Total Hip Arthroplasty or Hemiarthroplasty for Hip Fracture.
Globally, hip fractures are among the top 10 causes of disability in adults. For displaced femoral neck fractures, there remains uncertainty regarding the effect of a total hip arthroplasty as compared with hemiarthroplasty. We randomly assigned 1495 patients who were 50 years of age or older and had a displaced femoral neck fracture to undergo either total hip arthroplasty or hemiarthroplasty. All enrolled patients had been able to ambulate without the assistance of another person before the fracture occurred. The trial was conducted in 80 centers in 10 countries. The primary end point was a secondary hip procedure within 24 months of follow-up. Secondary end points included death, serious adverse events, hip-related complications, health-related quality of life, function, and overall health end points. The primary end point occurred in 57 of 718 patients (7.9%) who were randomly assigned to total hip arthroplasty and 60 of 723 patients (8.3%) who were randomly assigned to hemiarthroplasty (hazard ratio, 0.95; 95% confidence interval [CI], 0.64 to 1.40; P = 0.79). Hip instability or dislocation occurred in 34 patients (4.7%) assigned to total hip arthroplasty and 17 patients (2.4%) assigned to hemiarthroplasty (hazard ratio, 2.00; 99% CI, 0.97 to 4.09). Function, as measured with the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, pain score, stiffness score, and function score, modestly favored total hip arthroplasty over hemiarthroplasty. Mortality was similar in the two treatment groups (14.3% among the patients assigned to total hip arthroplasty and 13.1% among those assigned to hemiarthroplasty, P = 0.48). Serious adverse events occurred in 300 patients (41.8%) assigned to total hip arthroplasty and in 265 patients (36.7%) assigned to hemiarthroplasty. Among independently ambulating patients with displaced femoral neck fractures, the incidence of secondary procedures did not differ significantly between patients who were randomly assigned to undergo total hip arthroplasty and those who were assigned to undergo hemiarthroplasty, and total hip arthroplasty provided a clinically unimportant improvement over hemiarthroplasty in function and quality of life over 24 months. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT00556842.).


Dynamic Cerebral Autoregulation Is an Independent Functional Outcome Predictor of Mild Acute Ischemic Stroke.
Background and Purpose- Cerebral autoregulation is impaired in patients with acute ischemic stroke. The purpose of this study was to investigate whether dynamic cerebral autoregulation (dCA) indices constitute an independent functional outcome predictor of acute ischemic stroke. Methods- In this study, 86 patients at days 3 to 7 after acute ischemic stroke and 40 age- and sex-matched controls were enrolled for assessing their dCA indices under spontaneous hemodynamic fluctuations. The dCA indices of patients with favorable outcomes (modified Rankin Scale score ≤1 at 3 months, n=65), patients with unfavorable outcomes (modified Rankin Scale score ≥2 at 3 months, n=21), and controls were compared. Results- The dCA indices, namely the phase shift at very low frequency band (phase_VLF), in the patients with unfavorable outcomes were significantly worse than those in the patients with favorable outcomes. However, the phase_VLF in the patients with favorable outcomes did not differ from those in the controls. Impaired dCA was associated with elevated mean arterial pressure and large infarction volume but was also present in patients with normal mean arterial pressure or small infarction volume. Phase_VLF was a predictor of outcomes in the receiver operating characteristic analysis (area under the curve: 0.722; P<0.001). Multivariate analysis revealed that a phase_VLF value of <61° was independently associated with unfavorable outcomes (odds ratio=4.90; P=0.024). Conclusions- Phase_VLF is an independent functional outcome predictor of acute ischemic stroke.


Normative consent and presumed consent for organ donation: a critique.
Ben Saunders claims that actual consent is not necessary for organ donation due to 'normative consent', a concept he borrows from David Estlund. Combining normative consent with Peter Singer's 'greater moral evil principle', Saunders argues that it is immoral for an individual to refuse consent to donate his or her organs. If a presumed consent policy were thus adopted, it would be morally legitimate to remove organs from individuals whose wishes concerning donation are not known. This paper disputes Saunders' arguments. First, if death caused by the absence of organ transplant is the operational premise, then, there is nothing of comparable moral precedence under which a person is not obligated to donate. Saunders' use of Singer's principle produces a duty to donate in almost all circumstances. However, this premise is based on a flawed interpretation of cause and effect between organ availability and death. Second, given growing moral and scientific agreement that the organ donors in heart-beating and non-heart-beating procurement protocols are not dead when their organs are surgically removed, it is not at all clear that people have a duty to consent to their lives being taken for their organs. Third, Saunders' claim that there can be good reasons for refusing consent clashes with his claim that there is a moral obligation for everyone to donate their organs. Saunders' argument is more consistent with a conclusion of 'mandatory consent'. Finally, it is argued that Saunders' policy, if put into place, would be totalitarian in scope and would therefore be inconsistent with the freedom required for a democratic society.


A novel GLP-1/GIP dual receptor agonist protects from 6-OHDA lesion in a rat model of Parkinson's disease.
The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors that have shown neuroprotective effects in animal models of Parkinson's and Alzheimer's disease. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. GLP-1 analogues are currently on the market as treatments for type II diabetes. We previously showed that the novel dual agonist (DA-JC1) was effective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Here we demonstrate that DA-JC1 is neuroprotective in the 6-OHDA brain lesion rat model of PD. When treating rats for 6 weeks with DA-JC1 at 25 nmol/kg ip once-daily, motor activity as tested in the Rotarod and in the open field was much improved. In the amphetamine and apomorphine circling behaviour tests, the 6-OHDA induced impairments were much reduced by the DA-JC1 treatment. The number of TH positive dopaminergic neurons in the substantia nigra was decreased by 6-OHDA lesion and was increased by DA-JC1 treatment. Dopamine levels in the basal ganglia were reduced by 6-OHDA lesion and increased by DA-JC1. In western blot analysis, levels of the growth factor GDNF and pAkt/CREB cell signaling was enhanced by DA-JC1. The autophagy marker Beclin1 was also activated by the drug. The results demonstrate that dual GLP-1/GIP receptor agonists show promise as a novel treatment for PD.


The matrix metalloproteinase-7 polymorphism rs10895304 is associated with increased recurrence risk in patients with clinically localized prostate cancer.
To evaluate whether selected high-risk matrix metalloproteinase-7 single nucleotide polymorphisms influence clinicopathologic outcomes in patients with early-stage prostate cancer. Two hundred twelve prostate cancer patients treated with radical prostatectomy were evaluated with a median follow-up of 9.8 years. Genotyping was performed using hybridization with custom-designed allele-specific probes. Three single nucleotide polymorphisms within the matrix metalloproteinase-7 gene were assessed with respect to age at diagnosis, margin status, extracapsular extension, lymph node involvement, recurrence-free survival, and overall survival in paraffin-embedded prostate tissue specimens from patients with early-stage prostate cancer who underwent radical prostatectomy. Rs10895304 was the sole significant polymorphism. The A/G genotype of rs10895304 had a statistically significant association with recurrence-free survival in postprostatectomy patients (p = 0.0061, log-rank test). The frequency of the risk-reducing genotype (A/A) was 74%, whereas that of the risk-enhancing genotypes (A/G and G/G) were 20% and 6%, respectively. Multivariable Cox regression analyses detected a significant association between rs10895304 and recurrences after adjustment for known prognostic factors. The G allele of this polymorphism was associated with increased risk of prostate cancer recurrence (adjusted hazards ratio, 3.375; 95% confidence interval 1.567-7.269; p < 0.001). The other assayed polymorphisms were not significant, and no correlations were made to other clinical variables. The A/G genotype of rs10895304 is predictive of decreased recurrence-free survival in patients with clinically localized prostate cancer. Our data suggest that for this subset of patients, prostatectomy alone may not be adequate for local control. This is a novel and relevant marker that should be evaluated for improved risk stratification of patients who may be candidates for adjuvant radiation therapy to improve local control.


Correlation between knowledge-based and detailed atomic potentials: application to the unfolding of the GCN4 leucine zipper.
The relationship between the unfolding pseudo free energies of reduced and detailed atomic models of the GCN4 leucine zipper is examined. Starting from the native crystal structure, a large number of conformations ranging from folded to unfolded were generated by all-atom molecular dynamics unfolding simulations in an aqueous environment at elevated temperatures. For the detailed atomic model, the pseudo free energies are obtained by combining the CHARMM all-atom potential with a solvation component from the generalized Born, surface accessibility, GB/SA, model. Reduced model energies were evaluated using a knowledge-based potential. Both energies are highly correlated. In addition, both show a good correlation with the root mean square deviation, RMSD, of the backbone from native. These results suggest that knowledge-based potentials are capable of describing at least some of the properties of the folded as well as the unfolded states of proteins, even though they are derived from a database of native protein structures. Since only conformations generated from an unfolding simulation are used, we cannot assess whether these potentials can discriminate the native conformation from the manifold of alternative, low-energy misfolded states. Nevertheless, these results also have significant implications for the development of a methodology for multiscale modeling of proteins that combines reduced and detailed atomic models.


Who gets the disability grant in South Africa? An analysis of the characteristics of recipients in urban and rural areas.
This study was to establish whether there was a difference in the characteristics of people who received a disability grant and those who did not in rural and urban samples of isiXhosa-speaking people with disability in South Africa. The sample was a convenience sample and was identified through a 'snowballing' process. A demographic survey and isiXhosa versions of the International Classification of Functioning, Disability and Health (ICF) and EQ-5D, a health-related quality of life measure were utilized. The sample consisted of 244 rural and 61 urban respondents, demonstrating a preponderance of physical disabilities. The groups who received or did not receive grants were equivalent in terms of age, gender, marital status and employment status. A significantly higher proportion of rural dwellers accessed the grant. The grant holders displayed significantly more problems related to mobility and to technology and policies and services relating to mobility and transport. Those who did not receive grants reported more barriers with regard to the attitudes of health workers but not with regard to any other aspect of social support. The majority of men and women with disability identified in this study received the grant, whether or not they lived in remote rural or in urban areas. As there were few differences between the groups, it is likely that several non-grant holders might qualify if they were informed of the grant and applied. The role of medical doctors as 'gatekeepers' to the grant might need to be examined.


A Preliminary Metagenome Analysis Based on a Combination of Protein Domains.
Metagenomic data have mainly been addressed by showing the composition of organisms based on a small part of a well-examined genomic sequence, such as ribosomal RNA genes and mitochondrial DNAs. On the contrary, whole metagenomic data obtained by the shotgun sequence method have not often been fully analyzed through a homology search because the genomic data in databases for living organisms on earth are insufficient. In order to complement the results obtained through homology-search-based methods with shotgun metagenomes data, we focused on the composition of protein domains deduced from the sequences of genomes and metagenomes, and we utilized them in characterizing genomes and metagenomes, respectively. First, we compared the relationships based on similarities in the protein domain composition with the relationships based on sequence similarities. We searched for protein domains of 325 bacterial species produced using the Pfam database. Next, the correlation coefficients of protein domain compositions between every pair of bacteria were examined. Every pairwise genetic distance was also calculated from 16S rRNA or DNA gyrase subunit B. We compared the results of these methods and found a moderate correlation between them. Essentially, the same results were obtained when we used partial random 100 bp DNA sequences of the bacterial genomes, which simulated raw sequence data obtained from short-read next-generation sequences. Then, we applied the method for analyzing the actual environmental data obtained by shotgun sequencing. We found that the transition of the microbial phase occurred because the seasonal change in water temperature was shown by the method. These results showed the usability of the method in characterizing metagenomic data based on protein domain compositions.


Effects of teamwork training on adverse outcomes and process of care in labor and delivery: a randomized controlled trial.
To evaluate the effect of teamwork training on the occurrence of adverse outcomes and process of care in labor and delivery. A cluster-randomized controlled trial was conducted at seven intervention and eight control hospitals. The intervention was a standardized teamwork training curriculum based on crew resource management that emphasized communication and team structure. The primary outcome was the proportion of deliveries at 20 weeks or more of gestation in which one or more adverse maternal or neonatal outcomes or both occurred (Adverse Outcome Index). Additional outcomes included 11 clinical process measures. A total of 1,307 personnel were trained and 28,536 deliveries analyzed. At baseline, there were no differences in demographic or delivery characteristics between the groups. The mean Adverse Outcome Index prevalence was similar in the control and intervention groups, both at baseline and after implementation of teamwork training (9.4% versus 9.0% and 7.2% versus 8.3%, respectively). The intracluster correlation coefficient was 0.015, with a resultant wide confidence interval for the difference in mean Adverse Outcome Index between groups (-5.6% to 3.2%). One process measure, the time from the decision to perform an immediate cesarean delivery to the incision, differed significantly after team training (33.3 minutes versus 21.2 minutes, P=.03). Training, as was conducted and implemented, did not transfer to a detectable impact in this study. The Adverse Outcome Index could be an important tool for comparing obstetric outcomes within and between institutions to help guide quality improvement. (www.ClinicalTrials.gov), NCT00381056 I.


Scattering of light into silicon by spherical and hemispherical silver nanoparticles.
The interaction of light with noble metal nanoparticles deposited onto the top surface of a semiconductor has been investigated using the finite-difference time-domain method. The scattering is calculated for spherical and hemispherical silver nanoparticles placed in a periodic two-dimensional array on the upper surface of a semi-infinite silicon substrate. The results show that the contact area between hemispherical particles and the silicon significantly reduces the forward scattering. The use of an oxide buffer layer to separate the particle from the semiconductor is investigated and is seen to be important if the forward scattering of light is to be enhanced.


An approach for optimal allocation of safety resources: using the knapsack problem to take aggregated cost-efficient preventive measures.
On the basis of the combination of the well-known knapsack problem and a widely used risk management technique in organizations (that is, the risk matrix), an approach was developed to carry out a cost-benefits analysis to efficiently take prevention investment decisions. Using the knapsack problem as a model and combining it with a well-known technique to solve this problem, bundles of prevention measures are prioritized based on their costs and benefits within a predefined prevention budget. Those bundles showing the highest efficiencies, and within a given budget, are identified from a wide variety of possible alternatives. Hence, the approach allows for an optimal allocation of safety resources, does not require any highly specialized information, and can therefore easily be applied by any organization using the risk matrix as a risk ranking tool.


Immobilization Versus Observation in Children With Toddler's Fractures: A Retrospective Review.
While long leg casts have been historically recommended for immobilization of toddler's fractures, short leg casts are often used by treating physicians. Others question whether any immobilization is necessary because of the internal stability provided by the thickened periosteum of pediatric bones. The purpose of this study is to review the results of toddler's fractures treated with long leg casts, short leg casts, or without immobilization. Eighty-five patients were included in a retrospective review of nondisplaced spiral or oblique tibial shaft fractures in children under 6 years old from 2007 to 2012. Treatments included long leg casts (19), short leg casts (59), and no immobilization (7). Average time to ambulation was 15.5 days. There were 11 casting complications. Only one patient, in a short leg cast, had measurable displacement or angulation. There were no complications reported in the nonimmobilized group. The results suggest that toddler's fractures can be effectively treated with short leg casts or without immobilization. (Journal of Surgical Orthopaedic Advances 27(2):142-147, 2018).


Hormesis: policy implications.
Protecting workers and the public from toxic chemicals, particularly carcinogens, has been a principal focus of public policy. Uncertainty regarding the toxicity of particular chemicals and their dose-response relationship has led to the use of the 'precautionary principle' in which regulators are willing to accept more costly regulation than necessary in order to prevent exposure and disease from these toxic chemicals. The Environmental Protection Agency's (EPA's) current policy of using 'mechanism of action' to set regulations means that hormesis could be used by the EPA without any change in policy if hormesis is accepted as scientifically valid. Hormesis could result in a qualitative change in regulatory policy. Because exposure to toxic chemicals conveys no health benefit in the current dose-response model, public risk aversion leads to a Delaney Clause-like 'no-risk' model for policy: ban toxic chemicals or lower exposure to trivial levels. Hormesis implies that individuals benefit from low exposure to toxicants. Although hormesis may not be relevant for individuals with compromised immune systems, it would be expected to help the vast majority of people. If so, permitting exposure levels that provided the greatest health benefit to most people would be balanced against these same levels hurting the most immune-compromised individuals. Public health routinely makes these trade-offs using a 'risk-risk' model. Thus, hormesis could transform the 'no-risk' approach into a 'risk-risk' approach that could tolerate much higher exposures to toxic chemicals than the current policy.


[Factors burdening the caregiving relatives of community-dwelling disable Japanese people].
This study examined the factors associated with burdens on the primary caregivers of community-dwelling disabled people. Participants were 78 disabled people (40 men, 38 women; mean age 77.8+/-11.5 years) who received home-based physical therapy and/or occupational therapy, and their 78 caregivers (20 men, 58 women; mean age 66.8+/-10.2 years). The caregiver burden was assessed using the short version of the Japanese version of the Zarit Caregiver Burden Interview (J-ZBI_8). In addition, the primary caregivers completed questionnaires about burdens arising from supporting the activities of daily living (ADL) using a visual analogue scale, available social support, subjective well-being, and the Motor Fitness Scale. The performance of the disabled subjects was assessed using the Bedside Mobility Scale and the Barthel Index. The disabled subjects and the caregivers were divided into higher burden (J-ZBI_8 score, 10 points and over) and lower burden groups (J-ZBI_8 score, 9 points and under) to compare the group differences in the measurements. The disabled participants in the lower burden group (n=41) showed significantly higher Bedside Mobility Scale scores and Barthel Index scores than those in the higher burden group (n=37). The primary caregivers in the higher burden group showed significantly higher burden due to supporting the ADL, lower subjective well-being, and lower social support as compared to those in the lower-burden group. The burden levels of the primary caregivers relating to the mobility and ADL of their recipients were assessed. The caregivers with higher burden showed less social support and low subjective well-being.


Interappointment emergencies in teeth with necrotic pulps.
The incidence of interappointment emergencies in symptomatic and asymptomatic teeth with necrotic pulps was evaluated, and severity of flare-ups was determined by a quantitative method using a flare-up index. There were no significant differences in the incidence of flare-ups attributable to gender, age, diameter of lesion, taking analgesics, placebos, or no medication, or preoperative symptomatic or asymptomatic tooth diagnoses (p > 0.05). There were significantly more painful flare-ups in mandibular teeth than in maxillary (p < 0.05).


Impact of renal failure on survival of African patients with cirrhosis.
To assess the effect of renal failure on the survival of black African patients with cirrhosis, we studied 132 (82 males, 50 females) cirrhotic black African patients with mean age of 47.5+/-14.4 years and mean follow-up period of 373+/-194 days. The edema and ascitis were the main reasons for admission to hospital. Renal failure was present in 30 (22.7%) patients, and it was positively correlated to the severity of the stage of the liver disease, and associated with severe hyponatremia. Survival at 1 year was 60.1% and 37.6% in the absence or presence of renal failure, respectively (p<0.001)). The stage of the liver disease was significantly inversely correlated with survival, which was further diminished in the presence of renal failure:23.7% versus 12.5% for Child-Pugh-Turcote (CPT) A-B in the absence or presence of renal failure, respectively (p=0.67), 30.2% versus 81.8% for CPT C in the absence or the presence of renal failure respectively (p<0.001). Hyponatremia has also appeared detrimental to survival, since mortality was 38.4% versus 81.8% in the absence or the presence of hyponatremia respectively (p<0.001). By multivariate analysis, renal failure, CPT stage C, and hyponatremia independently significantly correlated to mortality in patients with cirrhosis. We conclude that renal failure is frequently associated with decompensated cirrhosis. The presence of renal failure in this setting often results in high mortality. Renal failure that occurs in the setting of a severe liver disease and hyponatremia may be part of hepatorenal syndrome.


Metoprolol in acute myocardial infarction (MIAMI). A randomised placebo-controlled international trial. The MIAMI Trial Research Group.
The effect of metoprolol on mortality and morbidity after 15 days, was compared with that of placebo in a double-blind randomised international trial (the MIAMI trial) in patients with definite or suspected acute myocardial infarction (AMI). Treatment with intravenous metoprolol (15 mg) or placebo was started shortly after the patient's arrival in hospital within 24 h of the onset of symptoms, and then oral treatment (200 mg daily) was continued for the study period (15 days). Of the 5778 patients included, 2901 were allocated to placebo and 2877 to metoprolol. Definite AMI was confirmed in 4127 patients. There were 142 deaths in the placebo group (4.9%) and 123 deaths in the metoprolol group (4.3%), a difference of 13 per cent with 95 per cent confidence limits of -8 to +33 per cent, not statistically significant (P = 0.29). Previously recorded risk indicators of mortality were analysed in retrospect. These indicated that there was a category which showed higher risk which contained approximately 30% of all randomized patients. In these, the mortality rate in the metoprolol treated group was 29% less than in the placebo group. In the remaining lower risk categories there was no difference between the treatment groups. This subset analysis must be interpreted with caution in view of the findings from other similar studies. Positive effects were observed on the incidence of definite AMI and on serum enzyme activity in patients treated early (less than 7 h). There was no significant effect on ventricular fibrillation but the number of episodes tended to be lower in the metoprolol treated patients during the later phase (6-15 days; 24 vs 54 episodes). The incidence of supraventricular tachyarrhythmias, the use of cardiac glycosides and other antiarrhythmics, and the need for pain-relieving treatment were significantly diminished by metoprolol amongst all randomised patients. Adverse events associated with metoprolol were infrequent, expected, and relatively mild.


Mutual regulation of follicle-stimulating hormone signaling and bone morphogenetic protein system in human granulosa cells.
Bone morphogenetic proteins (BMPs) play critical roles in folliculogenesis by modulating the actions of follicle-stimulating hormone (FSH) in the ovary. However, the effects of FSH on the BMP system remain unknown. Here, we have investigated the effects of FSH on BMP signaling using the human granulosa-like tumor cell line KGN. KGN cells express BMP type I and type II receptors and the BMP signaling molecules SMADs. FSH administration upregulated BMP type IA (BMPR1A) and IB (BMPR1B) receptors, activin type II receptor (ACVR2), and BMP type II receptor (BMPR2). FSH also augmented SMAD1 and SMAD5 expression, and conversely, FSH suppressed the expression of the inhibitory SMADs, SMAD6 and SMAD7. Bioassays revealed that FSH enhances BMP-induced SMAD1/5/8 phosphorylation and cellular DNA synthesis induced by BMP6 and BMP7. Since overexpression of BMPR1A and BMPR1B, but not SMADs, significantly enhanced the BMP responses, these type I receptors were revealed to be limiting factors for BMP signaling in KGN cells. BMPs significantly suppressed progesterone synthesis induced by forskolin and dibutyryl-cAMP (BtcAMP) but had no effect on estradiol induced by the same factors. KGN cAMP levels induced by forskolin were not altered by BMPs, suggesting that BMPs regulate steroidogenesis at a level downstream of cAMP synthesis in KGN cells. In this regard, BMPs specifically reduced the STAR transcription, whereas the levels of CYP11A, HSD3B2, and CYP19 stimulated by forskolin as well as BtcAMP were not altered. Collectively, the two major factors, FSH-cAMP pathway and BMP system, are reciprocally and functionally linked. Given that BMPs downregulate FSH receptors in KGN cells, this interaction may contribute to fine-tuning of the mutual sensitivity toward BMP ligands and FSH.


Full color generation with Fano-type resonant HfO2 nanopillars designed by a deep-learning approach.
In contrast to lossy plasmonic metasurfaces (MSs), wideband dielectric MSs comprising subwavelength nanostructures supporting Mie resonances are of great interest in the visible wavelength range. Here, for the first time to our knowledge, we experimentally demonstrate a reflective MS consisting of a square-lattice array of hafnia (HfO2) nanopillars to generate a wide color gamut. To design and optimize these MSs, we use a deep-learning algorithm based on a dimensionality reduction technique. Good agreement is observed between simulation and experimental results in yielding vivid and high-quality colors. We envision that these structures not only empower the high-resolution digital displays and sensitive colorimetric biosensors but also can be applied to on-demand applications of beaming in a wide wavelength range down to deep ultraviolet.


Comparison of transforming growth factor beta expression in healthy and diseased human tendon.
Diseased tendons are characterised by fibrotic scar tissue, which adversely affects tendon structure and function and increases the likelihood of re-injury. The mechanisms and expression profiles of fibrosis in diseased tendon is understudied compared to pulmonary and renal tissues, where transforming growth factor (TGF)β and its associated superfamily are known to be key drivers of fibrosis and modulate extracellular matrix homeostasis. We hypothesised that differential expression of TGFβ superfamily members would exist between samples of human rotator cuff tendons with established disease compared to healthy control tendons. Healthy and diseased rotator cuff tendons were collected from patients presenting to an orthopaedic referral centre. Diseased tendinopathic (intact) and healthy rotator cuff tendons were collected via ultrasound-guided biopsy and torn tendons were collected during routine surgical debridement. Immunohistochemistry and quantitative real-time polymerase chain reaction were used to investigate the protein and gene expression profiles of TGFβ superfamily members in these healthy and diseased tendons. TGFβ superfamily members were dysregulated in diseased compared to healthy tendons. Specifically, TGFβ-1, TGFβ receptor (R)1 and TGFβ R2 proteins were reduced (p < 0.01) in diseased compared to healthy tendons. At the mRNA level, TGFβ R1 was significantly reduced in samples of diseased tendons, whereas TGFβ R2 was increased (p < 0.01). BMP-2, BMP-7 and CTGF mRNA remained unchanged with tendon disease. We propose that downregulation of TGFβ pathways in established tendon disease may be a protective response to limit disease-associated fibrosis. The disruption of the TGFβ axis with disease suggests associated downstream pathways may be important for maintaining healthy tendon homeostasis. The findings from our study suggest that patients with established tendon disease would be unlikely to benefit from therapeutic TGFβ blockade, which has been investigated as a treatment strategy in several animal models. Future studies should investigate the expression profile of fibrotic mediators in earlier stages of tendon disease to improve understanding of the targetable mechanisms underpinning tendon fibrosis.


Effects of omega-3 fatty acids on inflammatory mediators and splenocyte cytokine mRNA expressions in rats with polymicrobial sepsis.
Many studies have shown that omega-3 fatty acids (FAs) have immunomodulatory effects. However, the influence of omega-3 FAs on septic conditions is not certain. This study examined the effect of fish oil (FO)-enriched diets before and/or omega-3 FA-containing total parenteral nutrition (TPN) after sepsis on the distribution of T-lymphocyte subpopulations and splenocyte cytokine mRNA expressions in rats with polymicrobial sepsis. Rats were assigned to a control group and four experimental groups. The control group and groups 1 and 2 were fed a semipurified diet, and groups 3 and 4 had 20% soybean oil replaced by FO. After feeding the diets for 10 d, sepsis was induced by cecal ligation and puncture (CLP) in the experimental groups, whereas sham operation was performed on the control group. TPN was maintained for 3 d after CLP or sham operation. The control group and groups 1 and 3 were infused with conventional TPN, whereas the TPN solution of groups 2 and 4 was supplemented with FO. All rats were sacrificed 3 d after the operation to examine their immune responses. Messenger RNA expressions of interleukin-2 and tumor necrosis factor-alpha in splenocytes were higher in groups 3 and 4 than in the control group and group 1. Interleukin-10 mRNA expression in group 3 was higher than in the control group and group 2. Blood CD4 percentage and CD4/CD8 ratio in group 1 were significantly lower, whereas no differences were observed in FO-supplemented groups compared with the control group. FO administration before and/or after CLP maintained blood T-lymphocyte subpopulations and modulated T-helper type 1 and 2 cytokine mRNA expressions in rats with polymicrobial sepsis.


Reduced activation in lateral prefrontal cortex and anterior cingulate during attention and cognitive control functions in medication-naïve adolescents with depression compared to controls.
There is increasing recognition of major depressive disorder (MDD) in adolescence. In adult MDD, abnormalities of fronto-striatal and fronto-cingulate circuitries mediating cognitive control functions have been implicated in the pathogenesis and been related to problems with controlling negative thoughts. No neuroimaging studies of cognitive control functions, however, exist in paediatric depression. This study investigated whether medication-naïve adolescents with MDD show abnormal brain activation of fronto-striatal and fronto-cingulate networks when performing tasks of attentional and cognitive control. Event-related functional magnetic resonance imaging was used to compare brain activation between 21 medication-naïve adolescents with a first-episode of MDD aged 14-17 years and 21 healthy adolescents, matched for handedness, age, sex, demographics and IQ. Activation paradigms were tasks of selective attention (Simon task), attentional switching (Switch task), and motor response inhibition and error detection (Stop task). In all three tasks, adolescents with depression compared to healthy controls demonstrated reduced activation in task-relevant right dorsolateral (DLPFC), inferior prefrontal cortex (IFC) and anterior cingulate gyrus (ACG). Additional areas of relatively reduced activation were in the parietal lobes during the Stop and Switch tasks, putamen, insula and temporal lobes during the Switch task and precuneus during the Simon task. This study shows first evidence that medication-naïve adolescents with MDD are characterised by abnormal function in ACG and right lateral prefrontal cortex during tasks of attention and performance monitoring, suggesting an early pathogenesis of these functional abnormalities attributed to MDD.


Engineering entrainment and adaptation in limit cycle systems : From biological inspiration to applications in robotics.
Periodic behavior is key to life and is observed in multiple instances and at multiple time scales in our metabolism, our natural environment, and our engineered environment. A natural way of modeling or generating periodic behavior is done by using oscillators, i.e., dynamical systems that exhibit limit cycle behavior. While there is extensive literature on methods to analyze such dynamical systems, much less work has been done on methods to synthesize an oscillator to exhibit some specific desired characteristics. The goal of this article is twofold: (1) to provide a framework for characterizing and designing oscillators and (2) to review how classes of well-known oscillators can be understood and related to this framework. The basis of the framework is to characterize oscillators in terms of their fundamental temporal and spatial behavior and in terms of properties that these two behaviors can be designed to exhibit. This focus on fundamental properties is important because it allows us to systematically compare a large variety of oscillators that might at first sight appear very different from each other. We identify several specifications that are useful for design, such as frequency-locking behavior, phase-locking behavior, and specific output signal shape. We also identify two classes of design methods by which these specifications can be met, namely offline methods and online methods. By relating these specifications to our framework and by presenting several examples of how oscillators have been designed in the literature, this article provides a useful methodology and toolbox for designing oscillators for a wide range of purposes. In particular, the focus on synthesis of limit cycle dynamical systems should be useful both for engineering and for computational modeling of physical or biological phenomena.


An Exponential Response Neural Net.
By using artificial neurons with exponential transfer functions one can design perfect autoassociative and heteroassociative memory networks, with virtually unlimited storage capacity, for real or binary valued input and output. The autoassociative network has two layers: input and memory, with feedback between the two. The exponential response neurons are in the memory layer. By adding an encoding layer of conventional neurons the network becomes a heteroassociator and classifier. Because for real valued input vectors the dot-product with the weight vector is no longer a measure for similarity, we also consider a euclidean distance based neuron excitation and present Lyapunov functions for both cases. The network has energy minima corresponding only to stored prototype vectors. The exponential neurons make it simpler to build fast adaptive learning directly into classification networks that map real valued input to any class structure at its output.


Gendered races: implications for interracial marriage, leadership selection, and athletic participation.
Six studies explored the overlap between racial and gender stereotypes, and the consequences of this overlap for interracial dating, leadership selection, and athletic participation. Two initial studies captured the explicit and implicit gender content of racial stereotypes: Compared with the White stereotype, the Asian stereotype was more feminine, whereas the Black stereotype was more masculine. Study 3 found that heterosexual White men had a romantic preference for Asians over Blacks and that heterosexual White women had a romantic preference for Blacks over Asians; preferences for masculinity versus femininity mediated participants' attraction to Blacks relative to Asians. The pattern of romantic preferences observed in Study 3 was replicated in Study 4, an analysis of the data on interracial marriages from the 2000 U.S. Census. Study 5 showed that Blacks were more likely and Asians less likely than Whites to be selected for a masculine leadership position. In Study 6, an analysis of college athletics showed that Blacks were more heavily represented in more masculine sports, relative to Asians. These studies demonstrate that the gender content of racial stereotypes has important real-world consequences.


Honokiol-Mediated Mitophagy Ameliorates Postoperative Cognitive Impairment Induced by Surgery/Sevoflurane via Inhibiting the Activation of NLRP3 Inflammasome in the Hippocampus.
The potential mechanism of postoperative cognitive impairment is still largely unclear. The activation of NLRP3 inflammasome had been reported to be involved in neurodegenerative diseases, including postoperative cognitive change, and is closely related to mitochondrial ROS and mitophagy. Honokiol (HNK) owns multiple organic protective effects. This study is aimed at observing the neuroprotective effect of HNK in postoperative cognitive change and examining the role of HNK in the regulation of mitophagy and the relationship between these effects and NLRP3 inflammasome activation in mice induced by surgery/anesthesia. In this study, mice were divided into several groups: control group, surgery group, surgery+HNK group, and surgery+HNK+3-methyladenine (3-MA) group. Hippocampal tissue samples were harvested and used for proinflammatory cytokines, mitochondrial ROS, and malondialdehyde (MDA) assay. The process of mitophagy and the activation of NLRP3 inflammasome were observed by Western blot, immunohistochemistry, and transmission electron microscopy. The results showed that HNK treatment obviously recovered the postoperative decline and enhanced the expressions of LC3-II, Beclin-1, Parkin, and PINK1 at protein levels after surgery/sevoflurane treatment, which are both an autophagy marker and a mitophagy marker. In addition, HNK attenuated mitochondrial structure damage and reduced mtROS and MDA generation, which are closely associated with NLRP3 inflammasome activation. Honokiol-mediated mitophagy inhibited the activation of NLRP3 inflammasome and neuroinflammation in the hippocampus. Using 3-MA, an autophagy inhibitor, the neuroprotective effects of HNK on mitophagy and NLRP3 inflammasome activation were eliminated. These results indicated that HNK-mediated mitophagy ameliorates postoperative cognitive impairment induced by surgery/sevoflurane. This neuroprotective effect may be involved in inhibiting the activation of NLRP3 inflammasome and suppressing inflammatory responses in the hippocampus.


Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein.
Most isolates of hepatitis C virus (HCV) infections are resistant to interferon, the only available therapy, but the mechanism underlying this resistance has not been defined. Here it is shown that the HCV envelope protein E2 contains a sequence identical with phosphorylation sites of the interferon-inducible protein kinase PKR and the translation initiation factor eIF2alpha, a target of PKR. E2 inhibited the kinase activity of PKR and blocked its inhibitory effect on protein synthesis and cell growth. This interaction of E2 and PKR may be one mechanism by which HCV circumvents the antiviral effect of interferon.


A Monte Carlo based method to estimate radiation dose from multidetector CT (MDCT): cylindrical and anthropomorphic phantoms.
The purpose of this work was to extend the verification of Monte Carlo based methods for estimating radiation dose in computed tomography (CT) exams beyond a single CT scanner to a multidetector CT (MDCT) scanner, and from cylindrical CTDI phantom measurements to both cylindrical and physical anthropomorphic phantoms. Both cylindrical and physical anthropomorphic phantoms were scanned on an MDCT under the specified conditions. A pencil ionization chamber was used to record exposure for the cylindrical phantom, while MOSFET (metal oxide semiconductor field effect transistor) detectors were used to record exposure at the surface of the anthropomorphic phantom. Reference measurements were made in air at isocentre using the pencil ionization chamber under the specified conditions. Detailed Monte Carlo models were developed for the MDCT scanner to describe the x-ray source (spectra, bowtie filter, etc) and geometry factors (distance from focal spot to isocentre, source movement due to axial or helical scanning, etc). Models for the cylindrical (CTDI) phantoms were available from the previous work. For the anthropomorphic phantom, CT image data were used to create a detailed voxelized model of the phantom's geometry. Anthropomorphic phantom material compositions were provided by the manufacturer. A simulation of the physical scan was performed using the mathematical models of the scanner, phantom and specified scan parameters. Tallies were recorded at specific voxel locations corresponding to the MOSFET physical measurements. Simulations of air scans were performed to obtain normalization factors to convert results to absolute dose values. For the CTDI body (32 cm) phantom, measurements and simulation results agreed to within 3.5% across all conditions. For the anthropomorphic phantom, measured surface dose values from a contiguous axial scan showed significant variation and ranged from 8 mGy/100 mAs to 16 mGy/100 mAs. Results from helical scans of overlapping pitch (0.9375) and extended pitch (1.375) were also obtained. Comparisons between the MOSFET measurements and the absolute dose value derived from the Monte Carlo simulations demonstrate agreement in terms of absolute dose values as well as the spatially varying characteristics. This work demonstrates the ability to extend models from a single detector scanner using cylindrical phantoms to an MDCT scanner using both cylindrical and anthropomorphic phantoms. Future work will be extended to voxelized patient models of different sizes and to other MDCT scanners.


Integrative RNA- and miRNA-Profile Analysis Reveals a Likely Role of BR and Auxin Signaling in Branch Angle Regulation of B. napus.
Oilseed rape (Brassica napus L.) is the second largest oilseed crop worldwide and one of the most important oil crops in China. As a component of plant architecture, branch angle plays an important role in yield performance, especially under high-density planting conditions. However, the mechanisms underlying the regulation of branch angle are still largely not understood. Two oilseed rape lines with significantly different branch angles were used to conduct RNA- and miRNA-profiling at two developmental stages, identifying differential expression of a large number of genes involved in auxin- and brassinosteroid (BR)-related pathways. Many auxin response genes, including AUX1, IAA, GH3, and ARF, were enriched in the compact line. However, a number of genes involved in BR signaling transduction and biosynthesis were down-regulated. Differentially expressed miRNAs included those involved in auxin signaling transduction. Expression patterns of most target genes were fine-tuned by related miRNAs, such as miR156, miR172, and miR319. Some miRNAs were found to be differentially expressed at both developmental stages, including three miR827 members. Our results provide insight that auxin- and BR-signaling may play a pivotal role in branch angle regulation.


A comparison of the thoracolumbosacral orthoses and providence orthosis in the treatment of adolescent idiopathic scoliosis: results using the new SRS inclusion and assessment criteria for bracing studies.
This is a retrospective cohort study comparing the effectiveness of the thoracolumbosacral orthosis (TLSO) and the Providence orthosis in the treatment of adolescent idiopathic scoliosis (AIS) using the new Scoliosis Research Society (SRS) Committee on Bracing and Nonoperative Management inclusion and assessment criteria for bracing studies. These new criteria will make future studies comparable and more valid and accurate. We have used a custom TLSO (duration, 22 hours/day) and the Providence orthosis (duration, 8-10 hours/night) to control progressive AIS curves. Only 83 of 160 patients met the new SRS inclusion criteria: age of 10 years and older at initiation of bracing; initial curve of 25 to 40 degrees; Risser sign 0 to 2; female; premenarcheal or less than 1 year past menarche; and no previous treatment. There were 48 patients in the TLSO group and 35 in the Providence group. The new SRS assessment criteria of effectiveness included the percentage of patients who had 5 degrees or less and 6 degrees or more of curve progression at maturity, the percentage of patients whose curve progressed beyond 45 degrees, the percentage of patients who had surgery recommended or undertaken, and a minimum of 2 years of follow-up beyond maturity in those patients who were thought to have been successfully treated. All patients are evaluated regardless of compliance (intent to treat). There were no significant differences in age at brace initiation, initial primary curve magnitude, sex, or initial Risser sign between the 2 groups. In the TLSO group, only 7 patients (15%) did not progress (<or=5 degrees), whereas 41 patients (85%) progressed by 6 degrees or more, including the 30 patients whose curves exceeded 45 degrees. Thirty-eight patients (79%) required surgery. In the Providence group, 11 patients (31%) did not progress, whereas 24 patients (69%) progressed by 6 degrees or more, including 15 patients whose curves exceeded 45 degrees. Twenty-one patients (60%) required surgery. However, when the initial curve at initiation of bracing was 25 to 35 degrees, the results improved. Five (15%) of 34 patients in the TLSO group and 10 (42%) of 24 patients in the Providence group did not progress, whereas 29 patients (85%) and 14 patients (58%), respectively, progressed by 6 degrees or more, and 26 patients (76%) and 11 patients (46%), respectively, required surgery. Using the new SRS bracing criteria, the Providence orthosis was more effective for avoiding surgery and preventing curve progression when the primary initial curves at bracing was 35 degrees or less. However, the overall success of orthotic management for AIS in both groups was inferior to previous studies. Our results raise the question of the effectiveness of orthotic management in AIS and support the need for a multicenter, randomized study using these new criteria.


Multisensory object perception in infancy: 4-month-olds perceive a mistuned harmonic as a separate auditory and visual object.
Infants learn to use auditory and visual information to organize the sensory world into identifiable objects with particular locations. Here we use a behavioural method to examine infants' use of harmonicity cues to auditory object perception in a multisensory context. Sounds emitted by different objects sum in the air and the auditory system must figure out which parts of the complex waveform belong to different sources (auditory objects). One important cue to this source separation is that complex tones with pitch typically contain a fundamental frequency and harmonics at integer multiples of the fundamental. Consequently, adults hear a mistuned harmonic in a complex sound as a distinct auditory object (Alain, Theunissen, Chevalier, Batty, & Taylor, 2003). Previous work by our group demonstrated that 4-month-old infants are also sensitive to this cue. They behaviourally discriminate a complex tone with a mistuned harmonic from the same complex with in-tune harmonics, and show an object-related event-related potential (ERP) electrophysiological (EEG) response to the stimulus with mistuned harmonics. In the present study we use an audiovisual procedure to investigate whether infants perceive a complex tone with an 8% mistuned harmonic as emanating from two objects, rather than merely detecting the mistuned cue. We paired in-tune and mistuned complex tones with visual displays that contained either one or two bouncing balls. Four-month-old infants showed surprise at the incongruous pairings, looking longer at the display of two balls when paired with the in-tune complex and at the display of one ball when paired with the mistuned harmonic complex. We conclude that infants use harmonicity as a cue for source separation when integrating auditory and visual information in object perception.


Using electronic mail for a small-group curriculum in ethical and social issues.
To initiate an electronic mail (e-mail) program as a supplement to a medical humanities curriculum focusing on ethical and social issues. In 1991-92 an e-mail track (called NET) was established for second-year students participating in Medicine in Contemporary Society, a four-year curriculum in medical humanities at the State University of New York at Stony Brook School of Medicine. In 1991-92 ten students volunteered to form a NET group; in 1992-93 22 students, forming two groups, were randomly selected from a volunteer pool of 76 students (from a class of 100). In both study years, the NET students analyzed and discussed electronically a series of cases posted sequentially through the academic year. Faculty tutors reviewed the students' responses, interacting with the groups and with individual students by e-mail. NET was evaluated in two ways: at the end of the course, the students completed e-mail questionnaires that included quantitative and qualitative assessments; and throughout the course, the tutors assessed the students' participation, quality of case analysis and discussion, and quality of writing. The students' assessments indicated that they considered NET to be more educational than the lectures, "live" group discussions, problem-based learning exercises, and formal papers in the medical humanities curriculum; that they made gains in computer literacy; and that NET enhanced their abilities to think about ethical and social issues. The tutors judged that the students had improved their written self-expression as the course progressed. NET adequately accomplished the goals set for it as an adjunct to the small-group sessions and other components of the medical humanities curriculum.


Three-dimensional matching by use of phase-only holographic information and the Wigner distribution.
Matching of three-dimensional (3-D) objects is achieved by Wigner analysis of the correlation pattern between the phase-only holographic information of a reference object and that of a target object. First, holographic information on the reference object and on the target object is extracted by use of optical scanning holography as a form of electrical signal. This electrical information is then stored in a computer for digital processing. In the digital computer, the correlation between the phase-only information of the hologram of the reference object and that of the target object is calculated and analyzed by use of a Wigner distribution. The Wigner distribution yields a space-frequency map of the correlation pattern that indicates whether the 3-D image of the target object matches that of the reference object. When the 3-D image of the target object matches that of the reference object, the Wigner distribution gives a well-defined line that directly indicates the 3-D location of the matched target object. Optical experiments with digital processing are described to demonstrate the proposed matching technique.


N-terminal specific conjugation of extracellular matrix proteins to 2-pyridinecarboxaldehyde functionalized polyacrylamide hydrogels.
Polyacrylamide hydrogels have been used extensively to study cell responses to the mechanical and biochemical properties of extracellular matrix substrates. A key step in fabricating these substrates is the conjugation of cell adhesion proteins to the polyacrylamide surfaces, which typically involves nonspecifically anchoring these proteins via side-chain functional groups. This can result in a loss of presentation control and altered bioactivity. Here, we describe a new functionalization strategy in which we anchor full-length extracellular matrix proteins to polyacrylamide substrates using 2-pyridinecarboxaldehyde, which can be co-polymerized into polyacrylamide gels and used to immobilize proteins by their N-termini. This one-step reaction proceeds under mild aqueous conditions and does not require additional reagents. We demonstrate that these substrates can readily conjugate to various extracellular matrix proteins, as well as promote cell adhesion and spreading. Notably, this chemistry supports the assembly and cellular remodeling of large collagen fibers, which is not observed using conventional side-chain amine-conjugation chemistry.


Genetic relatedness in social groups of the emerald coral goby Paragobiodon xanthosoma creates potential for weak kin selection.
Animals forming social groups that include breeders and nonbreeders present evolutionary paradoxes; why do breeders tolerate nonbreeders? And why do nonbreeders tolerate their situation? Both paradoxes are often explained with kin selection. Kin selection is, however, assumed to play little or no role in social group formation of marine organisms with dispersive larval phases. Yet, in some marine organisms, recent evidence suggests small-scale patterns of relatedness, meaning that this assumption must always be tested. Here, we investigated the genetic relatedness of social groups of the emerald coral goby, Paragobiodon xanthosoma. We genotyped 73 individuals from 16 groups in Kimbe Bay, Papua New Guinea, at 20 microsatellite loci and estimated pairwise relatedness among all individuals. We found that estimated pairwise relatedness among individuals within groups was significantly higher than the pairwise relatedness among individuals from the same reef, and pairwise relatedness among individuals from the same reef was significantly higher than the pairwise relatedness among individuals from different reefs. This spatial signature suggests that there may be very limited dispersal in this species. The slightly positive relatedness within groups creates the potential for weak kin selection, which may help to resolve the paradox of why breeders tolerate subordinates in P. xanthosoma. The other paradox, why nonbreeders tolerate their situation, is better explained by alternative hypotheses such as territory inheritance, and ecological and social constraints. We show that even in marine animals with dispersive larval phases, kin selection needs to be considered to explain the evolution of complex social groups.


Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer.
Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered.


Rapid Sample Preparation Workflow for Serum Sample Analysis with Different Mass Spectrometry Acquisition Strategies.
Fast, robust, and high-throughput mass spectrometry-based serum proteomic pipelines have great potential to yield information for biomarker discovery and daily clinical practice. Here, we developed a simple and rapid sample preparation (RSP) workflow by reducing the classical pretreatment time from overnight to less than 1.5 h in an ordinary system. In HeLa cell lysates and serum samples, the number of proteins and tryptic peptides generated using the RSP was comparable to that generated using conventional methods. For fast scanning of the serum proteome, the RSP-supported pipeline could complete a test in less than 2 h with 30 min of LC-MS/MS analysis. Nearly 390 proteins spanning 8 magnitudes of abundance range were identified with high reproducibility, containing over 90 cancer-associated proteins and over 50 FDA-approved biomarkers. For fast assay development, eight candidate biomarker peptides for cardiovascular disease (CVD) were quantified by MRM with high accuracy (CV% <10). After a simple highly abundant protein removal, a deep serum proteome of over 1400 proteins was reached. By analyzing the depleted serum in DIA acquisition mode, over 700 proteins were quantified. The differentially expressed proteins could help us unambiguously distinguish the serum samples from healthy people and patients with pancreatic cancer (PC). Potential biomarkers for PC were also found. The new RSP method, which is rapid and simple, meets the demands of both deep mining and fast analysis of serum proteins. We believe that it will be widely used in serum protein studies and accelerate the transformation from biomarker discovery to clinical application.


Natural history of patients with recurrent parotitis and punctate sialectasis.
The clinical features of 68 patients (26 children and 42 adults) who suffered recurrent attacks of parotitis and in whom sialography had revealed punctate sialectasis of the affected gland is described. The sex incidence was equal in those patients in whom symptoms commenced during childhood (younger than 15). When symptoms commenced later in life, however, there was a marked preponderance of females (female:male = 7.5:1). Bilateral sialography in 16 patients with unilateral symptoms revealed punctate sialectasis in the asymptomatic gland in 11 (69 per cent) of patients. Neither the presence of the sicca syndrome nor auto-antibodies had a significant predictive value as to the outcome of the disease. Five-year follow-up of 52 patients revealed that 56 per cent of adults and 64 per cent of children had shown spontaneous improvement of symptoms with symptomatic treatment alone. In 40 per cent of adults and 4 per cent of children, however, the persistence or worsening of symptoms necessitated parotidectomy. We believe that these results of conservative management indicate that, at least in the first instance and particularly in children, conservative management is justified and that the use of radiotherapy or steroids (with their attendant morbidity) is unnecessary.


Temperature deviation index and elderly mortality in Japan.
Few studies have examined how the precedence of abnormal temperatures in previous neighboring years affects the population's health. In the present study, we attempted to quantify the health effects of abnormal weather patterns by creating a metric called the temperature deviation index (TDI) and estimated the effects of TDI on mortality in Japan. We used data from 47 prefectures in Japan to compute the TDI on days between May and September from 1966 to 2010. The TDI is a summed product of an indicator of absence of high temperatures in the neighboring years, and more weights were assigned to the years closest to the current year. To estimate the TDI effects on elderly mortality, we used generalized linear modeling with a Poisson distribution after adjusting for apparent temperature, barometric pressure, day of the week, and time trend. For each prefecture, we estimated the TDI effects and pooled the estimates to yield a national average for 1991-2010 in Japan. The estimated effects of TDI in middle- or high-latitude prefectures were greater than in low-latitude prefectures. The estimated national average of TDI effects was a 0.5 % (95 % confidence intervals [CI], 0.1, 1.0) increase in elderly mortality per 1-unit (around 1 standard deviation) increase in the TDI. The significant pooled estimation of TDI effects was mainly due to the TDI effects on summer days with moderate temperature (25th-49th percentile, mean temperature 22.9 °C): a 1.9 % (95 % CI, 1.1, 2.6) increase in elderly mortality per 1-unit increase in the TDI. However, TDI effects were insignificant in other temperature ranges. These findings suggest that elderly deaths increased on moderate temperature days in the summer that differed substantially from days during that time window in the neighboring years. Therefore, not only high temperature itself but also temperature deviation compared to previous years could be considered to be a risk factor for elderly mortality in the summer.


ZnSe quantum dots modified with a Ni(cyclam) catalyst for efficient visible-light driven CO2 reduction in water.
A precious metal and Cd-free photocatalyst system for efficient CO2 reduction in water is reported. The hybrid assembly consists of ligand-free ZnSe quantum dots (QDs) as a visible-light photosensitiser combined with a phosphonic acid-functionalised Ni(cyclam) catalyst, NiCycP. This precious metal-free photocatalyst system shows a high activity for aqueous CO2 reduction to CO (Ni-based TONCO > 120), whereas an anchor-free catalyst, Ni(cyclam)Cl2, produced three times less CO. Additional ZnSe surface modification with 2-(dimethylamino)ethanethiol (MEDA) partially suppresses H2 generation and enhances the CO production allowing for a Ni-based TONCO of > 280 and more than 33% selectivity for CO2 reduction over H2 evolution, after 20 h visible light irradiation (λ > 400 nm, AM 1.5G, 1 sun). The external quantum efficiency of 3.4 ± 0.3% at 400 nm is comparable to state-of-the-art precious metal photocatalysts. Transient absorption spectroscopy showed that band-gap excitation of ZnSe QDs is followed by rapid hole scavenging and very fast electron trapping in ZnSe. The trapped electrons transfer to NiCycP on the ps timescale, explaining the high performance for photocatalytic CO2 reduction. With this work we introduce ZnSe QDs as an inexpensive and efficient visible light-absorber for solar fuel generation.


VEGF improves myocardial blood flow but produces EDRF-mediated hypotension in porcine hearts.
Several recent studies have demonstrated the potential for improving myocardial perfusion by the continuous administration of angiogenic growth factors. Studies in our laboratory have shown that a single intraarterial or intravenous bolus of the endothelial cell specific mitogen vascular endothelial growth factor (VEGF) can significantly improve perfusion in a rabbit ischemic limb model. To test the efficacy of this therapeutic approach in chronic myocardial ischemia, 18 Yorkshire pigs underwent a left thoracotomy followed by placement of an ameroid constrictor around the proximal circumflex coronary artery. Gradual occlusion of the artery (26 +/- 4 days) was accompanied by identifiable hypokinesis of the posterolateral wall of the left ventricle (2D echo). Thirty days postoperatively, rhVEGF(165) (2 mg; n = 8) or saline (n = 10) was administered directly into the left coronary ostium. Postadenosine myocardial perfusion studies using colored microspheres 30 days later demonstrated superior blood flow in the ischemic zone of the VEGF-treated hearts (ischemic/normal ratio 1.09 vs 0.97, P < 0.05) compared with those receiving saline injection. Four of eight VEGF-treated animals succumbed, however, to severe hypotension following VEGF administration. Therefore 500 micrograms of VEGF were administered intracoronary to five normal pigs. A significant drop in mean arterial pressure (-44.4 +/- 3.2%, P < 0.05 vs baseline) and peripheral resistance (-13.2 +/- 4.5%, P < 0.05 vs baseline) was accompanied by increased heart rate. IV administration of N(omega)-nitro-L-arginine (L-NNA), an EDRF inhibitor, restored blood pressure to baseline. We conclude that a single intracoronary bolus of VEGF is capable of significantly augmenting flow to collateral-dependent ischemic myocardium. The associated hypotension appears to be EDRF-mediated. Further studies are needed to define the best dose and route of administration of VEGF for the treatment of coronary insufficiency.


Childhood brain tumours and use of mobile phones: comparison of a case-control study with incidence data.
The first case-control study on mobile phone use and brain tumour risk among children and adolescents (CEFALO study) has recently been published. In a commentary published in Environmental Health, Söderqvist and colleagues argued that CEFALO suggests an increased brain tumour risk in relation to wireless phone use. In this article, we respond and show why consistency checks of case-control study results with observed time trends of incidence rates are essential, given the well described limitations of case-control studies and the steep increase of mobile phone use among children and adolescents during the last decade. There is no plausible explanation of how a notably increased risk from use of wireless phones would correspond to the relatively stable incidence time trends for brain tumours among children and adolescents observed in the Nordic countries. Nevertheless, an increased risk restricted to heavy mobile phone use, to very early life exposure, or to rare subtypes of brain tumours may be compatible with stable incidence trends at this time and thus further monitoring of childhood brain tumour incidence rate time trends is warranted.


Antibacterial silver-doped phosphate-based glasses prepared by coacervation.
Phosphate-based glasses are materials of great interest for the regeneration and repair of damaged hard or soft tissues. They have the desirable property of slowly dissolving in the physiological environment, eventually being totally replaced by regenerated tissue. Being bioresorbable, they can simultaneously induce tissue regeneration and deliver therapeutic agents (e.g. antibacterial ions) in a controlled way. In this work, we have synthesised a series of glasses in the P2O5-CaO-Na2O system doped with Ag2O using the coacervation method. The addition of silver is known to provide the glass with antibacterial properties due to the release of Ag+ ions into the body fluid. The coacervation method is a facile, water-based technique which offers significant advantages over the conventional melt-quench route for preparing phosphate-based glasses which requires melting of metal oxide powders at high temperatures (1000-1200 °C). The properties of the initial colloidal polyphosphate systems (coacervates) as a function of the Ag2O content were characterised using rheology and liquid state 31P NMR. The effect of Ag+ addition on the final dried glasses was investigated using thermal analysis, Raman spectroscopy and X-ray diffraction. The antibacterial activity was assessed against Staphylococcus aureus (S. aureus), a bacterial strain commonly found in post-surgery infections. A dose-dependent antimicrobial effect was seen with an increasing silver content.


Transforming growth factor-beta-dependent and -independent pathways of induction of tubulointerstitial fibrosis in beta6(-/-) mice.
Transforming growth factor-beta1 (TGF-beta1) and the renin-angiotensin-aldosterone system are key mediators in kidney fibrosis. Integrin alphavbeta6, a heterodimeric matrix receptor expressed in epithelia, binds and activates latent TGF-beta1. We used beta6 integrin-null mice (beta6(-/-)) to determine the role of local TGF-beta1 activation in renal fibrosis in the unilateral ureteral obstruction (UUO) model. Obstructed kidneys from beta6(-/-) mice showed less injury than obstructed kidneys from wild-type (WT) mice, associated with lower collagen I, collagen III, plasminogen activator inhibitor (PAI-1), and TGF-beta1 mRNA levels and lower collagen content. Infusion with either angiotensin II (Ang II) or aldosterone (Aldo) or combination in beta6(-/-) UUO mice significantly increased collagen contents to levels comparable to those in identically treated WT. Active TGF-beta protein expression in beta6(-/-) mice was less in UUO kidneys with or without Ang II infusion compared to matched WT mice. Activated Smad 2 levels in beta6(-/-) obstructed kidneys were lower than in WT UUO mice, and did not increase when fibrosis was induced in beta6(-/-) UUO mice by Ang II infusion. Anti-TGF-beta antibody only partially decreased this Ang II-stimulated fibrosis in beta6(-/-) UUO kidneys. In situ hybridization and immunostaining showed low expression of PAI-1 mRNA and protein in tubular epithelium in beta6(-/-) UUO kidneys, with increased PAI-1 expression in response to Ang II, Aldo, or both. Our results indicate that interruption of alphavbeta6-mediated activation of TGF-beta1 can protect against tubulointerstitial fibrosis. Further, the robust induction of tubulointerstitial fibrosis without increase in activated Smad 2 levels in obstructed beta6(-/-) mice by Ang II suggests the existence of a TGF-beta1-independent pathway of induction of fibrosis through angiotensin.


Measuring Mental Health Provider-Based Stigma: Development and Initial Psychometric Testing of a Self-Assessment Instrument.
This article describes the development and initial psychometric testing of the Mental Health Provider Self-Assessment of Stigma Scale (MHPSASS), a 20-item instrument crafted in reflection of Charles' (Social Work in Mental Health 11:360-375, 2013) empirically derived, experience-based, five-themed model of provider stigmatization. Following model and item review by construct experts, 220 mental health service providers in Virginia's public mental health centers and in-patient facilities completed the survey package. Results indicate the refined MHPSASS is a reliable measure of provider-based stigma with promising face and content validity. However, rather than they hypothesized five-factors, analysis indicates a four-factor solution, a key finding signaling a discrepancy between what providers endorse and what clients' experience. Notably absent from the MHPSASS' were items related to blame and shame, in contrast to the experience of clients and families. Further refinement is indicated, particularly reconsideration of blame and shame items due to their practical and theoretical significance.


Toll-like receptor 3 (TLR3) promotes the resolution of Chlamydia muridarum genital tract infection in congenic C57BL/6N mice.
Chlamydia trachomatis urogenital serovars primarily replicate in epithelial cells lining the reproductive tract. Epithelial cells recognize Chlamydia through cell surface and cytosolic receptors, and/or endosomal innate receptors such as Toll-like receptors (TLRs). Activation of these receptors triggers both innate and adaptive immune mechanisms that are required for chlamydial clearance, but are also responsible for the immunopathology in the reproductive tract. We previously demonstrated that Chlamydia muridarum (Cm) induces IFN-β in oviduct epithelial cells (OE) in a TLR3-dependent manner, and that the synthesis of several cytokines and chemokines are diminished in Cm-challenged OE derived from TLR3-/- 129S1 mice. Furthermore, our in vitro studies showed that Cm replication in TLR3-/- OE is more efficient than in wild-type OE. Because TLR3 modulates the release inflammatory mediators involved in host defense during Cm infection, we hypothesized that TLR3 plays a protective role against Cm-induced genital tract pathology in congenic C57BL/6N mice. Using the Cm mouse model for human Chlamydia genital tract infections, we demonstrated that TLR3-/- mice had increased Cm shedding during early and mid-stage genital infection. In early stage infection, TLR3-/- mice showed a diminished synthesis of IFN-β, IL-1β, and IL-6, but enhanced production of IL-10, TNF-α, and IFN-γ. In mid-stage infection, TLR3-/- mice exhibited significantly enhanced lymphocytic endometritis and salpingitis than wild-type mice. These lymphocytes were predominantly scattered along the endometrial stroma and the associated smooth muscle, and the lamina propria supporting the oviducts. Surprisingly, our data show that CD4+ T-cells are significantly enhanced in the genital tract TLR3-/- mice during mid-stage Chlamydial infection. In late-stage infections, both mouse strains developed hydrosalpinx; however, the extent of hydrosalpinx was more severe in TLR3-/- mice. Together, these data suggest that TLR3 promotes the clearance of Cm during early and mid-stages of genital tract infection, and that loss of TLR3 is detrimental in the development hydrosalpinx.


Generation of low-flux X-ray micro-planar beams and their biological effect on a murine subcutaneous tumor model.
We generated low-flux X-ray micro-planar beams (MPBs) using a laboratory-scale industrial X-ray generator (60 kV/20 mA) with custom-made collimators with three different peak/pitch widths (50/200 μm, 100/400 μm, 50/400 μm). To evaluate normal skin reactions, the thighs of C3H/HeN mice were exposed to 100 and 200 Gy MPBs in comparison with broad beams (20, 30, 40, 50, 60 Gy). Antitumor effects of MPBs were evaluated in C3H/HeN mice with subcutaneous tumors (SCCVII). After the tumors were irradiated with 100 and 200 Gy MPBs and 20 and 30 Gy broad beams, the tumor sizes were measured and survival analyses were performed. In addition, the tumors were excised and immunohistochemically examined to detect γ-H2AX, ki67 and CD34. It was shown that antitumor effects of 200 Gy MPBs at 50/200 μm and 100/400 μm were significantly greater than those of 20 Gy broad beams, and were comparable with 30 Gy broad beams. γ-H2AX-positive cells demonstrated clear stripe-patterns after MPB irradiation; the pattern gradually faded and intermixed over 24 h. The chronological changes in ki67 positivity did not differ between MPBs and broad beams, whereas the CD34-positive area decreased significantly more in MPBs than in broad beams. In addition, it was shown that skin injury after MPB irradiation was significantly milder when compared with broad-beam irradiation at equivalent doses for achieving the same tumor control effect. Bystander effect and tumor vessel injury may be the mechanism contributing to the efficacy of MPBs.


Relation between free cytosolic calcium and amylase release by pancreatic acini.
Pancreatic acini were loaded with the Ca-selective fluorescent indicator quin-2 by incubation with its acetyoxymethyl ester. Loading acini with 844 +/- 133 microM quin-2 altered neither their ultrastructure nor their viability. The rate of amylase release from quin-2-loaded acini in response to the secretagogue carbachol, however, was significantly smaller than that of control acini. Studies in which acini were loaded with both quin-2 and a similar Ca-chelating compound, BAPTA, indicated that this reduced amylase release was related to the Ca buffering properties of quin-2. The concentration of free intracellular Ca calculated from the fluorescence of quin-2 was 90 +/- 18 nM. Stimulation by carbachol of acini suspended in media containing 1.25 mM Ca caused a rapid, transient enhancement of this value. After stimulation amylase release, the onset of the rise in free cytosolic Ca levels was observed in 1.1 +/- 0.1 s following the addition of agonist, and peak Ca levels (545 +/- 112 nM) were obtained within 5.3 +/- 0.3 s. For concentrations of carbachol less than or equal to 10(-6) M, a stoichiometric relation was found between stimulated amylase release and the peak concentration of free cytosolic Ca achieved. At higher concentrations of carbachol, however, the peak free cytosolic Ca remained constant while amylase release declined. The latency of the rise in intracellular Ca following stimulation of acini suspended in Ca-free media was not different from that observed for acini suspended in normal media, but the rise time was significantly prolonged. In the presence of extracellular Ca, the intracellular level of Ca remained elevated 2.8-fold above basal levels for at least 15 min following stimulation with 10(-6) M carbachol, whereas it had returned to near resting levels by 15 min when either 3 X 10(-7) or 3 X 10(-5) M carbachol was the stimulus. The Ca ionophore ionomycin (10-6 M) induced changes in the level of free cytosolic Ca similar to those caused by 10(-6) M carbachol. Ionomycin, however, stimulated only approximately one-third as much amylase release. These data suggest that factors in addition to changes in free cytosolic Ca may be important in regulating enzyme secretion by pancreatic acinar cells.


[Pulse oximetry in perioperative monitoring].
Monitoring with pulse oximetry might improve patient outcome by enabling an early diagnosis and consequently, correction of perioperative events that might cause postoperative complications or even death. Only a few randomised clinical trials of pulse oximetry have been performed during anaesthesia and in the recovery room which describe perioperative hypoxaemic events, postoperative cardiopulmonary complications and cognitive dysfunction. To study the effect of perioperative monitoring with pulse oximetry to clearly identify the adverse outcomes that might be prevented or improved by the use of pulse oximetry. Trials were identified by computerised searches of the Cochrane Library, MEDLINE, EMBASE, and by checking the reference lists of trials and review articles. All controlled trials that randomised patients to either pulse oximetry or no pulse oximetry during the perioperative period, including the operating and recovery room. We collected data in relation to events detectable by pulse oximetry, any serious complications that occurred during anaesthesia or in the postoperative period, intra- or postoperative mortality, and duration of recovery or intensive care stay. Formal statistical synthesis of individual trials was not performed in view of the variety of outcomes studied. Searching identified six reports; four studies with data from a total of 21,773 patients were considered eligible for analysis. Only two studies specifically addressed the outcomes in question; both found no effect on the rate of postoperative complications using perioperative pulse oximetry. Two studies used hypoxaemia detectable by pulse oximetry to assess the value of perioperative monitoring, although outcomes were not given. It was found that hypoxaemia was reduced in the pulse oximetry group both in the operating theratre and in the recovery room. During observation in the recovery room, the incidence of hypoxaemia in the pulse oximetry group was 1.5-3 times less. The postoperative cognitive function using the Wechsler memory scale and continuous reaction time was independent of perioperative monitoring with pulse oximetry. The other study showed that postoperative complications occurred in 10% of the patients in the oximetry group and in 9.4% in the control group. The two groups did not differ in cardiovascular, respiratory, neurologic, or infectious complications. The duration of hospital stay was a median of 5 days in both groups, and an equal number of in-hospital deaths was registered in the two groups. The studies confirmed that pulse oximetry can detect hypoxaemia and related events. However, we have found no evidence that pulse oximetry affects the outcome of anaesthesia. The conflicting subjective and objective results of the studies, despite an intense, methodical collection of data from a relatively large population, indicate that the value of perioperative monitoring with pulse oximetry is questionable in relation to improved reliable outcomes, effectiveness and efficiency.


Value of a QALY and VSI estimated with the chained approach.
The value of a quality-adjusted life-year (QALY) and the value of a statistical injury (VSI) are important measures within health economics and transport economics. Several studies have, therefore, estimated people's willingness to pay (WTP) for these estimates, but most results show scale insensitivity. The 'original' chained approach (CA) is a method developed to mitigate this problem by combining the contingent valuation (CV) with standard gamble (SG). In contrast to the version of the CA applied by the previous research of the WTP for a QALY, the original version allows the value of major health gains to be estimated without having the respondents express their WTP directly. The objective of this study was to estimate the value of a QALY and VSI in the context of non-fatal road traffic accidents using the original CA to test if the approach, applied to a wide range of health gains, is able to derive valid estimates and a constant value of a QALY which the previous research has not been able to show. Data were collected from a total of 800 individuals in the Swedish adult general population using two web-based questionnaires. The values of a QALY based on trimmed estimates were close to constant at €300,000 irrespective of the size of the QALY gain. The study shows that the original CA method may be a valid method to estimate the value of a QALY and VSI for major health losses. It also supports the use of a higher threshold value for a QALY than that which is currently applied by several health technology assessment agencies in different countries.


High incidence of Haemophilus influenzae type b infection in children in Pacific island countries.
The Haemophilus influenzae type b (Hib) disease burden among children <5 years old in 4 Pacific island countries (PICs) was estimated. The incidence of confirmed Hib meningitis was calculated using the numbers of culture-confirmed isolates. In addition, the World Health Organization (WHO) Hib Rapid Assessment Tool (RAT) was used to estimate the true Hib meningitis incidence and the number of Hib meningitis and pneumonia cases, as well as the number of deaths due to Hib meningitis and pneumonia. The Hib meningitis annual incidence in 3 PICs was 70-84 cases per 100,000 children <5 years old. For PICs, the RAT is likely to overestimate the Hib pneumonia burden, as it assumes a 5 : 1 ratio of Hib pneumonia to Hib meningitis. The true ratio is likely to be 1 : 1. The high Hib disease burden and the relative cost-effectiveness of Hib vaccine make the introduction of Hib vaccine a good investment for PICs, costing US1000 dollars-US10,000 dollars for each death prevented--a number that ignores savings from reductions in the cost of treatment.


Evaluation of laparoscopic appendectomy vs. open appendectomy: a retrospective study at Aga Khan University Hospital, Karachi, Pakistan.
To compare open and laparoscopic appendectomies and to evaluate the level of efficacy of both types of appendectomy performed at Aga Khan University Hospital (AKUH). Based on this strong study rationale, a clinical audit of patient's records was performed to evaluate the significance of this technique as a treatment modality. The study population comprised of patients with appendicitis admitted in the Department of Surgery from January 2004 to December 2004. The patients' charts were reviewed to ascertain whether the procedure was done as an acute case or as an elective procedure. The predictor variables explored in this study were: age, gender, ultrasound and CT focused procedure, operative time, post-operative stay, number of hours required for the return of bowel function, use of narcotic analgesia and the total hospital bill of the respective patients. A total of 49 patients' clinical charts were reviewed. Of these, 29 patients had had laparoscopic appendectomies and the remaining 20 had open appendectomies. The mean post-operative stay in days was relatively shorter for laparoscopic appendectomy (1.97 +/- 2.3) compared to open appendectomy (3.1 +/- 1.8). The average time for the return of bowel movement was remarkably lesser for laparoscopic appendectomy (10.6 +/- 8.2) hours than open appendectomy (21 +/- 13) hours. Two of the independent variables: CT focused (P-value: 0.01) and operative times in minutes (P-value: 0.06) were found to be significantly associated with the types of appendectomy. Hence our study found that laparoscopic appendectomy, although relatively expensive, is a safe and effective procedure for the removal of appendix over open appendectomy.


Recommendations for the Development and Reform of Microtia and Atresia Services.
The initial step in setting up standardized microtia-atresia service is investigating the current status of the service and comparing this to internationally recognized guidelines or care standards. In many countries, documented information about microtia care is lacking. This study is an initiative to guide reform efforts of national microtia service in any country. The UK care standards for microtia-atresia can be a useful model to help set up a comprehensive microtia-atresia service. The authors conducted a survey to investigate different aspects of microtia service in Egypt. The major plastic surgery centers (n = 22) were surveyed by a structured questionnaire. The results were compared with the UK care standards for microtia-atresia to identify the aspects that need improvement. Thorough analysis of the main problems in microtia-atresia service is presented. The authors found that microtia service is fragmented between the surveyed centers with 65% of the centers treating less than 10 microtia cases annually. Multiple surgeons are responsible for ear reconstruction in 90% of centers and only 25% of them practise a multidisciplinary team approach. None of the centers uses validated tools of aesthetic or psychological patient-reported outcome measures. These 5 recommendations are the keys to reforming microtia service in any country:(1) Establishing nationally designated centers to concentrate the required expertise.(2) Assigning fewer high-volume surgeons to optimize the surgical outcomes.(3) Providing treatment by experienced multidisciplinary teams.(4) Using validated tools of patient-reported outcome measures.(5) Collecting and keeping standardized records for regular audit and intercenter studies.


In cellulo crystallization of Trypanosoma brucei IMP dehydrogenase enables the identification of genuine co-factors.
Sleeping sickness is a fatal disease caused by the protozoan parasite Trypanosoma brucei (Tb). Inosine-5'-monophosphate dehydrogenase (IMPDH) has been proposed as a potential drug target, since it maintains the balance between guanylate deoxynucleotide and ribonucleotide levels that is pivotal for the parasite. Here we report the structure of TbIMPDH at room temperature utilizing free-electron laser radiation on crystals grown in living insect cells. The 2.80 Å resolution structure reveals the presence of ATP and GMP at the canonical sites of the Bateman domains, the latter in a so far unknown coordination mode. Consistent with previously reported IMPDH complexes harboring guanosine nucleotides at the second canonical site, TbIMPDH forms a compact oligomer structure, supporting a nucleotide-controlled conformational switch that allosterically modulates the catalytic activity. The oligomeric TbIMPDH structure we present here reveals the potential of in cellulo crystallization to identify genuine allosteric co-factors from a natural reservoir of specific compounds.


Building workforce capacity in Australia and New Zealand: a profile of psychiatrists with an interest in intellectual and developmental disability mental health.
To describe the characteristics of psychiatrists working in the area of intellectual and developmental disability mental health (IDDMH) across Australia and New Zealand. A secondary analysis of data collected by the Royal Australian and New Zealand College of Psychiatrists 2014 workforce survey. Characteristics of the IDDMH workforce ( n=146 psychiatrists) were compared with those of the broader psychiatry workforce ( n=1050 psychiatrists). The IDDMH workforce were more likely than the broader psychiatry workforce to be working across both the public and private health sectors, be engaged in outreach work, endorse specialty practice areas pertinent to IDDMH, treat younger patients and work more clinical hours per week. Part-time status and retirement plans of the IDDMH workforce matched those of the broader psychiatry workforce. While some elements of the IDDMH workforce profile suggest this workforce is tailored to the needs of the population, the potential shortage of IDDMH psychiatrists highlights the need for the development of a specific training programme and pathway in this area.


Theoretical study of the effect of slow light on BOTDA spatial resolution.
Due to the resonant nature of Brillouin scattering, delay occurs while pulse is propagating in an optical fiber. This effect influences the location accuracy of distributed Brillouin sensors. The maximum delay in sensing fibers depends on length, position, pump and Stokes powers. Considering pump depletion, we have obtained integral solutions for the coupled amplitude equations under steady state conditions and then calculated the group delay. The results show that moderate pump depletion (which is the optimized sensor working range) mitigates significantly the delay, and the maximum delay induced at resonance is only a fraction of Brillouin Optical Time Domain (BOTDA) spatial resolution, which means that the use of pulse width to define the spatial resolution is valid when Brillouin slow light is considered. We have shown that uniform strain and temperature distribution in a fiber gives the maximum delay induced uncertainty.


Estimation of type- and subtype-specific influenza vaccine effectiveness in Victoria, Australia using a test negative case control method, 2007-2008.
Antigenic variation of influenza virus necessitates annual reformulation of seasonal influenza vaccines, which contain two type A strains (H1N1 and H3N2) and one type B strain. We used a test negative case control design to estimate influenza vaccine effectiveness (VE) against influenza by type and subtype over two consecutive seasons in Victoria, Australia. Patients presenting with influenza-like illness to general practitioners (GPs) in a sentinel surveillance network during 2007 and 2008 were tested for influenza. Cases tested positive for influenza by polymerase chain reaction and controls tested negative for influenza. Vaccination status was recorded by sentinel GPs. Vaccine effectiveness was calculated as [(1--adjusted odds ratio) × 100%]. There were 386 eligible study participants in 2007 of whom 50% were influenza positive and 19% were vaccinated. In 2008 there were 330 eligible study participants of whom 32% were influenza positive and 17% were vaccinated. Adjusted VE against A/H3N2 influenza in 2007 was 68% (95% CI, 32 to 85%) but VE against A/H1N1 (27%; 95% CI, -92 to 72%) and B (84%; 95% CI, -2 to 98%) were not statistically significant. In 2008, the adjusted VE estimate was positive against type B influenza (49%) but negative for A/H1N1 (-88%) and A/H3N2 (-66%); none was statistically significant. Type- and subtype-specific assessment of influenza VE is needed to identify variations that cannot be differentiated from a measure of VE against all influenza. Type- and subtype-specific influenza VE estimates in Victoria in 2007 and 2008 were generally consistent with strain circulation data.


Why is the correlation between gene importance and gene evolutionary rate so weak?
One of the few commonly believed principles of molecular evolution is that functionally more important genes (or DNA sequences) evolve more slowly than less important ones. This principle is widely used by molecular biologists in daily practice. However, recent genomic analysis of a diverse array of organisms found only weak, negative correlations between the evolutionary rate of a gene and its functional importance, typically measured under a single benign lab condition. A frequently suggested cause of the above finding is that gene importance determined in the lab differs from that in an organism's natural environment. Here, we test this hypothesis in yeast using gene importance values experimentally determined in 418 lab conditions or computationally predicted for 10,000 nutritional conditions. In no single condition or combination of conditions did we find a much stronger negative correlation, which is explainable by our subsequent finding that always-essential (enzyme) genes do not evolve significantly more slowly than sometimes-essential or always-nonessential ones. Furthermore, we verified that functional density, approximated by the fraction of amino acid sites within protein domains, is uncorrelated with gene importance. Thus, neither the lab-nature mismatch nor a potentially biased among-gene distribution of functional density explains the observed weakness of the correlation between gene importance and evolutionary rate. We conclude that the weakness is factual, rather than artifactual. In addition to being weakened by population genetic reasons, the correlation is likely to have been further weakened by the presence of multiple nontrivial rate determinants that are independent from gene importance. These findings notwithstanding, we show that the principle of slower evolution of more important genes does have some predictive power when genes with vastly different evolutionary rates are compared, explaining why the principle can be practically useful despite the weakness of the correlation.