these changes are evidence of an effect on the surface of the cell; the interior of the cell does not undergo disturbances; at least, the physiological properties of the hemoglobin remain normal. The chemical reaction which causes these physical changes in the cell is a precipitation of insoluble lead phosphate and a formation of acid. This causes the "leaded" red blood cell to change from an elastic distensible sac, to one which is contracted, relatively inelastic and brittle. In such condition the cell can poorly withstand the trauma involved in circulation of the blood, and this lack of resistance probably explains the marked destruction of peripheral blood in lead poisoning.


Retaining Mechanical Properties of GMA-Welded Joints of 9%Ni Steel Using Experimentally Produced Matching Ferritic Filler Metal.
Motivated by the loss of tensile strength in 9%Ni steel arc-welded joints performed using commercially available Ni-based austenitic filler metals, the viability of retaining tensile strength using an experimentally produced matching ferritic filler metal was confirmed. Compared to the austenitic Ni-based filler metal (685 MPa), higher tensile strength in gas metal arc (GMA) welded joints was achieved using a ferritic filler metal (749 MPa) due to its microstructure being similar to the base metal (645 MPa). The microstructure of hard martensite resulted in an impact energy of 71 J (-196 °C), which was two times higher than the specified minimum value of ≥34 J. The tensile and impact strength of the welded joint is affected not only by its microstructure, but also by the degree of its mechanical mismatch depending on the type of filler metal. Welds with a harder microstructure and less mechanical mismatch are important for achieving an adequate combination of tensile strength and notched impact strength. This is achievable with the cost-effective ferritic filler metal. A more desirable combination of mechanical properties is guaranteed by applying low preheating temperature (200 °C), which is a more practicable and economical solution compared to the high post-weld heat treatment (PWHT) temperature (580 °C) suggested by other research.


Evaluation of HLA matching in unrelated hematopoietic stem cell transplantation for nonmalignant disorders.
The importance of human leukocyte antigen (HLA) matching in unrelated donor transplantation for nonmalignant diseases (NMD) has yet to be defined. We analyzed data from 663 unrelated marrow and peripheral blood stem cell transplants performed from 1995 to 2007 for treatment of NMD. Transplantation from a donor mismatched at the HLA-A, -B, -C, or -DRB1, but not -DQB1 or -DPB1, loci was associated with higher mortality in multivariate analyses (P = .002). The hazard ratio for mortality for single (7/8) and double mismatched (6/8) transplants was 1.29 (0.97-1.72; P = .079) and 1.82 (1.30-2.55; P = .0004), respectively, compared with 8/8 matched transplants. HLA mismatches were not associated with acute or chronic GVHD, but were strongly associated with graft failure. After adjustment for other factors, the odds ratio for graft failure for 7/8 and 6/8 (allele and/or antigen) matched pairs compared with 8/8 matched transplants was 2.81 (1.74-4.54; P < .0001) and 2.22 (1.26-3.97; P = .006), respectively. Patients with NMD should receive transplants from allele matched (8/8) donors if possible. Unlike the case with malignancies, HLA mismatching in NMD is associated with graft failure rather than GVHD.


The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men.
To elucidate the role of leptin in regulating neuroendocrine and metabolic function during an acute fast, six to eight healthy, lean men were studied under four separate conditions: a baseline fed state and three 72-hour fasting studies with administration of either placebo, low-dose recombinant-methionyl human leptin (r-metHuLeptin), or replacement-dose r-metHuLeptin designed to maintain serum leptin at levels similar to those in the fed state. Replacement-dose r-metHuLeptin administered during fasting prevents the starvation-induced changes in the hypothalamic-pituitary-gonadal axis and, in part, the hypothalamic-pituitary-thyroid axis and IGF-1 binding capacity in serum. Thus, in normal men, the fall in leptin with fasting may be both necessary and sufficient for the physiologic adaptations of these axes, which require leptin levels above a certain threshold for activation. In contrast to findings in mice, fasting-induced changes in the hypothalamic-pituitary-adrenal, renin-aldosterone, and growth hormone-IGF-1 axes as well as fuel utilization may be independent of leptin in humans. The role of leptin in normalizing several starvation-induced neuroendocrine changes may have important implications for the pathophysiology and treatment of eating disorders and obesity.


Continuing psychological care.
This article draws together thoughts derived from an experienced clinical psychologist's practice, with parents of ill and premature infants in the context of a psychological service for children and parents in a paediatric and maternity teaching hospital. Parents were those referred by attendant neonatologists in intensive neonatal care who observed acute distress. Referral was usually some weeks after birth and help continued until after discharge, in some instances after the death of the infant. The particular approach adopted was that of offering parents a therapeutic contact which, allowed them talk over these thoughts and feelings for which they had little other skilled listening environment. Parents chose the opportunity of a safe, calm and confidential contact to explore deep feelings and draw on their own strengths and an understanding of their own vulnerabilities. The novel insights derived and the clinical material presented were used to develop an understanding of the issues a support service should address. Key aims are described and should be incorporated to restore and enhance personal strengths and the mother child relationship hence contributing to positive outcome in infant development. Reference is made to the importance of understanding how women achieve soothed states and restoration of empowerment when birth presents extra challenge.


Medical talc pleurodesis: which patient with cancer benefits least?
Successful talc pleurodesis (TP) for malignant pleural effusion (MPE) gives symptom relief, but may be too exhaustive in cases with poor performance status. The selection of eligible patients is therefore a challenging task. The study was undertaken to evaluate frequency of successful TPs, side effects, complications, performance status, hospitalization time, remaining time alive, and the responsible physician's prediction of a successful TP judged by radiologic findings prior to TP. Side effects of TPs performed during a 1-year period were consecutively recorded and the TP outcomes were retrospectively evaluated 6 years later. TP success rate was 56% and 79% among best support of care subjects (BSC; n=10) and subjects eligible for cancer therapy (non-BSC; n=19), respectively, while side effects did not differ. Performance status was poorer and survival shorter among BSC subjects. Time spent in hospital of the remaining time alive for BSC and non-BSC subjects was 42%±27% and 4%±4%, respectively. Poor performance status of subjects with lung cancer correlated with short survival time, which in turn correlated with many days at hospital for TP. The physician's prediction of a successful TP was correct in 50% of all cases. Performance status of BSC subjects are probably too poor for TP and these subjects have to spend too much time at hospital during the procedure. The responsible physician is able to correctly predict a successful TP outcome in only every second case, supporting the need of additional predictive analysis.


Using sutures to attach miniature tracking tags to small bats for multimonth movement and behavioral studies.
Determining the detailed movements of individual animals often requires them to carry tracking devices, but tracking broad-scale movement of small bats (<30 g) has been limited by transmitter technology and long-term attachment methods. This limitation inhibits our understanding of bat dispersal and migration, particularly in the context of emerging conservation issues such as fatalities at wind turbines and diseases. We tested a novel method of attaching lightweight global positioning system (GPS) tags and geolocating data loggers to small bats. We used monofilament, synthetic, absorbable sutures to secure GPS tags and data loggers to the skin of anesthetized big brown bats (Eptesicus fuscus) in Colorado and hoary bats (Lasiurus cinereus) in California. GPS tags and data loggers were sutured to 17 bats in this study. Three tagged bats were recaptured 7 months after initial deployment, with tags still attached; none of these bats showed ill effects from the tag. No severe injuries were apparent upon recapture of 6 additional bats that carried tags up to 26 days after attachment; however, one of the bats exhibited skin chafing. Use of absorbable sutures to affix small tracking devices seems to be a safe, effective method for studying movements of bats over multiple months, although additional testing is warranted. This new attachment method has the potential to quickly advance our understanding of small bats, particularly as more sophisticated miniature tracking devices (e.g., satellite tags) become available.


Content analysis of subjective experiences in partial epileptic seizures.
A new content analysis method for systematically describing the phenomenology of subjective experiences in connection with partial epileptic seizures is described. Forty patients provided 262 descriptions of subjective experience relative to their partial epileptic seizures. The results revealed that subjective experiences during seizures consist mostly of sensory and bodily sensations, hallucinatory experiences, and thinking. The majority of subjective experiences during seizures are bizarre and distorted; nevertheless, the patients are able to engage in adequate behavior. To the best of our knowledge, this is the first study for which detailed subjective seizure descriptions were collected immediately after each seizure and the first study in which the content of verbal reports of subjective experiences during seizures, including both the ictal and postictal experiences, has been analyzed in detail.


Heme oxygenase-1 deletion affects stress erythropoiesis.
Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1) deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis. We used a transplant model to induce stress conditions. In irradiated recipients that received hmox(+/-) or hmox(+/+) bone marrow cells, we evaluated (i) the erythrocyte parameters in the peripheral blood; (ii) the staining intensity of CD71-, Ter119-, and CD49d-specific surface markers during erythroblast differentiation; (iii) the patterns of histological iron staining; and (iv) the number of Mac-1(+)-cells expressing TNF-α. In the spleens of mice that received hmox(+/-) cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1(+)-cells expressing TNF-α; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations. As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases.


Influence of galloyl moiety in interaction of epicatechin with bovine serum albumin: a spectroscopic and thermodynamic characterization.
The health benefits stemming from green tea are well known, but the exact mechanism of its biological activity is not elucidated. Epicatechin (EC) and epicatechin gallate (ECG) are two dietary catechins ubiquitously present in green tea. Serum albumins functionally carry these catechins through the circulatory system and eliminate reactive oxygen species (ROS) induced injury. In the present study ECG is observed to have higher antioxidant activity; which is attributed to the presence of galloyl moiety. The binding affinity of these catechins to bovine serum albumin (BSA) will govern the efficacy of their biological activity. EC and ECG bind with BSA with binding constants 1.0 × 10(6) M(-1) and 6.6 × 10(7) M(-1), respectively. Changes in secondary structure of BSA on interaction with EC and ECG have been identified by circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopy. Thermodynamic characterization reveals the binding process to be exothermic, spontaneous and entropy driven. Mixed binding forces (hydrophobic, electrostatic and hydrogen bonding) exist between ECG and BSA. Binding site for EC is primarily site-II in sub-domain IIIA of BSA and for ECG; it is site-I in sub-domain IIA. ECG with its high antioxidant activity accompanied by high affinity for BSA could be a model in drug designing.


Preliminary study on carprofen concentration measurements after transcutaneous treatment with Vetdrop® in a microfracture joint defect model in sheep.
The present preliminary study describes concentration time courses of the NSAID carprofen in the plasma and synovial fluid in a microfrature sheep model after transcutaneous treatments with a novel application device (Vetdrop®). To treat circumscribed inflammatory processes a transcutaneous application device could potentially be beneficial. After transcutaneous application normally lower systemic concentrations are measured which may reduce the incidence of side effects, whereas efficacy is still maintained. In this study carprofen was used based on its capacity to provide analgesia after orthopaedic procedures in sheep and it is considered that it may have a positive influence on the healing of cartilage in low concentrations. In all transcutaneously treated animals, carprofen plasma concentrations exceeded those of synovial fluid, although plasma levels remained significantly reduced (300-fold) as compared to carprofen administered intravenously. Furthermore, in contrast to the intravenously treated animals, a modest accumulation of carprofen in plasma and synovial fluid was observed in the transcutaneously treated animals over the 6-week treatment period. The transcutaneously administered carprofen using the Vetdrop® device penetrated the skin and both, plasma- and synovial concentrations could be measured repeatedly over time. This novel device may be considered a valuable transcutaneous drug delivery system.


Context-aware modeling of neuronal morphologies.
physical overlap between dendrites and axons constrain the circuit topology, and the precise shape and composition of dendrites determine the integration of inputs to produce an output signal. At the same time, morphologies are highly diverse and variant. The variance, presumably, originates from neurons developing in a densely packed brain substrate where they interact (e.g., repulsion or attraction) with other actors in this substrate. However, when studying neurons their context is never part of the analysis and they are treated as if they existed in isolation. Here we argue that to fully understand neuronal morphology and its variance it is important to consider neurons in relation to each other and to other actors in the surrounding brain substrate, i.e., their context. We propose a context-aware computational framework, NeuroMaC, in which large numbers of neurons can be grown simultaneously according to growth rules expressed in terms of interactions between the developing neuron and the surrounding brain substrate. As a proof of principle, we demonstrate that by using NeuroMaC we can generate accurate virtual morphologies of distinct classes both in isolation and as part of neuronal forests. Accuracy is validated against population statistics of experimentally reconstructed morphologies. We show that context-aware generation of neurons can explain characteristics of variation. Indeed, plausible variation is an inherent property of the morphologies generated by context-aware rules. We speculate about the applicability of this framework to investigate morphologies and circuits, to classify healthy and pathological morphologies, and to generate large quantities of morphologies for large-scale modeling.


Genomic Analysis and Comparison of Two Gonorrhea Outbreaks.
Gonorrhea is a sexually transmitted disease causing growing concern, with a substantial increase in reported incidence over the past few years in the United Kingdom and rising levels of resistance to a wide range of antibiotics. Understanding its epidemiology is therefore of major biomedical importance, not only on a population scale but also at the level of direct transmission. However, the molecular typing techniques traditionally used for gonorrhea infections do not provide sufficient resolution to investigate such fine-scale patterns. Here we sequenced the genomes of 237 isolates from two local collections of isolates from Sheffield and London, each of which was resolved into a single type using traditional methods. The two data sets were selected to have different epidemiological properties: the Sheffield data were collected over 6 years from a predominantly heterosexual population, whereas the London data were gathered within half a year and strongly associated with men who have sex with men. Based on contact tracing information between individuals in Sheffield, we found that transmission is associated with a median time to most recent common ancestor of 3.4 months, with an upper bound of 8 months, which we used as a criterion to identify likely transmission links in both data sets. In London, we found that transmission happened predominantly between individuals of similar age, sexual orientation, and location and also with the same HIV serostatus, which may reflect serosorting and associated risk behaviors. Comparison of the two data sets suggests that the London epidemic involved about ten times more cases than the Sheffield outbreak. The recent increases in gonorrhea incidence and antibiotic resistance are cause for public health concern. Successful intervention requires a better understanding of transmission patterns, which is not uncovered by traditional molecular epidemiology techniques. Here we studied two outbreaks that took place in Sheffield and London, United Kingdom. We show that whole-genome sequencing provides the resolution to investigate direct gonorrhea transmission between infected individuals. Combining genome sequencing with rich epidemiological information about infected individuals reveals the importance of several transmission routes and risk factors, which can be used to design better control measures.


Case Report: Prenatal Genetic Counseling to Parents of Fetuses Suspected of Having Ambiguous Genitalia.
The occurrence of fetuses suspected of having ambiguous genitalia will likely increase in the future. Currently, the impact of prenatal genetic counseling on parents' understanding and psychological preparedness has not been addressed. We provided prenatal genetic counseling to parents of two fetuses suspected of ambiguous genitalia. Case 1: At 22 weeks of gestation, swelling of the labia majora, and a clitoris-like structure were noted despite 46,XY detected in amniotic fluid cells. Case 2: At 28 weeks of gestation, bladder exstrophy and a scrotum-like structure were noted. At 32 weeks (Case 1) and 37 weeks (Case 2) of gestation, we shared information with parents regarding the possible difficulty of legal sex assignment at birth, and a scenario for registration of the birth certificate. At birth, both babies presented with ambiguous genitalia. For both cases, the parents remained calm on seeing their baby's genitalia for the first time. After a month, we shared medical information with parents, including karyotype, testosterone production capacity, and surgical schedule. In both cases parents assigned their respective baby's legal sex as male. Several months later, parents were questioned on prenatal genetic counseling. Case 1: Mother, "I was prepared to address our baby's genitalia calmly." Father, "I understood the procedure of legal sex assignment." Case 2: Mother, "Without counseling, I would have been more upset and worried." Father, "We were assured that multidisciplinary experts would support us." Prenatal genetic counseling provides reassurance to parents, who remain informed and emotionally secure throughout the legal sex assignment of their child.


Guidelines for Monitoring and Management of Pediatric Patients Before, During, and After Sedation for Diagnostic and Therapeutic Procedures.
The safe sedation of children for procedures requires a systematic approach that includes the following: no administration of sedating medication without the safety net of medical/dental supervision, careful presedation evaluation for underlying medical or surgical conditions that would place the child at increased risk from sedating medications, appropriate fasting for elective procedures and a balance between the depth of sedation and risk for those who are unable to fast because of the urgent nature of the procedure, a focused airway examination for large (kissing) tonsils or anatomic airway abnormalities that might increase the potential for airway obstruction, a clear understanding of the medication's pharmacokinetic and pharmacodynamic effects and drug interactions, appropriate training and skills in airway management to allow rescue of the patient, age- and size-appropriate equipment for airway management and venous access, appropriate medications and reversal agents, sufficient numbers of appropriately trained staff to both carry out the procedure and monitor the patient, appropriate physiologic monitoring during and after the procedure, a properly equipped and staffed recovery area, recovery to the presedation level of consciousness before discharge from medical/dental supervision, and appropriate discharge instructions. This report was developed through a collaborative effort of the American Academy of Pediatrics and the American Academy of Pediatric Dentistry to offer pediatric providers updated information and guidance in delivering safe sedation to children.


Construct relationships, psychological disorder and therapeutic change.
The problem of interpretation of construct relationships of abnormal content is considered in the context of the use of the repertory grid to assess therapeutic outcome in neurotics. With a view to providing a rationale for such interpretation, examples are presented of construct relationships indicative of psychopathology, and of predicted changes in them during therapy. Implications for the planning and evaluation of therapy are discussed, and the importance of exploring the personal meaning of the patient's complaints is emphasized.


Learning for heart failure patients (The L-HF patient study).
To investigate the learning style and preferences for information delivery of heart failure patients for the purpose of informing the design of educational resources. Patient education is a vital component of heart failure management programmes however the content and delivery of education varies in each programme. Traditionally education programmes for patients have focussed on educational needs as identified by health care providers however research has shown there are discrepancies between patients' and nurses' perceptions of the learning needs of heart failure patients. There is no evidence that educational programmes for heart failure patients are based on identification of patients learning needs or their preferred learning style. Qualitative. A purposive sample of 12 participants, diagnosed with heart failure and enrolled in a heart failure management programme, participated in semi-structured interviews. Four themes emerged: knowledge quest (L-loading), barriers to learning (L-inhibitors), facilitators for learning (L-agonists), and meeting educational needs (L-titration). Integral to these themes was the participant's relationship with health care professionals. This study provides unique information regarding the preferred learning modality of heart failure patients and, as such, serves to inform the development of appropriate education resources specifically tailored for this population. The development of effective modes of education is likely to further enhance heart failure management programmes service organisation and delivery and improve health outcomes for heart failure patients.


Dissecting the components of the humoral immune response elicited by DNA vaccines.
Although DNA vaccines appear to be efficient at inducing strong cellular immune responses, a number of questions remain regarding their ability to induce humoral immunity. The essential components for generating an antibody response include B and T cell recognition of antigen, subsequent activation, clonal expansion of each lymphocyte type and migration of T cells into B cell follicles to provide help, all leading to germinal centre formation and antibody production. We have employed a double adoptive transfer system based on ovalbumin (OVA)-specific CD4+ DO11.10 T cells and hen egg lysozyme (HEL)-specific MD4 B cells to assess all of these parameters in the context of DNA vaccination in vivo. We find that vaccination with DNA constructs expressing an OVA-HEL gene fusion (encoding contiguous T and B cell epitopes) can induce T cell activation, clonal expansion and migration into B cell follicles accompanied by B cell activation, blastogenesis, expansion and antibody production. These findings show that DNA vaccination can induce all of the components required for humoral immunity and also provide a system for in depth analysis of factors that influence the development of antibody responses. Such strategies may facilitate the rational design of vaccines capable of inducing effective humoral immunity.


Delivering Single-Walled Carbon Nanotubes to the Nucleus Using Engineered Nuclear Protein Domains.
Single-walled carbon nanotubes (SWCNTs) have great potential for cell-based therapies due to their unique intrinsic optical and physical characteristics. Consequently, broad classes of dispersants have been identified that individually suspend SWCNTs in water and cell media in addition to reducing nanotube toxicity to cells. Unambiguous control and verification of the localization and distribution of SWCNTs within cells, particularly to the nucleus, is needed to advance subcellular technologies utilizing nanotubes. Here we report delivery of SWCNTs to the nucleus by noncovalently attaching the tail domain of the nuclear protein lamin B1 (LB1), which we engineer from the full-length LMNB1 cDNA. More than half of this low molecular weight globular protein is intrinsically disordered but has an immunoglobulin-fold composed of a central hydrophobic core, which is highly suitable for associating with SWCNTs, stably suspending SWCNTs in water and cell media. In addition, LB1 has an exposed nuclear localization sequence to promote active nuclear import of SWCNTs. These SWCNTs-LB1 dispersions in water and cell media display near-infrared (NIR) absorption spectra with sharp van Hove peaks and an NIR fluorescence spectra, suggesting that LB1 individually disperses nanotubes. The dispersing capability of SWCNTs by LB1 is similar to that by albumin proteins. The SWCNTs-LB1 dispersions with concentrations ≥150 μg/mL (≥30 μg/mL) in water (cell media) remain stable for ≥75 days (≥3 days) at 4 °C (37 °C). Further, molecular dynamics modeling of association of LB1 with SWCNTs reveal that the exposure of the nuclear localization sequence is independent of LB1 binding conformation. Measurements from confocal Raman spectroscopy and microscopy, NIR fluorescence imaging of SWCNTs, and fluorescence lifetime imaging microscopy show that millions of these SWCNTs-LB1 complexes enter HeLa cells, localize to the nucleus of cells, and interact with DNA. We postulate that the modification of native cellular proteins as noncovalent dispersing agents to provide specific transport will open new possibilities to utilize both SWCNT and protein properties for multifunctional subcellular targeting applications. Specifically, nuclear targeting could allow delivery of anticancer therapies, genetic treatments, or DNA to the nucleus.


Comparative sequence analyses of genome and transcriptome reveal novel transcripts and variants in the Asian elephant Elephas maximus.
The Asian elephant Elephas maximus and the African elephant Loxodonta africana that diverged 5-7 million years ago exhibit differences in their physiology, behaviour and morphology. A comparative genomics approach would be useful and necessary for evolutionary and functional genetic studies of elephants. We performed sequencing of E. maximus and map to L. africana at ~15X coverage. Through comparative sequence analyses, we have identified Asian elephant specific homozygous, non-synonymous single nucleotide variants (SNVs) that map to 1514 protein coding genes, many of which are involved in olfaction. We also present the first report of a high-coverage transcriptome sequence in E. maximus from peripheral blood lymphocytes. We have identified 103 novel protein coding transcripts and 66-long non-coding (lnc)RNAs. We also report the presence of 181 protein domains unique to elephants when compared to other Afrotheria species. Each of these findings can be further investigated to gain a better understanding of functional differences unique to elephant species, as well as those unique to elephantids in comparison with other mammals. This work therefore provides a valuable resource to explore the immense research potential of comparative analyses of transcriptome and genome sequences in the Asian elephant.


The progressive ankylosis protein regulates cementum apposition and extracellular matrix composition.
Tooth root cementum is sensitive to modulation of inorganic pyrophosphate (PP(i)), an inhibitor of hydroxyapatite precipitation. Factors increasing PP(i) include progressive ankylosis protein (ANK) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) while tissue nonspecific alkaline phosphatase hydrolyzes PP(i). Studies here aimed to define the role of ANK in root and cementum by analyzing tooth development in Ank knock-out (KO) mice versus wild type. Periodontal development in KO versus control mice was analyzed by histology, histomorphometry, immunohistochemistry, in situ hybridization, electron microscopy, and nanoindentation. Cementoblast cultures were used in vitro to provide mechanistic underpinnings for PP(i) modulation of cell function. Over the course of root development, Ank KO cervical cementum became 8- to 12-fold thicker than control cervical cementum. Periodontal ligament width was maintained and other dentoalveolar tissues, including apical cementum, were unaltered. Cervical cementum uncharacteristically included numerous cells, from rapid cementogenesis. Ank KO increased osteopontin and dentin matrix protein 1 gene and protein expression, and markedly increased NPP1 protein expression in cementoblasts but not in other cell types. Conditional ablation of Ank in joints and periodontia confirmed a local role for ANK in cementogenesis. In vitro studies employing cementoblasts indicated that Ank and Enpp1 mRNA levels increased in step with mineral nodule formation, supporting a role for these factors in regulation of cementum matrix mineralization. ANK, by modulating local PP(i), controls cervical cementum apposition and extracellular matrix. Loss of ANK created a local environment conducive to rapid cementogenesis; therefore, approaches modulating PP(i) in periodontal tissues have potential to promote cementum regeneration.


MED-SuMoLig: a new ligand-based screening tool for efficient scaffold hopping.
The identification of small molecules with selective bioactivity, whether intended as potential therapeutics or as tools for experimental research, is central to progress in medicine and in the life sciences. To facilitate such study, we have developed a ligand-based program well-suited for effective screening of large compound collections. This package, MED-SuMoLig, combines a SMARTS-driven substructure search aiming at 3D pharmacophore profiling and computation of the local atomic density of the compared molecules. The screening utility was then investigated using 52 diverse active molecules (against CDK2, Factor Xa, HIV-1 protease, neuraminidase, ribonuclease A, and thymidine kinase) merged to a library of about 40,000 putative inactive (druglike) compounds. In all cases, the program recovered more than half of the actives in the top 3% of the screened library. We also compared the performance of MED-SuMoLig with that of ChemMine or of ROCS and found that MED-SuMoLig outperformed both methods for CDK2 and Factor Xa in terms of enrichment rates or performed equally well for the other targets.


Development of a Postgraduate Year 1 pharmacy residency program at a large teaching hospital.
The development, implementation, and early evaluation of a postgraduate year 1 (PGY1) pharmacy residency program at a large tertiary care hospital are described. In keeping with long-range initiatives by the American Society of Health-System Pharmacists (ASHP) and other pharmacy organizations to increase pharmacists' involvement in direct patient care and expand opportunities for advanced training, a PGY1 program was developed at Baystate Medical Center (BMC), a 653-bed hospital in Massachusetts. A residency advisory committee appointed in the fall of 2006 led the program development process, including curriculum planning, establishment of initial funding, recruitment procedures, and integration of faculty at an affiliated school of pharmacy (Massachusetts College of Pharmacy and Health Sciences). Recruitment efforts began in the fall of 2006; in the summer of 2007 the first group of PGY1 residents began a curriculum of 12 one-month core and elective learning experiences, as well as longitudinal direct-care experiences (e.g., performing medication reconciliations and related duties at an affiliated outpatient pharmacotherapy clinic) and teaching and management requirements. In the spring of 2009, the residency program received ASHP accreditation and federal funding for program expansion. The residency advisory committee's evaluation of early experience with the program guided adjustments in areas such as recruitment, applicant screening, resident selection, preceptor scheduling, monitoring of residents' progress through the program, and accreditation survey preparation. A PGY1 residency at BMC was developed to enhance the pharmacy department's clinical services. Residents were successfully recruited, and the program received accreditation within two years.


Basal body multipotency and axonemal remodelling are two pathways to a 9+0 flagellum.
Eukaryotic cilia/flagella exhibit two characteristic ultrastructures reflecting two main functions; a 9+2 axoneme for motility and a 9+0 axoneme for sensation and signalling. Whether, and if so how, they interconvert is unclear. Here we analyse flagellum length, structure and molecular composition changes in the unicellular eukaryotic parasite Leishmania during the transformation of a life cycle stage with a 9+2 axoneme (the promastigote) to one with a 9+0 axoneme (the amastigote). We show 9+0 axonemes can be generated by two pathways: by de novo formation and by restructuring of existing 9+2 axonemes associated with decreased intraflagellar transport. Furthermore, pro-basal bodies formed under conditions conducive for 9+2 axoneme formation can form a 9+0 axoneme de novo. We conclude that pro-centrioles/pro-basal bodies are multipotent and not committed to form either a 9+2 or 9+0 axoneme. In an alternative pathway structures can also be removed from existing 9+2 axonemes to convert them to 9+0.


Biological mechanisms in breast cancer invasiveness: relevance to preventive interventions.
Migration studies suggest that the high incidence of postmenopausal breast cancer in Western women is related mainly to epigenetic factors. Progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) also appears to involve environmental rather than genetic factors, and a role has been postulated for metabolic-endocrine changes related to the Western lifestyle. Protein kinase C (PKC) is important in cell signal transduction, and laboratory studies show that PKC stimulates the activities of urokinase plasminogen activator, matrix metalloproteinases and cell adhesion molecules, all of which are known to increase invasiveness in human mammary cancer cell lines. In rodents, the activity of PKC in tissue cells is enhanced by insulin, and PKC isoenzymes have been shown to stimulate the development of hyperinsulinaemic insulin resistance in rodents. Clinically, hyperinsulinaemia and the concomitant increase in circulating levels of free oestradiol and bioactive insulin-like growth factor 1 (IGF1) are each confirmed markers of high risk for breast cancer in women. Lesions of DCIS show evidence of regression with mammary involution, but it is postulated that this may be opposed by the concomitants of hyperinsulinaemic insulin resistance. The prevalence of the latter is increasing in Western populations, and a combination of high IGF1 and low IGF-binding protein 3 concentrations has been associated with the presence of DCIS lesions in premenopausal women. Measures that enhance insulin sensitivity in such women may reduce the risk of progression in DCIS lesions, and a clinical trial is proposed to test the hypothesis.


CRIB scores as a tool for assessing risk for the development of pulmonary hypertension in extremely preterm infants with bronchopulmonary dysplasia.
Bronchopulmonary dysplasia (BPD) increases the risk for developing pulmonary hypertension (PH). However, the risk factors associated with BPD-associated PH remain unclear. Our primary aim was to determine perinatal risk factors associated with the development of PH in infants with BPD. We retrospectively reviewed medical records of 303 infants born at ≤ 28 weeks' gestation. Infants were categorized as having no, mild, moderate, or severe BPD. PH was diagnosed by echocardiogram. Data were analyzed using Fisher exact test, two-sample t-test, and multivariable logistic regression. The incidence of PH in our cohort was 12%. Infants with PH had lower birth weights and gestational ages (p < 0.001). After controlling for confounding variables, severe BPD (p < 0.001), and higher Clinical Risk Index for Babies (CRIB) scores (p = 0.04) were associated with the development of PH. Severe BPD increases the risk for developing PH. Higher CRIB scores correlate with PH development in infants with BPD. We speculate that CRIB scores may allow for early categorization of preterm infants with a higher likelihood of developing PH.


Bayesian Small Area Estimates of Diabetes Incidence by United States County, 2009.
In the United States, diabetes is common and costly. Programs to prevent new cases of diabetes are often carried out at the level of the county, a unit of local government. Thus, efficient targeting of such programs requires county-level estimates of diabetes incidence-the fraction of the non-diabetic population who received their diagnosis of diabetes during the past 12 months. Previously, only estimates of prevalence-the overall fraction of population who have the disease-have been available at the county level. Counties with high prevalence might or might not be the same as counties with high incidence, due to spatial variation in mortality and relocation of persons with incident diabetes to another county. Existing methods cannot be used to estimate county-level diabetes incidence, because the fraction of the population who receive a diabetes diagnosis in any year is too small. Here, we extend previously developed methods of Bayesian small-area estimation of prevalence, using diffuse priors, to estimate diabetes incidence for all U.S. counties based on data from a survey designed to yield state-level estimates. We found high incidence in the southeastern United States, the Appalachian region, and in scattered counties throughout the western U.S. Our methods might be applicable in other circumstances in which all cases of a rare condition also must be cases of a more common condition (in this analysis, "newly diagnosed cases of diabetes" and "cases of diabetes"). If appropriate data are available, our methods can be used to estimate proportion of the population with the rare condition at greater geographic specificity than the data source was designed to provide.