Base of thumb osteoarthritis in UK interface services-a cohort and survey-based study to assess current practice.
Base of thumb OA (BTOA) is a common age-related disease that has a significant negative impact on quality of life, while little is known about the structure and pathways of interface services. Our aim was to assess disease burden, referral pathways, service structure and management pathways in UK interface services. A structured questionnaire was carried out with a participating clinician at each centre to detail the local guidelines and management of BTOA. Five patients referred with BTOA were prospectively identified in each of 32 UK interface centres. Most centres (72%) had a local guideline and a standardized treatment regime consisting of education (100%), joint protection (100%), range of motion exercises (84%), strengthening exercises (88%), splintage (100%) and use of assistive devices (78%). No centre routinely offered a steroid injection at the first appointment and no centre had a specific threshold for offering an injection. Injection delivery was variable. Most patients had not been referred previously (82%). Most patients used analgesia (72%), but a minority of patients had been treated with a splint (46%), therapy (43%) and steroid injection (27%) prior to their latest attendance. Most BTOA patients newly referred to interface services have been treated with analgesics and have not received comprehensive multimodal intervention. The management of BTOA at interface services is standardized in terms of education, splintage and therapy. However, there is a lack of standardization in terms of both the threshold for, timing of and mode of delivery of injection therapy.


Human model of burn injury that quantifies the benefit of cooling as a first aid measure.
Burn injuries are a major cause of morbidity and mortality worldwide. Cooling is widely practised as a first aid measure, but the efficacy of cooling burns in human skin has not been demonstrated. A safe, consistent, ethically acceptable model of burning and cooling in live human skin in vivo was developed, and used to quantify the effects of cooling. Novel apparatus was manufactured to create and cool burns in women who were anaesthetized for breast reconstruction surgery using a deep inferior epigastric artery perforator flap. Burns were excised between 1 and 3 h after creation, and analysed using histopathological assessment. All 25 women who were approached agreed to take part in the study. There were no adverse events. Increased duration of contact led to increased burn depth, with a contact time of 7·5 s at 70°C leading to a mid-dermal burn. Burn depth progressed over time following injury, but importantly this was modified by cooling the burn at 16°C for 20 min. On average, cooling salvaged 25·2 per cent of the dermal thickness. This study demonstrated the favourable effects of cooling on human burns. Public heath messaging should emphasize cooling as first aid for burns. This model will allow analysis of the molecular effects of cooling burns, and provide a platform for testing novel therapies aimed at reducing the impact of burn injury.


Production and characterization of a monoclonal antibody against Niemann Pick type C protein.
Niemann Pick type C is a severe, incurable disease caused, in the majority of cases, by mutations in the Niemann Pick type C protein 1 (NPC1). The pathology and biochemical changes associated with the disease have been extensively studied. However, the function of the protein is still unknown, and recent studies challenge the established concept that a defect in cholesterol and sphingolipids transport is the primary cause of this human lipidosis. Clearly defining the mechanisms by which defects in this protein lead to the disease phenotype will require further studies on the structure and function of this protein. Therefore, the development of a well-characterized monoclonal antibody (MAb) against this protein to facilitate such studies is an important goal. Here, we describe the production and characterization of such a MAb. The antibody is demonstrated to be highly specific and species cross-reactive. Function studies show that the antibody induces the NPC1 disease phenotype in cells, making it highly likely that the antibody blocks function of the NPC1 protein.


Avoidable mortality in people with schizophrenia or bipolar disorder in England.
To quantify the extent of 'avoidable mortality' in those with schizophrenia or bipolar disorder and to quantify the effect a reduction in these might have on the mortality gap associated with severe mental illness. A cohort was studied of people aged <75 years, discharged from inpatient care with schizophrenia or bipolar disorder in 2006-2007, and followed up for 365 days. Standardised mortality ratios (SMRs) were calculated followed by hypothetical SMRs, estimating the residual mortality gap if 'avoidable' causes and suicide in the cohorts had occurred at the same level as those in the general population. Avoidable deaths comprised 60.2% and 59.2% of all deaths in the schizophrenia and bipolar disorder cohorts respectively. All-cause SMRs were 4.23 (95% CI 3.85-4.60) and 2.60 (2.21-3.00) respectively. After discounting the excess attributable to avoidable causes and suicide, the SMRs fell to 2.38 (2.09-2.66) and 1.66 (1.35-1.98) respectively. Bringing mortality from avoidable causes and suicide down to general population levels would reduce the overall mortality excess in severe mental illness substantially, by about 50%, but would not eliminate it. Other underlying factors beyond those conventionally considered as 'avoidable' need further research.


Carbon-coated MoO2 nanoclusters anchored on RGO sheets as high-performance electrodes for symmetric supercapacitors.
A carbon-coated molybdenum dioxide-reduced graphene oxide (RGO@MoO2/C) composite was synthesized as a high-performance electrode for supercapacitors via a facile hydrothermal method. In this composite, RGO not only provided high conductivity to benefit effective electron transfer, but also offered nucleation sites to load in situ formed MoO2/C nanoparticles. The MoO2@C nanoparticles interconnected with each other forming nanoclusters and were anchored uniformly on RGO sheets instead of self-agglomerating into large aggregates. This allowed more MoO2 grains to gain easy access to both the conductive network and the electrolyte for efficient electron and ion transfer. Moreover, this effect was achieved after the addition of a rather small amount of GO (5 wt%), which allowed high MoO2/C loading to contribute to the overall capacitance. When the RGO@MoO2/C composite was evaluated as an electrode material for supercapacitors, a synergistic effect was exerted with high specific capacitance (1224.5 F g-1 at 1 A g-1) and large reversibility (92% capacitance retention after 3000 cycles), both of which were of great advantage over individual MoO2/C composite. RGO@MoO2/C was also used to construct a symmetric supercapacitor, which showed enhanced voltage profiles and could light an LED device for dozens of minutes, thus confirming its excellent electrochemical performance.


Major defect to the brachial artery following blunt trauma--a five year follow-up.
A 29-year-old soldier was injured when a collapsible side of an army truck fell on his left upper arm creating lesion to the brachial artery with a defect in the artery of about 10 cm in length. Injury to one brachial vein, of the same length, was also sustained without bone or neural injury. Intraoperative Doppler ultrasonography was performed. A reverse autologous saphenous vein interposition graft with a circumference similar to that of the injured brachial artery was used to perform end-to-end anastomosis between artery and reversed vein graft. The patient returned to his military formation 16 days post operatively, with a return to full military calisthenics routine 2 months after injury. Surgical and Doppler ultrasonography control was kept regularly. Excellent late result revascularization of the injured brachial artery with reversed interposition vein graft can be seen in CT angiography five years after injury.


Susceptibility of Faba Bean (Vicia faba L.) to Heat Stress During Floral Development and Anthesis.
Experiments were conducted over 2 years to quantify the response of faba bean (Vicia faba L.) to heat stress. Potted winter faba bean plants (cv. Wizard) were exposed to temperature treatments (18/10; 22/14; 26/18; 30/22; 34/26 °C day/night) for 5 days during floral development and anthesis. Developmental stages of all flowers were scored prior to stress, plants were grown in exclusion from insect pollinators to prevent pollen movement between flowers, and yield was harvested at an individual pod scale, enabling effects of heat stress to be investigated at a high resolution. Susceptibility to stress differed between floral stages; flowers were most affected during initial green-bud stages. Yield and pollen germination of flowers present before stress showed threshold relationships to stress, with lethal temperatures (t50) ˜28 °C and ~32 °C, while whole plant yield showed a linear negative relationship to stress with high plasticity in yield allocation, such that yield lost at lower nodes was partially compensated at higher nodal positions. Faba bean has many beneficial attributes for sustainable modern cropping systems but these results suggest that yield will be limited by projected climate change, necessitating the development of heat tolerant cultivars, or improved resilience by other mechanisms such as earlier flowering times.


An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits.
Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6x10(-8)), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6x10(-13); SOX6, p = 6.4x10(-10)) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation.


Long-term Outcome of Prostate Cancer Patients Who Exhibit Biochemical Failure Despite Salvage Radiation Therapy After Radical Prostatectomy.
Salvage radiation therapy (SRT) is an effective treatment for recurrent prostate cancer (PCa) after radical prostatectomy. We report the long-term outcome of men who developed biochemical recurrence (BCR) after SRT and were treated >14 years ago. In total, 61 patients treated with SRT from 1992 to 2000 at our institution were identified. Survival was calculated by Kaplan-Meier method. Log-rank test and Cox regression were used to determine significance of clinical parameters. The median follow-up was 126 months (interquartile range, 66-167 mo). Thirty-four (56%) had prostate-specific antigen (PSA) failure after SRT. At 10 years, overall survival (OS) was 67%, freedom from PSA failure (FFPF) was 33%, prostate cancer-specific survival (PCSS) was 84%, and distant metastases-free survival (DMFS) was 84%. Pathologic T-stage, Gleason score, seminal vesicle involvement, and pre-SRT PSA were associated with FFPF. For patients who failed SRT, the median time to BCR after SRT was 30 mo. A total of 19 (68%) received androgen deprivation therapy. The median OS was 13.6 years. At 10 years from time of BCR, OS was 59%, PCSS was 73%, DMFS was 75%, and castration-resistant-free survival was 70%. Early SRT failure correlated with significantly decreased DMFS and PCSS. Ten-year DMFS from SRT was 43% (BCR≤1 y) versus 91% (BCR>1 y). Extended follow-up demonstrates that despite SRT failure, PCSS remains high in select patients. Early failure (≤1 y after SRT) predicted for significantly worse outcome and may represent a subgroup with more aggressive disease that may be considered for further prospective clinical studies.


Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators.
During the invasive phase of implantation, trophoblasts and maternal decidual stromal cells secrete products that regulate trophoblast differentiation and migration into the maternal endometrium. Paracrine interactions between the extravillous trophoblast and the maternal decidua are important for successful embryonic implantation, including establishing the placental vasculature, anchoring the placenta to the uterine wall, and promoting the immunoacceptance of the fetal allograph. To our knowledge, global crosstalk between the trophoblast and the decidua has not been elucidated to date, and the present study used a functional genomics approach to investigate these paracrine interactions. Human endometrial stromal cells were decidualized with progesterone and further treated with conditioned media from human trophoblasts (TCM) or, as a control, with control conditioned media (CCM) from nondecidualized stromal cells for 0, 3, and 12 h. Total RNA was isolated and processed for analysis on whole-genome, high-density oligonucleotide arrays containing 54,600 genes. We found that 1374 genes were significantly upregulated and that 3443 genes were significantly downregulated after 12 h of coincubation of stromal cells with TCM, compared to CCM. Among the most upregulated genes were the chemokines CXCL1 (GRO1) and IL8,CXCR4, and other genes involved in the immune response (CCL8 [SCYA8], pentraxin 3 (PTX3), IL6, and interferon-regulated and -related genes) as well as TNFAIP6 (tumor necrosis factor alpha-induced protein 6) and metalloproteinases (MMP1, MMP10, and MMP14). Among the downregulated genes were growth factors, e.g., IGF1, FGF1, TGFB1, and angiopoietin-1, and genes involved in Wnt signaling (WNT4 and FZD). Real-time RT-PCR and ELISAs, as well as immunohistochemical analysis of human placental bed specimens, confirmed these data for representative genes of both up- and downregulated groups. The data demonstrate a significant induction of proinflammatory cytokines and chemokines, as well as angiogenic/static factors in decidualized endometrial stromal cells in response to trophoblast-secreted products. The data suggest that the trophoblast acts to alter the local immune environment of the decidua to facilitate the process of implantation and ensure an enriched cytokine/chemokine environment while limiting the mitotic activity of the stromal cells during the invasive phase of implantation.


Immunosenescence and vaccine failure in the elderly.
An age-related decline in immune responses in the elderly results in greater susceptibility to infection and reduced responses to vaccination. This decline in immune function affects both innate and adaptive immune systems. A meeting of experts in immunology and gerontology in Paris, France, in April 2008, considered current understanding of immunosenescence and its clinical consequences. Essential features of immunosenescence include: reduced natural killer cell cytotoxicity on a per cell basis; reduced number and function of dendritic cells in blood; decreased pools of naive T and B cells; and increases in the number of memory and effector T and B cells. In particular, an accumulation of late differentiated effector T cells, commonly associated with cytomegalovirus infection, contributes to a decline in the capacity of the adaptive immune system to respond to novel antigens. Consequently, vaccine responsiveness is compromised in the elderly, especially frail patients. Strategies to address the effects of immunosenescence include ensuring that seroprotective antibody levels against preventable infectious diseases are maintained throughout adulthood, and improving diet and exercise to address the effects of frailty. New vaccines are being developed, such as intradermal and high-dose vaccines for influenza, to improve the efficacy of immunization in the elderly. In the future, the development and use of markers of immunosenescence to identify patients who may have impaired responses to vaccination, as well as the use of end-points other than antibody titers to assess vaccine efficacy, may help to reduce morbidity and mortality due to infections in the elderly.


Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants.
The recent Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola and Zika virus outbreaks exemplify the continued threat of (re-)emerging viruses to human health, and our inability to rapidly develop effective therapeutic countermeasures. Many viruses, including MERS-CoV and the Crimean-Congo hemorrhagic fever virus (CCHFV) encode deubiquitinating (DUB) enzymes that are critical for viral replication and pathogenicity. They bind and remove ubiquitin (Ub) and interferon stimulated gene 15 (ISG15) from cellular proteins to suppress host antiviral innate immune responses. A variety of viral DUBs (vDUBs), including the MERS-CoV papain-like protease, are responsible for cleaving the viral replicase polyproteins during replication, and are thereby critical components of the viral replication cycle. Together, this makes vDUBs highly attractive antiviral drug targets. However, structural similarity between the catalytic cores of vDUBs and human DUBs complicates the development of selective small molecule vDUB inhibitors. We have thus developed an alternative strategy to target the vDUB activity through a rational protein design approach. Here, we report the use of phage-displayed ubiquitin variant (UbV) libraries to rapidly identify potent and highly selective protein-based inhibitors targeting the DUB domains of MERS-CoV and CCHFV. UbVs bound the vDUBs with high affinity and specificity to inhibit deubiquitination, deISGylation and in the case of MERS-CoV also viral replicative polyprotein processing. Co-crystallization studies further revealed critical molecular interactions between UbVs and MERS-CoV or CCHFV vDUBs, accounting for the observed binding specificity and high affinity. Finally, expression of UbVs during MERS-CoV infection reduced infectious progeny titers by more than four orders of magnitude, demonstrating the remarkable potency of UbVs as antiviral agents. Our results thereby establish a strategy to produce protein-based inhibitors that could protect against a diverse range of viruses by providing UbVs via mRNA or protein delivery technologies or through transgenic techniques.


Early serial Q-switched ruby laser therapy for medium-sized to giant congenital melanocytic naevi.
Medium-sized to giant congenital melanocytic naevi (CMN) are difficult to treat, especially if the lesions appear on the face or extremities where treated areas are visible and cosmesis is important. In infants, nests of pigmented naevus reside more superficially and the skin is more transparent than in adults, so we treated medium-sized to giant CMN with early serial Q-switched ruby laser therapy from infancy. We treated nine patients with medium-sized to giant CMN on the face or upper limbs from 1 month of age with early serial Q-switched ruby laser therapy. The laser power was initially 5 J cm(-2) and increased in 0.5 J cm(-2) steps to a maximum of 10 J cm(-2). There were three treatment sites on the forehead, one on the temple, one on the cheek and four on the upper arm. It took 8-15 treatments for the CMN to become a colour similar to the surrounding skin. The mean number of treatments was 9.6. The colour was reduced to 0-20% of the colour of the baseline lesion in all nine patients. Partial slight repigmentation occurred in eight of these patients. These naevi were treated with an additional one or two Q-switched ruby laser irradiations and successfully lightened for at least 1 year. In the remaining patient, pigmentation returned to a level similar to the original lesion within 1 month of the last treatment. Therefore, the lesion was excised for cosmetic reasons. After the treatment series, the skin texture was fine and no patients had hypertrophic scarring. Although treatment of one patient with the Q-switched ruby laser therapy failed, the remaining patients responded well and had good to excellent skin texture without hypertrophic scarring. Early serial Q-switched ruby laser treatment, starting from infancy, is a promising treatment method for this condition.


Correlation Between Bile Reflux Gastritis and Biliary Excreted Contrast Media in the Stomach.
This study aimed to evaluate the relationship between biliary excreted contrast media in the stomach and the presence of bile reflux gastritis. Consecutive 111 patients who underwent both gadoxetic acid-enhanced magnetic resonance cholangiography (gadoxetic MRC) and gastric endoscopy were included in this study. We performed a review of the gadoxetic-MRC image sets acquired 60 minutes after intravenous injection of contrast media and endoscopic images. We recorded amount of contrast media in the stomach. The sensitivity, specificity, and accuracy of duodenogastric bile reflux diagnosis were evaluated for the gadoxetic MRC. Statistical analysis was performed using the Fisher exact test and the linear-by-linear association test. Among the 111 patients, 39 had 60-minute delayed images showing the presence of contrast media in the stomach. Of these 39 patients, 13 had bile reflux gastritis and 5 showed bile in the stomach without evidence of erythematous gastritis. Of the 72 patients who did not show contrast media in the stomach, none had bile reflux gastritis and 2 patients showed bile staining in the stomach without evidence of erythematous gastritis. Bile reflux gastritis was significantly more frequent in patients with contrast media in the stomach on gadoxetic MRC than in those without. Patients with high-grade extension of contrast media in the stomach had significantly frequent bile reflux gastritis than did those with low-grade extension. Biliary excreted contrast media in the stomach on 60-minute delayed gadoxetic MRC has a correlation with the presence of bile reflux gastritis on endoscopic examination.


Photophysical properties of rhenium(i) complexes and photosensitized generation of singlet oxygen.
fac-[Re(ampy)(CO)3(NN)]+ complexes (ampy = 2-aminomethylpyridine and NN = 1,10-phenanthroline (phen), and 2,2'-bipyridine (bpy)) were synthesized, purified and characterized by proton nuclear magnetic resonance (1H NMR), UV-visible and Fourier-transformed infrared (FT-IR) spectroscopies, and their photophysical properties were investigated using steady state and time-resolved emission spectroscopies. The electronic absorption spectra exhibit two main absorption bands: the higher energy band, which was assigned to intraligand transition (IL), and the lower energy band assigned to metal-to-ligand charge transfer (MLCT). Both complexes showed emission at room temperature in a CH3CN solution (λmax = 560 nm, ϕ = 0.091, τ = 560 ns for fac-[Re(ampy)(CO)3(phen)]+; λmax = 568 nm, ϕ = 0.024, τ = 100 ns for fac-[Re(ampy)(CO)3(bpy)]+) and rigid media (λmax = 530 nm, τ = 3300 ns for fac-[Re(ampy)(CO)3(phen)]+; λmax = 530 nm, τ = 853 ns for fac-[Re(ampy)(CO)3(bpy)]+) arising from the lowest lying 3MLCTRe→NN excited state. Both complexes along with fac-[Re(L)(CO)3(NN)]+/0 complexes, L = Cl or pyridine, were capable of efficiently photosensitizing the generation of singlet oxygen with quantum yield in the range of 0.59-0.28. These results highlight the potential application of fac-[Re(L)(CO)3(NN)]+/0 complexes in the development of sensitizers for the generation of singlet oxygen.


Proteomics of exhaled breath: methodological nuances and pitfalls.
The analysis of exhaled breath condensate (EBC) can be an alternative to traditional endoscopic sampling of lower respiratory tract secretions. This is a simple non-invasive method of diagnosing respiratory diseases, in particular, respiratory inflammatory processes. Samples were collected with a special device-condenser (ECoScreen, VIASYS Healthcare, Germany), then treated with trypsin according to the proteomics protocol for standard protein mixtures and analyzed by nanoflow high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) with a 7-Tesla Finnigan LTQ-FT mass spectrometer (Thermo Electron, Germany). Mascot software (Matrixscience) was used for screening the database NCBInr for proteins corresponding to the peptide maps that were obtained. EBCs from 17 young healthy non-smoking donors were collected. Different methods for concentrating protein were compared in order to optimize EBC preparations for proteomic analysis. The procedure that was chosen allowed identification of proteins exhaled by healthy people. The major proteins in the condensates were cytoskeletal keratins. Another 12 proteins were identified in EBC from healthy non-smokers. Some keratins were found in the ambient air and may be considered exogenous components of exhaled air. Knowledge of the normal proteome of exhaled breath allows one to look for biomarkers of different disease states in EBC. Proteins in ambient air can be identified in the respiratory tract and should be excluded from the analysis of the proteome of EBC. The results obtained allowed us to choose the most effective procedure of sample preparation when working with samples containing very low protein concentrations.


[Allergens and their relationships to childhood bronchial asthma in the Jiading District of Shanghai].
To study allergens and their relationship to the occurrence of childhood bronchial asthma in the Jiading District of Shanghai. Three hundred and eighty-two 4 to 12-year-old children with asthma in the remission stage from Nanxiang Hospital in the Jiading District of Shanghai were used as a case group (asthma group), and 402 children from two primary schools and two kindergartens in Jiading were enrolled by cluster sampling and served as control group. Parents of the children completed a questionnaire on living conditions and allergy-related disease history. Skin prick test (SPT) for 18 common allergens was carried out in both groups. In order to examine the effect of environment and living conditions on SPT results, children in the control group were further divided into two sub-groups according to birth place: migrant (219 cases) and resident (183 cases). SPT results revealed that the main allergens identified in the Jiading region were dermatophagoides farinae, house dust mites, shrimps, cockroaches, and dog hair. The SPT positive rate was 67.9% in the asthma group, and this was significantly higher than in the control group (31.8%) (P<0.01). The environment and living conditions in the migrant group were significantly different from the resident group (P<0.01), whereas the SPT positive rate for this group was significantly lower than in the resident group (P<0.01). Allergens in the Jiading region mainly originate from dermatophagoides farinae, household dust mites, shrimps, cockroaches and dog hair. Children with asthma are more susceptible to allergens. Environment and living conditions may be relevant, to a certain extent, to an SPT positive rate.


Immunology, Immunotherapy, and Translating Basic Science into the Clinic for Bladder Cancer.
The Fourth Annual Albert Institute Bladder Cancer Care and Research Symposium was held from September 14th-16th in Houston, Texas. The symposium covered a range of topics relevant to bladder cancer, including basic science aspects of immunology and immunotherapy that inform clinical management; intravesical therapy for non-muscle invasive disease; understanding the nuances of carcinoma in situ; and optimizing patient care and outcomes following therapy. The moving landscape of bladder cancer from an industry perspective was also discussed. In the following sections we discuss intrinsic and extrinsic factors, including the immune microenvironment and sex bias, in the context of bladder cancer; how these influence tumor development, progression, and treatment strategies; and how the interpretation of immune features in relation to molecular subtypes informs both treatment decisions and response. We conclude with a summary of key points that will need to be addressed to ensure best use of new knowledge in this area for improved clinical management of patients with bladder cancer.


Clinicopathologic features of Buschke-Löwenstein tumor: a multi-institutional analysis of 38 cases.
Buschke-Löwenstein tumor (BLT) is a rare sexually transmitted disease, mostly described in clinical literature as case reports or small series. Here, we investigated the clinicopathologic features of BLT in a total of 38 cases retrieved from multiple academic institutions. The average age was 47.6 ± 12.8 (mean ± SD) years old at diagnosis. The male to female ratio was 4.4:1. Common presenting symptoms were pain/discomfort, bleeding, mass lesion, and discharge. It was frequently linked to smoking and positive human immunodeficiency virus status. The tumor size and thickness were 8.5 ± 6.6 cm and 1.5 ± 1.3 cm, respectively. Histologically, 19 (50%) cases had an invasive squamous cell carcinoma component and were associated with high-risk human papillomavirus infection. There was no lymphovascular or perineural invasion, or nodal metastasis at initial diagnosis. BLTs with invasion had higher frequency of dyskeratosis, neutrophilic microabscesses, and abnormal mitoses, but lower frequency of pushing border compared with BLTs without invasion. All patients underwent wide excision, and some also received chemoradiation therapy. After a median follow-up of 23 months (range 1-207), the recurrence rate was 23.7% and disease-specific mortality was 2.6%. In summary, we presented the largest case series of BLT to date to characterize its unique clinicopathologic features. Our study indicated that certain histologic features such as dyskeratosis, neutrophilic microabscess, and abnormal mitosis in the non-invasive portion may be important clues on lesional biopsy to predict the presence of underlying invasive carcinoma.


Thermal stresses in optical waveguides.
Birefringence of optical waveguides is closely related to the anisotropy of thermal stresses in the core. Closed-form solutions for estimating the thermal stresses in the cladding layers and in the core of an embedded channel waveguide are presented. The solutions are verified by finite-element simulation. It is found that the thermal stress in the core in the direction perpendicular to the wafer cannot be ignored, and one can tune the core stress anisotropy in the plane normal to the light-propagation direction by varying the thermal-expansion mismatch between the upper cladding and the substrate.


Simultaneous stereoselective analysis of tramadol and its primary phase I metabolites in plasma by liquid chromatography. Application to a pharmacokinetic study in humans.
This paper describes a bioanalytical method involving a simple liquid-liquid extraction for the simultaneous HPLC determination of the enantiomers of tramadol, the active metabolite O-desmethyltramadol (M1), and the other main metabolite N-desmethyltramadol (M2) in biological samples. Chromatography was performed at 5 degrees C on a Chiracel OD-R column containing cellulose tris(3,5-dimethylphenylcarbamate) as chiral selector, preceded by a achiral end-capped C8 column (LiChrospher 60-RP-selected B 5 microm, 250 mm x 4 mm). The mobile phase was a mixture of phosphate buffer containing sodium perchlorate (1 M) adjusted to pH 2.5-acetonitrile-N,N-dimethyloctylamine (74.8:25:0.2). The flow rate was 0.5 ml/min. Fluorescence detection (lambda(ex) 200 nm/lambda(em) 301 nm) was used. Fluconazol was selected as internal standard. The limit of quantitation of each enantiomer of tramadol and their metabolites was 0.5 ng/ml (sample size = 0.5 ml). The chiral conditions and the LC optimisation were investigated in order to select the most appropriate operating conditions. The method developed has also been validated. Mean recoveries above of 95% for each enantiomer were obtained. Calibration curves for tramadol enantiomers (range 1-500 ng/ml), M1 enantiomers (range 0.5-100 ng/ml), and M2 enantiomers (range 0.5-250 ng/ml) were linear with coefficients of correlation better than 0.996. Within-day variation determined on four different concentrations showed acceptable values. The relative standard deviation (R.S.D.) was determined to be less than 10%. This method was successfully used to investigate plasma concentration of enantiomers of tramadol, O-desmethyltramadol and N-desmethyltramadol in a pharmacokinetic study.


Whipple Disease Presenting as Cystic Brain Tumor: Case Report and Review of the Literature.
Although neurological features are commonly encountered in Whipple"s disease (WD), presentation with purely neurological patterns is uncommon. Exclusive confinement to the central nervous system (CNS) is extremely rare. In these cases, the development of an isolated cerebral mass is exceptional. In the present paper, the authors describe a case of a 68-year-old man who presented with partial seizures. The neurological examination was normal. The imaging showed a cystic lesion. This tumor-like lesion was removed by performing frontal craniotomy. A histopathological investigation revealed the presence of numerous perivascular foamy histiocytes infiltrating the brain parenchyma. The majority of these histiocytes showed Periodic acid-schiff (PAS)-positive intense staining, which is distinctive feature of cerebral WD. The diagnosis was confirmed by polymerase chain reaction (PCR) analysis of cerebrospinal fluid. There were no gastrointestinal symptoms and no PAS inclusions in intestinal mucosa. The patient received Ceftriaxone intravenously followed by oral trimethoprime-sulfamethoxazole (TMP-SMZ) for 12 months and recovered well. This case illustrates atypical WD, confined exclusively to the central nervous system.


Refining animal research: The Animal Study Registry.
The Animal Study Registry (ASR; www.animalstudyregistry.org) was launched in January 2019 for preregistration of animal studies in order to increase transparency and reproducibility of bioscience research and to promote animal welfare. The registry is free of charge and is designed for exploratory and confirmatory studies within applied science as well as basic and preclinical research. The registration form helps scientists plan their study thoroughly by asking detailed questions concerning study design, methods, and statistics. With registration, the study automatically receives a digital object identifier (DOI) that marks it as intellectual property of the researcher. To accommodate the researchers concerns about theft of ideas, users can restrict the visibility of their registered studies for up to 5 years. The full content of the study becomes publicly accessible at the end of the embargo period. Because the platform is embedded in the infrastructure of the German Federal Government, continuity and data security are provided. By registering a study in the ASR, researchers can show their commitment to transparency and data quality to reviewers and editors, to third-party donors, and to the general public.


Unique medical issues in adult patients with mucopolysaccharidoses.
The mucopolysaccharidoses are a group of inherited metabolic diseases caused by deficiencies in enzymes involved in the sequential degradation of glycosaminoglycans (GAGs) leading to substrate accumulation in various tissues and organs. GAG accumulation can cause growth retardation and progressive damage to respiratory, cardiovascular, musculoskeletal, nervous, gastrointestinal, auditory, and visual systems. In the past, few people with severe phenotypic mucopolysaccharidosis (MPS) reached adulthood. However, better methods for diagnosis, multi-disciplinary care, and new therapies have extended lifespan, leading to an increasing number of patients surviving beyond childhood. The growing number of adult MPS patients poses significant challenges for clinicians who may not be familiar with the clinical manifestations of MPS. In addition, as new interventions have changed the natural history of these disorders, it is difficult to anticipate both the impact on life expectancy and other complications that may occur as these patients age. Because the MPS disorders are multi-organ diseases, their management requires a coordinated multi-disciplinary approach. Here we discuss the unique pattern of medical issues and multi-organ involvement in adult patients with MPS and identify the challenges that are associated with management of MPS. This review is based on information from an expert investigator meeting with MPS specialists held October 2-4, 2014 in Dublin, Ireland, as well as on current literature searches focusing on MPS and adults.


Challenges of patient handover process in healthcare services: A systematic review.
The patient handover process is in fact a valuable and essential part of the care processes in the hospitals. This can be a factor in increasing the quality and effectiveness of medical care. Incorrect and incomplete handover can increase the percentage of errors and cause serious problems for patients. The aim of this study was to identify the handover challenges concerning safety and quality of health services. A systematic review was conducted according to the Preferred Reporting Item for Systematic Reviews and Meta-analyses guideline. The key words "challenges of patient handover" or "challenges of patient handoff" were used in combination with the Boolean operators OR and AND. The ProQuest, Ovid, Doaj, Magiran, SID, Scopus, Science Direct, PubMed, and ISI were searched. A total of 263 articles were extracted, and 20 articles were selected for final review. The results of selected articles indicated that there are various challenges such as communication, noncoordination, nonuse of checklist, poor management, time management, and other things. These studies reported that communication was the main challenge of handover process. Hospitals try to provide a lot of services to the patients and other customers in a safe and healthy environment. Lack of communication among the incoming and outgoing nurses in handover process is one of the main causes of reduced safety and quality of services and patient dissatisfaction.


Methylation Analysis of DNA Mismatch Repair Genes Using DNA Derived from the Peripheral Blood of Patients with Endometrial Cancer: Epimutation in Endometrial Carcinogenesis.
Germline mutation of DNA mismatch repair (MMR) genes is a cause of Lynch syndrome. Methylation of MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) has been detected in peripheral blood cells of patients with colorectal cancer. This methylation is referred to as epimutation. Methylation of these genes has not been studied in an unselected series of endometrial cancer cases. Therefore, we examined methylation of MLH1, MSH2, and MSH6 promoter regions of peripheral blood cells in 206 patients with endometrial cancer using a methylation-specific polymerase chain reaction (MSP). Germline mutation of MMR genes, microsatellite instability (MSI), and immunohistochemistry (IHC) were also analyzed in each case with epimutation. MLH1 epimutation was detected in a single patient out of a total of 206 (0.49%)-1 out of 58 (1.72%) with an onset age of less than 50 years. The patient with MLH1 epimutation showed high level MSI (MSI-H), loss of MLH1 expression and had developed endometrial cancer at 46 years old, complicated with colorectal cancer. No case had epimutation of MSH2 or MSH6. The MLH1 epimutation detected in a patient with endometrial cancer may be a cause of endometrial carcinogenesis. This result indicates that it is important to check epimutation in patients with endometrial cancer without a germline mutation of MMR genes.


A modeling-based approach to optimize COVID-19 vaccine dosing schedules for improved protection.
While the development of different vaccines slowed the dissemination of SARS-CoV-2, the occurrence of breakthrough infections has continued to fuel the COVID-19 pandemic. To secure at least partial protection in the majority of the population through 1 dose of a COVID-19 vaccine, delayed administration of boosters has been implemented in many countries. However, waning immunity and emergence of new variants of SARS-CoV-2 suggest that such measures may induce breakthrough infections due to intermittent lapses in protection. Optimizing vaccine dosing schedules to ensure prolonged continuity in protection could thus help control the pandemic. We developed a mechanistic model of immune response to vaccines as an in silico tool for dosing schedule optimization. The model was calibrated with clinical data sets of acquired immunity to COVID-19 mRNA vaccines in healthy and immunocompromised participants and showed robust validation by accurately predicting neutralizing antibody kinetics in response to multiple doses of COVID-19 mRNA vaccines. Importantly, by estimating population vulnerability to breakthrough infections, we predicted tailored vaccination dosing schedules to minimize breakthrough infections, especially for immunocompromised individuals. We identified that the optimal vaccination schedules vary from CDC-recommended dosing, suggesting that the model is a valuable tool to optimize vaccine efficacy outcomes during future outbreaks.


Case studies on employment-related health inequalities in countries representing different types of labor markets.
The authors selected nine case studies, one country from each cluster of their labor market inequalities typology, to outline the macro-political and economic roots of employment relations and their impacts on health. These countries illustrate variations in labor markets and health, categorized into a global empirical typology. The case studies illustrated that workers' health is significantly connected with labor market characteristics and the welfare system. For a core country, the labor market is characterized by a formal sector. The labor institutions of Sweden traditionally have high union density and collective bargaining coverage and a universal health care system, which correlate closely with positive health, in comparison with Spain and the United States. For a semi-periphery country, the labor market is delineated by a growing informal economy. Although South Korea, Venezuela, and El Salvador provide some social welfare benefits, a high proportion of irregular and informal workers are excluded from these benefits and experience hazardous working conditions that adversely affect their health. Lastly, several countries in the global periphery--China, Nigeria, and Haiti--represent informal work and severe labor market insecurity. In the absence of labor market regulations, the majority of their workers toil in the informal sector in unsafe conditions with inadequate health care.


Polarization encoded color camera.
Digital cameras would be colorblind if they did not have pixelated color filters integrated into their image sensors. Integration of conventional fixed filters, however, comes at the expense of an inability to modify the camera's spectral properties. Instead, we demonstrate a micropolarizer-based camera that can reconfigure its spectral response. Color is encoded into a linear polarization state by a chiral dispersive element and then read out in a single exposure. The polarization encoded color camera is capable of capturing three-color images at wavelengths spanning the visible to the near infrared.


Role of effector cells (CCR7(-)CD27(-)) and effector-memory cells (CCR7(-)CD27(+)) in drug-induced maculopapular exanthema.
Maculopapular exanthema (MPE) induced by drugs is a T-cell mediated reaction and effector cells may play an important role in its development. We assessed the effector and cutaneous homing phenotype in peripheral blood cells from allergic patients after drug stimulation. This study included 10 patients and 10 controls. The effector phenotype (CCR7(-)CD27(+/-)), chemokine receptors (CCR4 and CCR10), and activation (CD25(low)) and regulatory markers (CD25(high)) were measured by flow cytometry in both peripheral blood mononuclear cells (PBMCs) and CD4-T-lymphocytes. Proliferation was determined by 5-(-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) assay and the migratory capacity by a chemotaxis assay using CCL17 and CCL27. Compared to controls, CCR7(-)CD27(-) cells were increased in patients without (p=0.003) and with drug stimulation (p less than 0.001) and had significantly higher proliferation (p=0.010). CCR10 expression was increased in patients after drug stimulation in total and memory CD27(+) T-cells. Lymphocyte migration with CCL27 was higher in patients with drug stimulation (p=0.048), with a decrease in CCR7(-)CD27(-) (p less than 0.0001) and an increase in CCR7(-)CD27(+) (p=0.017). In patients, CD4-T-lymphocytes were significantly activated after drug stimulation (p less than 0.001). In conclusion, we show that effector memory CD4(+) T-cells (CCR7(-)CD27(+)) respond specifically to the drug responsible for MPE and confirm previous data about the involvement of CCR10 in cell trafficking to the skin.


Design and synthesis of nonionic copolypeptide hydrogels with reversible thermoresponsive and tunable physical properties.
Polypeptide-based formulations that undergo liquid to hydrogel transitions upon change in temperature have become desirable targets since they can be mixed with cells or injected into tissues as liquids, and subsequently transform into rigid scaffolds or depots. Such materials have been challenging to prepare using synthetic polypeptides, especially when reversible gelation and tunable physical properties are desired. Here, we designed and prepared new nonionic diblock copolypeptide hydrogels (DCH) containing hydrophilic poly(γ-[2-(2-methoxyethoxy)ethyl]-rac-glutamate) and hydrophobic poly(l-leucine) segments, named DCHEO, and also further incorporated copolypeptide domains into DCHEO to yield unprecedented thermoresponsive DCH, named DCHT. Although previous attempts to prepare nonionic hydrogels composed solely of synthetic polypeptides have been unsuccessful, our designs yielded materials with highly reversible thermal transitions and tunable properties. Nonionic, thermoresponsive DCHT were found to support the viability of suspended mesenchymal stem cells in vitro and were able to dissolve and provide prolonged release of both hydrophilic and hydrophobic molecules. The versatility of these materials was further demonstrated by the independent molecular tuning of DCHT liquid viscosity at room temperature and DCHT hydrogel stiffness at elevated temperature, as well as the DCHT liquid to hydrogel transition temperature itself.


Delayed HIV diagnosis and initiation of antiretroviral therapy: inequalities by educational level, COHERE in EuroCoord.
In Europe and elsewhere, health inequalities among HIV-positive individuals are of concern. We investigated late HIV diagnosis and late initiation of combination antiretroviral therapy (cART) by educational level, a proxy of socioeconomic position. We used data from nine HIV cohorts within COHERE in Austria, France, Greece, Italy, Spain and Switzerland, collecting data on level of education in categories of the UNESCO/International Standard Classification of Education standard classification: non-completed basic, basic, secondary and tertiary education. We included individuals diagnosed with HIV between 1996 and 2011, aged at least 16 years, with known educational level and at least one CD4 cell count within 6 months of HIV diagnosis. We examined trends by education level in presentation with advanced HIV disease (AHD) (CD4 <200 cells/μl or AIDS within 6 months) using logistic regression, and distribution of CD4 cell count at cART initiation overall and among presenters without AHD using median regression. Among 15 414 individuals, 52, 45,37, and 31% with uncompleted basic, basic, secondary and tertiary education, respectively, presented with AHD (P trend <0.001). Compared to patients with tertiary education, adjusted odds ratios of AHD were 1.72 (95% confidence interval 1.48-2.00) for uncompleted basic, 1.39 (1.24-1.56) for basic and 1.20 (1.08-1.34) for secondary education (P < 0.001). In unadjusted and adjusted analyses, median CD4 cell count at cART initiation was lower with poorer educational level. Socioeconomic inequalities in delayed HIV diagnosis and initiation of cART are present in European countries with universal healthcare systems and individuals with lower educational level do not equally benefit from timely cART initiation.


Bartonella henselae and Bartonella quintana adherence to and entry into cultured human epithelial cells.
Bartonella henselae expresses pili phenotypically similar to type 4 pili. B. henselae pilus expression undergoes phase variation with multiple passages. Low-passage-number, piliated B. henselae adhered to and invaded HEp-2 cells to a greater extent than did multiply passaged B. henselae with reduced pilus expression. Pili may be a pathogenic determinant for Bartonella species.


Clinical outcomes and predictive factors in oral corticosteroid-refractory active ulcerative colitis.
To evaluate the clinical outcomes and prognostic factors after intravenous corticosteroids following oral corticosteroid failure in active ulcerative colitis patients. Consecutive patients with moderate to severe ulcerative colitis who had been treated with a course of intravenous corticosteroids after oral corticosteroid therapy failure between January 1996 and July 2010 were recruited at Severance Hospital, Seoul, South Korea. The disease activity was measured by the Mayo score, which consists of stool frequency, rectal bleeding, mucosal appearance at flexible sigmoidoscopy, and Physician Global Assessment. We retrospectively evaluated clinical outcomes at two weeks, one month, three months, and one year after the initiation of intravenous corticosteroid therapy. Two weeks outcomes were classified as responders or non-responders. One month, three month and one year outcomes were classified into prolonged response, steroid dependency, and refractoriness. Our study included a total of 67 eligible patients. At two weeks, 56 (83.6%) patients responded to intravenous corticosteroids. At one month, complete remission was documented in 18 (32.1%) patients and partial remission in 26 (46.4%). Eleven patients (19.7%) were refractory to the treatment. At three months and one year, we found 37 (67.3%) and 25 (46.3%) patients in prolonged response, ten (18.2%) and 23 (42.6%) patients in corticosteroid dependency, 8 (14.5%) and 6 (11.1%) patients with no response, respectively. Total 9 patients were underwent elective proctocolectomy within 1 year. The duration of oral corticosteroid therapy (> 14 d vs ≤ 14 d, P = 0.049) and lower hemoglobin level (≤ 11.0 mg/dL vs >11.0 mg/dL, P = 0.02) were found to be poor prognostic factors for response at two weeks. For one year outcome, univariate analysis revealed that only a partial Mayo score (≥ 6 vs <6, P = 0.057) was found to be associated with a poor response. The duration of oral corticosteroid therapy and lower hemoglobin level were strongly associated with poor outcome.


Acetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder.
Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication and restrictive behavior, interests, and activities. Our previous case-control study showed that use of acetaminophen at age 12-18 months is associated with increased likelihood for ASD (OR 8.37, 95% CI 2.08-33.7). In this study, we again show that acetaminophen use is associated with ASD (p = 0.013). Because these children are older than in our first study, the association is reversed; fewer children with ASD vs. non-ASD children use acetaminophen as a "first choice" compared to "never use" (OR 0.165, 95% CI 0.045, 0.599). We found significantly more children with ASD vs. non- ASD children change to the use of ibuprofen when acetaminophen is not effective at reducing fever (p = 0.033) and theorize this change in use is due to endocannabinoid system dysfunction. We also found that children with ASD vs. non-ASD children are significantly more likely to show an increase in sociability when they have a fever (p = 0.037) and theorize that this increase is due to anandamide activation of the endocannabinoid system in ASD children with low endocannabinoid tone from early acetaminophen use. In light of this we recommend that acetaminophen use be reviewed for safety in children.


The success of continued steroid avoidance after kidney transplantation in the US.
There has been a significant increase in the use of steroid avoidance regimens as initial treatment for kidney transplant recipients. Early results of the effectiveness of this strategy has been mixed with certain prospective trials indicating increased acute rejection but population-based studies indicating similar or better graft survival as compared to steroid maintenance. We conducted a retrospective study of national registry data to evaluate risk factors for discontinuation of steroid avoidance protocols based on patient characteristics and concomitant immunosuppression. We evaluated 84 647 solitary kidney transplant recipients in the US with at least 6 months graft survival including 24 218 initially discharged without maintenance steroids. We utilized logistic models to assess risk factors for new initiation of steroids after initial steroid-avoidance and survival models to describe graft survival for patients after return to steroids. The most prominent risk factors for new initiation of steroids after deceased donor kidney transplantation included African-American race (AOR = 1.32, p < 0.01), retransplants (AOR = 1.81, p < 0.01), highly sensitized recipients (AOR = 1.29, p < 0.01), recipients with Medicaid (AOR = 1.85, p < 0.01), elevated HLA-MM (AOR = 1.26, p < 0.01) and older donor age (AOR = 1.19, p < 0.01). Concomitant medications were also significantly associated with the propensity to newly initiate steroids. Cumulatively the study suggests that both patient characteristics and concomitant medications are strongly associated with the success of steroid avoidance immunosuppressive regimens.


Bird and bat species' global vulnerability to collision mortality at wind farms revealed through a trait-based assessment.
Mitigation of anthropogenic climate change involves deployments of renewable energy worldwide, including wind farms, which can pose a significant collision risk to volant animals. Most studies into the collision risk between species and wind turbines, however, have taken place in industrialized countries. Potential effects for many locations and species therefore remain unclear. To redress this gap, we conducted a systematic literature review of recorded collisions between birds and bats and wind turbines within developed countries. We related collision rate to species-level traits and turbine characteristics to quantify the potential vulnerability of 9538 bird and 888 bat species globally. Avian collision rate was affected by migratory strategy, dispersal distance and habitat associations, and bat collision rates were influenced by dispersal distance. For birds and bats, larger turbine capacity (megawatts) increased collision rates; however, deploying a smaller number of large turbines with greater energy output reduced total collision risk per unit energy output, although bat mortality increased again with the largest turbines. Areas with high concentrations of vulnerable species were also identified, including migration corridors. Our results can therefore guide wind farm design and location to reduce the risk of large-scale animal mortality. This is the first quantitative global assessment of the relative collision vulnerability of species groups with wind turbines, providing valuable guidance for minimizing potentially serious negative impacts on biodiversity.


Incidence and risk of major heart diseases in middle-aged adults with moderate to severe vision impairment: a population-based cohort study.
To estimate the incidence and risk of major adverse cardiovascular events (MACEs), including heart failure and ischaemic heart disease, among middle-aged people with a visual disability (VD). We used a national health insurance research database to conduct a population-based cohort study from 1 January 2000 to 31 December 2013. Patients with VD aged 35~65 years were recruited. For each VD patient, five age-matched, sex-matched and comorbidity-matched patients were randomly selected and recruited as controls. Control patients had no documented disability. This study recruited 978 patients with VD (mean age±SD, 55.1±7.8 years; 48.9% male) and 4677 controls. Compared with the same sex of the controls, women with VD had higher incidence of MACE 1 (7.9 vs 2.8/1000 person-years, p<0.001), MACE 2 (27.5 vs 16.9/1000 person-years, p<0.001), MACE 3 (3.7 vs 1.4/1000 person-years, p<0.005) and MACE 4 (4.5 vs 2.5/1000 person-years, p<0.05), and men with VD had higher incidence of MACE 1 (4.6 vs 2.0/1000 person-years, p<0.005). Compared with the controls, patients with VD had lower cumulative MACE 1~MACE 4-free probabilities and had an independently higher risk of MACE 1~MACE 4 during the 13-year study, yielding an adjusted hazard ratio range of 1.31~2.75. Those persons with VD who had diabetes and hypertension had greater risks of MACE 1~MACE 4. Middle-aged adults with VD were at risk of MACEs. A programme for MACE prevention is important for middle-aged people with VD. This is especially true for women and for those who also have diabetes and hypertension.


Mineral formation in joints caused by complete or joint-specific loss of ANK function.
To reveal the ANK complete loss of function phenotype in mice, we generated conditional and null alleles. Mice homozygous for the null allele exhibited widespread joint mineralization, similar in severity to animals harboring the original ank allele. A delayed yet similar phenotype was observed in mice with joint-specific loss of ANK function. The ANK pyrophosphate regulator was originally identified and proposed to play a key role in articular cartilage maintenance based on a single spontaneous mouse mutation (ank) that causes severe generalized arthritis. A number of human mutations have subsequently been reported in the human ortholog (ANKH), some of which produce skull and long bone defects with no apparent defects in joints or articular cartilage. None of the currently known mouse or human mutations clearly eliminate the function of the endogenous gene. Two new Ank alleles were generated using homologous recombination in mouse embryonic stem (ES) cells. Joint range of motion assays and muCT studies were used to quantitatively assess phenotypic severity in wildtype, heterozygous, and homozygous mice carrying either the null (Anknull) or original (Ankank) allele. A Gdf5-Cre expressing line was crossed to mice harboring the conditional (Ankfloxp) allele to eliminate ANK function specifically in the joints. Histological stains and beta-galactosidase (LACZ) activity were used to determine the correlation between local loss of ANK function and defective joint phenotypes. Anknull/Anknull mice develop severe ectopic postnatal crystal deposition in almost every joint of the body, leading to eventual joint fusion and loss of mobility. The severity of phenotype in these mice is indistinguishable from that of Ankank/Ankank mice. In addition, despite the widespread expression of Ank in many tissues, the specific deletion of Ank in joints also produces joint mineralization and ankylosis. These studies show that ANK function is required locally in joints to inhibit mineral formation and that the Ank gene plays a key role in postnatal maintenance of joint mobility and function.


[Progressive or delayed early-onset pediatric sensorineural hearing loss].
The introduction of newborn-hearing screening has enabled early childhood hearing loss to be diagnosed and increased the number of children undergoing early care. Bilateral hearing loss is found in 0.08% of newborns and children whose hearing loss progresses or onset is delayed account for 4 to 30% of all pediatric hearing impairment. Children with perinatal risk factors tend to have deteriorated hearing or delayed-onset hearing loss in early childhood, necessitating audiometric follow-up. We also are aware of some children without risk factors who develop hearing impairment during infancy or early childhood. Hearing deterioration may be difficult to diagnose objectively, especially in young children, the presence of risk factors must be determines as soon as possible, especially given the lack of hearing management and close examination of children without apparent risk factors. We retrospectively studied children born from April 1998 to March 2007 and undergoing cochlear implantation as of April 2008. Among cases, we focused on 10 whose hearing impairment advanced during infancy -4 with risk factors known before hearing deterioration progressed, and 6 cases thought not to have any risk factors. We detected enlarged vestibular acquaduct in 3 of these 6 cases, and 3 more of whom had no risk factors -2 passing newborn-hearing screening and 1 in whom such screening detected hemilateral hearing loss. Our results underscore the need for early temporal computed tomography for detecting enlarged vestibular aquaduct. Even children with mild or hemilateral hearing loss should undergo audiometric and developmental testing at least every 6 months up to going to elementary school. Children suspected of impaired hearing should undergo thorough hearing tests regardless of newborn hearing-screening results to catch any problems early. Appropriate regular hearing and language development check-up tests must also be developed.


Introducing video recording in primary care midwifery for research purposes: procedure, dataset, and use.
video recording studies have been found to be complex; however very few studies describe the actual introduction and enrolment of the study, the resulting dataset and its interpretation. In this paper we describe the introduction and the use of video recordings of health care provider (HCP)-client interactions in primary care midwifery for research purposes. We also report on the process of data management, data coding and the resulting data set. we describe our experience in undertaking a study using video recording to assess the interaction of the midwife and her client in the first antenatal consultation, in a real life clinical practice setting in the Netherlands. Midwives from six practices across the Netherlands were recruited to videotape 15-20 intakes. The introduction, complexity of the study and intrusiveness of the study were discussed within the research group. The number of valid recordings and missing recordings was measured; reasons not to participate, non-response analyses, and the inter-rater reliability of the coded videotapes were assessed. Video recordings were supplemented by questionnaires for midwives and clients. The Roter Interaction Analysis System (RIAS) was used for coding as well as an obstetric topics scale. at the introduction of the study, more initial hesitation in co-operation was found among the midwives than among their clients. The intrusive nature of the recording on the interaction was perceived to be minimal. The complex nature of the study affected recruitment and data collection. Combining the dataset with the questionnaires and medical records proved to be a challenge. The final dataset included videotapes of 20 midwives (7-23 recordings per midwife). Of the 460 eligible clients, 324 gave informed consent. The study resulted in a significant dataset of first antenatal consultations involving recording 269 clients and 194 partners. video recording of midwife-client interaction was both feasible and challenging and resulted in a unique dataset of recordings of midwife-client interaction. Video recording studies will benefit from a tight design, and vigilant monitoring during the data collection to ensure effective data collection. We provide suggestions to promote successful introduction of video recording for research purposes.


Flower development as an interplay between dynamical physical fields and genetic networks.
In this paper we propose a model to describe the mechanisms by which undifferentiated cells attain gene configurations underlying cell fate determination during morphogenesis. Despite the complicated mechanisms that surely intervene in this process, it is clear that the fundamental fact is that cells obtain spatial and temporal information that bias their destiny. Our main hypothesis assumes that there is at least one macroscopic field that breaks the symmetry of space at a given time. This field provides the information required for the process of cell differentiation to occur by being dynamically coupled to a signal transduction mechanism that, in turn, acts directly upon the gene regulatory network (GRN) underlying cell-fate decisions within cells. We illustrate and test our proposal with a GRN model grounded on experimental data for cell fate specification during organ formation in early Arabidopsis thaliana flower development. We show that our model is able to recover the multigene configurations characteristic of sepal, petal, stamen and carpel primordial cells arranged in concentric rings, in a similar pattern to that observed during actual floral organ determination. Such pattern is robust to alterations of the model parameters and simulated failures predict altered spatio-temporal patterns that mimic those described for several mutants. Furthermore, simulated alterations in the physical fields predict a pattern equivalent to that found in Lacandonia schismatica, the only flowering species with central stamens surrounded by carpels.


[How effective is the teaching of critical analysis of scientific publications? Review of studies and their methodological quality].
To evaluate studies assessing the effectiveness of teaching critical appraisal of the literature to medical students. French and English articles published between 1980 and 1990 indexed on MEDLINE or FAMLI as well as articles identified from the bibliographies. Studies were evaluated if the subjects were undergraduate or postgraduate medical students and if the teaching intervention was aimed at improving one or more of the following areas: knowledge in clinical epidemiology and biostatistics, reading habits and ability to critically appraise a scientific article. The methodologic quality of the articles was assessed by three evaluators, who used a modified version of Poynard's checklist to assign a score. Articles with a score of 60% or more were considered satisfactory. The reliability of the checklist was evaluated by means of the kappa (kappa) coefficient and a coefficient of intraclass correlation. For the three evaluators the mean kappa coefficient was 0.33 and the coefficient of intraclass correlation 0.70. Five of the 10 studies had an overall score of 60% or higher. The quality of the individual sections of the articles varied: purpose of the study 85%, description of the population 58%, methods 44%, analysis of results 50%, and conclusions 90%. The effectiveness of teaching critical appraisal of the literature remains uncertain. More rigorous methods are needed in research in this area.


Protein surface softness is the origin of enzyme cold-adaptation of trypsin.
Life has effectively colonized most of our planet and extremophilic organisms require specialized enzymes to survive under harsh conditions. Cold-loving organisms (psychrophiles) express heat-labile enzymes that possess a high specific activity and catalytic efficiency at low temperatures. A remarkable universal characteristic of cold-active enzymes is that they show a reduction both in activation enthalpy and entropy, compared to mesophilic orthologs, which makes their reaction rates less sensitive to falling temperature. Despite significant efforts since the early 1970s, the important question of the origin of this effect still largely remains unanswered. Here we use cold- and warm-active trypsins as model systems to investigate the temperature dependence of the reaction rates with extensive molecular dynamics free energy simulations. The calculations quantitatively reproduce the catalytic rates of the two enzymes and further yield high-precision Arrhenius plots, which show the characteristic trends in activation enthalpy and entropy. Detailed structural analysis indicates that the relationship between these parameters and the 3D structure is reflected by significantly different internal protein energy changes during the reaction. The origin of this effect is not localized to the active site, but is found in the outer regions of the protein, where the cold-active enzyme has a higher degree of softness. Several structural mechanisms for softening the protein surface are identified, together with key mutations responsible for this effect. Our simulations further show that single point-mutations can significantly affect the thermodynamic activation parameters, indicating how these can be optimized by evolution.


Hindsight 20/20: The future of laterality research.
The last decade of laterality research has been bolstered by a significant broadening in theoretical framing and investigative approaches. Comparative research contributions continue to strengthen the position that ancient functional and anatomical brain biases are preserved in modern humans. However, how they unfold over developmental time and contribute to cognitive abilities is still unclear. To make further advances, we must position human brains and behaviors within an evolutionary framework. This includes viewing motor-sensory behavior as an integral part of a developing cognitive system.


Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment.
As brain testosterone plays both androgenic and estrogenic actions due to its conversion into estrogen via aromatase naturally, it is unclear that the age-related reduction of testosterone increased risk of Alzheimer's disease (AD) in men is mediated through androgen alone or both androgen and estrogen mechanisms. Our previous studies using a gene-based approach in mouse model to block the conversion of testosterone into estrogen (aromatase gene knock-out, ArKO), found a depletion of estrogen and increase in testosterone endogenously in males. Here, we use crossing the ArKO mice with APP23 transgenic mice, a mouse model of AD, to produce APP23/Ar(+/-) mice to study the estrogen-independent effect of testosterone on AD. We found a significant reduction in brain plaque formation, improved cognitive function and increase NEP activity in male APP23/Ar(+/-) mice compared with age-matched male APP23 controls. In addition, we found, for the first time, a reduction of beta-secretase (BACE1) enzyme activity, mRNA level and protein expression in the male APP23/Ar(+/-) mice, suggesting that endogenous testosterone, independent from estrogen, may protect against AD in males via two major mechanisms, downregulation of BACE1 activities at transcriptional level to reduce beta amyloid production and upregulation of NEP activities to enhance bate amyloid degradation.


Plasmid Complement of Lactococcus lactis NCDO712 Reveals a Novel Pilus Gene Cluster.
Lactococcus lactis MG1363 is an important gram-positive model organism. It is a plasmid-free and phage-cured derivative of strain NCDO712. Plasmid-cured strains facilitate studies on molecular biological aspects, but many properties which make L. lactis an important organism in the dairy industry are plasmid encoded. We sequenced the total DNA of strain NCDO712 and, contrary to earlier reports, revealed that the strain carries 6 rather than 5 plasmids. A new 50-kb plasmid, designated pNZ712, encodes functional nisin immunity (nisCIP) and copper resistance (lcoRSABC). The copper resistance could be used as a marker for the conjugation of pNZ712 to L. lactis MG1614. A genome comparison with the plasmid cured daughter strain MG1363 showed that the number of single nucleotide polymorphisms that accumulated in the laboratory since the strains diverted more than 30 years ago is limited to 11 of which only 5 lead to amino acid changes. The 16-kb plasmid pSH74 was found to contain a novel 8-kb pilus gene cluster spaCB-spaA-srtC1-srtC2, which is predicted to encode a pilin tip protein SpaC, a pilus basal subunit SpaB, and a pilus backbone protein SpaA. The sortases SrtC1/SrtC2 are most likely involved in pilus polymerization while the chromosomally encoded SrtA could act to anchor the pilus to peptidoglycan in the cell wall. Overexpression of the pilus gene cluster from a multi-copy plasmid in L. lactis MG1363 resulted in cell chaining, aggregation, rapid sedimentation and increased conjugation efficiency of the cells. Electron microscopy showed that the over-expression of the pilus gene cluster leads to appendices on the cell surfaces. A deletion of the gene encoding the putative basal protein spaB, by truncating spaCB, led to more pilus-like structures on the cell surface, but cell aggregation and cell chaining were no longer observed. This is consistent with the prediction that spaB is involved in the anchoring of the pili to the cell.


Biodistribution Survey of Oxidized Single-Wall Carbon Nanohorns Following Different Administration Routes by Using Label-Free Multispectral Optoacoustic Tomography.
Though widely studied for biomedical applications, the lack of current systemic studies on the in vivo fate of single-walled carbon nanohorns (SWCNHs) largely restricts their further applications, as real-time monitoring of their biodistribution remains a big challenge. Here, we aim to customize a label-free multispectral optoacoustic tomography (MSOT) method and systematically survey the fate of oxidized SWCNHs (SWCNHox) following different exposure routes by whole body imaging. Mice were given a suspension of SWCNHox with an average size of 136.4 nm via four different administration routes, and then imaged by MSOT. After oral gavage, SWCNHox were mainly distributed in the gastrointestinal tract then excreted through the gut. Compared with the observation post first dosing, the accumulation of SWCNHox in the gastrointestinal tract was not obvious even after four-time oral gavage. Almost no SWCNHox were found at detectable levels in kidney, liver, blood and spleen. Following intravenous (iv) injection, SWCNHox were mainly presented and persisted in the spleen and liver, while very little in the kidney and almost none detectable in the intestine. SWCNHox accumulated significantly in the liver and spleen after four IV administrations. Following hypodermic and intramuscular injections, almost no SWCNHox could cross biological barriers and transport to the spleen, kidney or liver, likely due to their very low absorption rate. Almost all SWCNHox remained around the injection sites. For the first time, we have systematically investigated the in vivo fate of SWCNHs in a label-free and real-time manner. The findings of this study provide insights into the selection of appropriate exposure routes for potential biomedical applications of carbon nanomaterials.


Gaze behavior among experts and trainees during optic disc examination: does how we look affect what we see?
The authors compared the visual gaze behaviors of glaucoma subspecialists with those of ophthalmology trainees during optic disc and retinal nerve fiber layer (RNFL) examination. Seven glaucoma subspecialists and 23 ophthalmology trainees participated in the project. Participants were shown eight glaucomatous optic disc images with varied morphology. Eye movements during examination of the optic disc photographs were tracked. For each disc image, graders were asked to assign a presumptive diagnosis for probability of glaucoma. There was no time restriction. Overall, trainees spent more time looking at disc images than glaucoma subspecialists (21.3 [13.9-37.7] vs. 16.6 [12.7-19.7]) seconds; median [interquartile range (IQR)], respectively; P < 0.01) and had no systematic patterns of gaze behavior, and gaze behavior was unaltered by disc morphology or topographic cues of pathology. Experienced viewers demonstrated more systematic and ordered gaze behavior patterns and spent longer times observing areas with the greatest likelihood of pathology (superior and inferior poles of the optic nerve head and adjacent RNFL) compared with the trainees. For discs with focal pathology, the proportion of total time spent examining definite areas of pathology was 28.9% (22.4%-33.6%) for glaucoma subspecialists and 13.5% (12.2%-19.2%) for trainees (median [IQR]; P < 0.05). Furthermore, experts adapted their viewing habits according to disc morphology. Glaucoma subspecialists adopt systematic gaze behavior when examining the optic nerve and RNFL, whereas trainees do not. It remains to be elucidated whether incorporating systematic viewing behavior of the optic disc and RNFL into teaching programs for trainees may expedite their acquisition of accurate and efficient glaucoma diagnosis skills.


Effects of 6 Weeks Resistance Training Combined With Plyometric and Speed Exercises on Physical Performance of Pre-Peak-Height-Velocity Soccer Players.
To analyze the effects of low-load, high-velocity resistance training (RT) combined with plyometrics on physical performance in pre-peak-height-velocity (PHV) soccer players. Thirty young soccer players from the same academy were randomly assigned to either a strength training (STG, n = 15) or a control group (CG, n = 15). Strength training consisted of full squat exercise with low load (45-58% 1RM) and low volume (4-8 repetitions/set) combined with jumps and sprints twice a week over 6 wk of preseason. The effect of the training protocol was assessed using sprint performance over 10 and 20 m, countermovement jump, estimated 1-repetition maximum, and average velocity attained against all loads common to pre- and posttests in full squat. STG showed significant improvements (P = .004-.001) and moderate to very large standardized effects (ES = 0.71-2.10) in all variables measured, whereas no significant gains were found in CG (ES = -0.29 to 0.06). Moreover, significant test × group interactions (P < .003-.001) and greater between-groups ESs (0.90-1.97) were found for all variables in favor of STG compared with CG. Only 6 wk of preseason low-volume and low-load RT combined with plyometrics can lead to relevant improvements in strength, jump, and sprint performance. Thus, the combination of field soccer training and lightweight strength training could be used for a greater development of the tasks critical to soccer performance in pre-PHV soccer players.


Using an Artificial Intelligence-Based Argument Theory to Generate Automated Patient Education Dialogues for Families of Children with Juvenile Idiopathic Arthritis.
Juvenile Idiopathic Arthritis (JIA) is the most common chronic rheumatic disease of childhood, with outcomes including pain, prolonged dependence on medications, and disability. Parents of children with JIA report being overwhelmed by the volume of information in the patient education materials that are available to them. This paper addresses this educational gap by applying an artificial intelligence method, based on an extended model of argument, to design and implement a dialogue system that allows users get the educational material they need, when they need it. In the developed system, the studied model of argument was leveraged as part of the system's dialogue manager. A qualitative evaluation of the system, using cognitive walkthroughs and semi-structured interviews with JIA domain experts, suggests that these methods show great promise for providing quality information to families of children with JIA when they need it.


Bothriocephalidean tapeworms (Cestoda) from the blackfish, Centrolophus niger (Perciformes: Centrolophidae).
Bothriocephalidean tapeworms parasitic in the blackfish, Centrolophus niger (Gmelin) (Perciformes: Centrolophidae), are redescribed on the basis of the evaluation of freshly collected specimens and museum material. This evaluation enabled us to supplement species diagnoses by new morphological characters of potential use for phylogenetic analyses, including the data from scanning electron microscopical observations, and to provide a key to identification of the following four species occurring in this fish: Amphicotyle heteropleura (Diesing, 1850); Milanella familiaris Kuchta et Scholz, 2008 (both Triaenophoridae); Bothriocotyle solinosomum Ariola, 1900; and Echinophallus wageneri (Monticelli, 1890) (both Echinophallidae). Large spiniform microtriches were observed on the surface of the posterodorsal margin of segments of B. solinosomum, E. wageneri and M. familiaris. The invalidity of Atelemerus Guiart, 1935, first proposed by Bray et al. (1994), is supported by the present data and its type species, A. acanthodes Guiart, 1935, is newly synonymised with E. wageneri.


Singlet oxygen luminescence detection with a fiber-coupled superconducting nanowire single-photon detector.
Direct monitoring of singlet oxygen (¹O₂) luminescence is a particularly challenging infrared photodetection problem. ¹O₂, an excited state of the oxygen molecule, is a crucial intermediate in many biological processes. We employ a low noise superconducting nanowire single-photon detector to record ¹O₂ luminescence at 1270 nm wavelength from a model photosensitizer (Rose Bengal) in solution. Narrow band spectral filtering and chemical quenching is used to verify the ¹O₂ signal, and lifetime evolution with the addition of protein is studied. Furthermore, we demonstrate the detection of ¹O₂ luminescence through a single optical fiber, a marked advance for dose monitoring in clinical treatments such as photodynamic therapy.


Time trends in the care-based incidence of schizophrenia.
Several studies have suggested a declining first-admission rate for schizophrenia. This study examines the care-based incidence of schizophrenia in a Dutch register area. Data from Groningen psychiatric case register were used to compare first-admission rates for schizophrenia over 1976-90 with those of other functional psychoses, and to consider various potential biases. Diagnostic habits probably affected time trends in incidence rates. Using a broader definition of schizophrenia, no evidence was found for a decrease in the incidence of schizophrenia. Although first admissions to intramural services showed a (non-significant) decrease, this effect seemed to be neutralised when all mental health services were taken into account. Care-based studies of time trends in psychiatric disorders should embrace all mental health services. Furthermore, unless a diagnostic classification system with univocal criteria is used, bias caused by changing diagnostic habits cannot be ruled out.


Using cohort studies to investigate rural and remote mental health.
This paper, presented at the 2010 rural health researchers' National Scientific Symposium on Rural and Remote Health, provides an overview of large Australian population mental health cohort studies which have a focus on climate-related and environmental adversity, social factors and mental health. These studies highlight the value of exploiting multiple exceptional datasets to better understand the drivers of rural health, including how to use population-level research to improve health resources in non-metropolitan areas. We show how the key characteristics of rural and remote mental health might be explored by exploiting the following cohort studies: Household, Income and Labour Dynamics in Australia Survey; Australian Rural Mental Health Study; Hunter Community Study; and Extending Treatments, Education and Networks in Depression study. Existing cohort studies that focus on significant rural and regional characteristics can be creatively analysed to better understand geographic variation in mental health. They have the potential to move understanding beyond simple prevalence to building knowledge about the trajectories of psychological distress and determinants of mental disorders and outcomes over time.


Bringing information technology into the veterinary curriculum.
The personal computer has been available to medical education for many years, but the role of the computer has changed. We have required students to purchase a personal computer since 1984, and used this tool in several ways throughout the intervening years. Our experience has shown that students and faculty derive greatest benefit from personal computers as information retrieval and communication devices. Requiring students to purchase computers has many benefits including student attitudes, employer's perception of computer literacy, and institutional access to current technological advancements in hardware and software.


Cognitive outcomes of TMS treatment in bipolar depression: Safety data from a randomized controlled trial.
Bipolar depression (BD) is a highly prevalent condition associated with marked cognitive deficits that persist even in the euthymic phase of the illness. Pharmacological treatments for BD might further aggravate cognitive impairment, highlighting the need of developing interventions that present cognitive safety. In this study, we evaluated the cognitive effects of H1-coil (deep) transcranial magnetic stimulation (TMS) in patients with treatment-resistant bipolar depression. Fourty-three patients were randomized to receive 20 sessions of active (55 trains, 18 Hz, 120% resting motor threshold intensity) or sham rTMS within a double-blind, sham-controlled trial. A battery of 20 neuropsychological assessments, grouped in 6 domains (attention and processing speed, working memory and executive function, inhibitory control, language, immediate verbal memory, and long-term verbal memory) was performed at baseline and after 4 and 8 weeks of trial onset. Depressive symptoms were assessed with the 17-item Hamilton Rating Scale for Depression. Cognitive improvement was shown for all cognitive domains. It occurred regardless of intervention group and depression improvement. For the language domain, greater improvement was observed in the sham group over time. No correlations between depression (at baseline or during treatment) and cognitive improvement were found. Absence of healthy control group. The results of this exploratory study provide evidence on the cognitive safety of H1-coil TMS for BD patients. Putative pro-cognitive effects of rTMS in BD were not observed and thus should be further investigated.


An overview of proximate factors affecting the nesting behavior of solitary wasps and bees (Hymenoptera: Aculeata) in preexisting cavities in wood.
Guilds of Aculeate solitary wasps and bees that nest in preexisting cavities in wood are important components of terrestrial ecosystems because they engage in several ecological interactions (e.g. predation and pollination) with other species of plants and animals. Spatial and temporal variations in richness and abundance of solitary wasps and bees can be related to changes in environmental structure and in the diversity of other groups of organisms. The nesting period of these Aculeata is their most critical life cycle stage. Females of solitary wasp and bee species invest relatively more time constructing and provisioning their nests than do females of social species. Differently from species that nest in the soil or construct exposed nests, the main factors affecting the reproductive success of solitary species nesting in preexisting wood holes are still unknown. Our objective is to provide an overview of the role of proximate causes of nesting failure or success among solitary wasps and bees (Aculeata), for designing effective conservation and management strategies for these Hymenoptera.


Modeling enzymatic reactions involving transition metals.
High-accuracy quantum chemistry has now been applied for almost 10 years to biological problems involving transition metal active sites. The leading theoretical method is hybrid density functional theory (DFT), usually with the B3LYP functional. The chemical models vary in size, commonly from 30 to 100 atoms treated fully quantum mechanically. Two schools exist, one using the smallest possible adequate models and the other using as large models as possible and sometimes including the entire enzyme by combining quantum mechanics with molecular mechanics. In our group, we have found that the latter approach, which is much more time-consuming and error prone, is seldom needed. In this Account, methods and models will be described and examples of recent applications given. The examples are chosen to illustrate trends and to show cases where theory has predicted new mechanisms not suggested previously.


Trajectories of quality of life and their association with anxiety in people with dementia in nursing homes: A 12-month follow-up study.
This study aimed to identify possible groups of people with dementia (PWD) in nursing homes with different trajectories of proxy-rated quality of life (QoL), and to explore how anxiety (along with other characteristics) was associated with these trajectories of QoL of PWD in nursing homes at a 12-month follow-up. We included 298 PWD aged 65 years and older from 17 Norwegian nursing homes. The Norwegian version of the Rating Anxiety in Dementia scale (RAID-N) was used to assess anxiety, defined as RAID-N score ≥12; proxy-rated QoL was assessed by Quality of Life in Late-Stage Dementia (QUALID). The assessments were made at baseline and after a mean follow-up period of 350 days (SD 12.3). A growth mixture model identified two distinct trajectories of QUALID scores. Association between the QUALID score trajectories and demographic and clinical characteristics were analyzed with logistic regression models. Trajectory group 1 (206 participants) had a lower proportion of participants with anxiety, and a more stable and better QoL, compared to trajectory group 2 (92 participants) at a 12-month follow-up. In a multivariate logistic regression analysis, more severe impairment in activities of daily living, along with presence of anxiety, depression, agitation, and use of antipsychotics at baseline, were associated with belonging to the trajectory group with proxy-rated poor QoL. This study reveals that anxiety is associated with proxy-rated poor QoL of PWD at a 12-month follow-up. Efforts should be made to identify anxiety among nursing home residents with dementia to initiate treatment.


Interaction between fibronectin and β1 integrin is essential for tooth development.
The dental epithelium and extracellular matrix interact to ensure that cell growth and differentiation lead to the formation of teeth of appropriate size and quality. To determine the role of fibronectin in differentiation of the dental epithelium and tooth formation, we analyzed its expression in developing incisors. Fibronectin mRNA was expressed during the presecretory stage in developing dental epithelium, decreased in the secretory and early maturation stages, and then reappeared during the late maturation stage. The binding of dental epithelial cells derived from postnatal day-1 molars to a fibronectin-coated dish was inhibited by the RGD but not RAD peptide, and by a β1 integrin-neutralizing antibody, suggesting that fibronectin-β1 integrin interactions contribute to dental epithelial-cell binding. Because fibronectin and β1 integrin are highly expressed in the dental mesenchyme, it is difficult to determine precisely how their interactions influence dental epithelial differentiation in vivo. Therefore, we analyzed β1 integrin conditional knockout mice (Intβ1lox-/lox-/K14-Cre) and found that they exhibited partial enamel hypoplasia, and delayed eruption of molars and differentiation of ameloblasts, but not of odontoblasts. Furthermore, a cyst-like structure was observed during late ameloblast maturation. Dental epithelial cells from knockout mice did not bind to fibronectin, and induction of ameloblastin expression in these cells by neurotrophic factor-4 was inhibited by treatment with RGD peptide or a fibronectin siRNA, suggesting that the epithelial interaction between fibronectin and β1 integrin is important for ameloblast differentiation and enamel formation.


Prediction of brain age and cognitive age: Quantifying brain and cognitive maintenance in aging.
The concept of brain maintenance refers to the preservation of brain integrity in older age, while cognitive reserve refers to the capacity to maintain cognition in the presence of neurodegeneration or aging-related brain changes. While both mechanisms are thought to contribute to individual differences in cognitive function among older adults, there is currently no "gold standard" for measuring these constructs. Using machine-learning methods, we estimated brain and cognitive age based on deviations from normative aging patterns in the Whitehall II MRI substudy cohort (N = 537, age range = 60.34-82.76), and tested the degree of correspondence between these constructs, as well as their associations with premorbid IQ, education, and lifestyle trajectories. In line with established literature highlighting IQ as a proxy for cognitive reserve, higher premorbid IQ was linked to lower cognitive age independent of brain age. No strong evidence was found for associations between brain or cognitive age and lifestyle trajectories from midlife to late life based on latent class growth analyses. However, post hoc analyses revealed a relationship between cumulative lifestyle measures and brain age independent of cognitive age. In conclusion, we present a novel approach to characterizing brain and cognitive maintenance in aging, which may be useful for future studies seeking to identify factors that contribute to brain preservation and cognitive reserve mechanisms in older age.


Effects of age and unaccustomed resistance exercise on mitochondrial transcript and protein abundance in skeletal muscle of men.
Mitochondrial dysfunction may contribute to age-associated muscle atrophy. Previous data has shown that resistance exercise (RE) increases mitochondrial gene expression and enzyme activity in older adults; however, the acute response to RE has not been well characterized. To characterize the acute mitochondrial response to unaccustomed RE, healthy young (21 ± 3 yr) and older (70 ± 4 yr) men performed a unilateral RE bout for the knee extensors. Muscle biopsies were taken at rest and 3, 24, and 48 h following leg press and knee extension exercise. The expression of the mitochondrial transcriptional regulator proliferator-activated receptor γ coactivator 1-α (PGC-1α) mRNA was increased at 3 h postexercise; however, all other mitochondrial variables decreased over the postexercise period, irrespective of age. ND1, ND4, and citrate synthase (CS) mRNA were all lower at 48 h postexercise, along with specific protein subunits of complex II, III, IV, and ATP synthase. Mitochondrial DNA (mtDNA) copy number decreased by 48 h postexercise, and mtDNA deletions were higher in the older adults and remained unaffected by acute exercise. Elevated mitophagy could not explain the reduction in mitochondrial proteins and DNA, because there was no increase in ubiquitinated voltage-dependent anion channel (VDAC) or its association with PTEN-induced putative kinase 1 (Pink1) or Parkin, and elevated p62 content indicated an impairment or reduction in autophagocytic flux. In conclusion, age did not influence the response of specific mitochondrial transcripts, proteins, and DNA to a bout of RE.


Patients with exon 19 deletion were associated with longer progression-free survival compared to those with L858R mutation after first-line EGFR-TKIs for advanced non-small cell lung cancer: a meta-analysis.
It has been extensively proved that the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is superior to that of cytotoxic chemotherapy in advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, the question of whether the efficacy of EGFR-TKIs differs between exon 19 deletion and exon 21 L858R mutation has not been yet statistically answered. Subgroup data on hazard ratio (HR) for progression-free survival (PFS) of correlative studies were extracted and synthesized based on random-effect model. Comparison of outcomes between specific mutations was estimated through indirect and direct methods, respectively. A total of 13 studies of advanced NSCLC patients with either 19 or 21 exon alteration receiving first-line EGFR-TKIs were included. Based on the data from six clinical trials for indirect meta-analysis, the pooled HRTKI/chemotherapy for PFS were 0.28 (95% CI 0.20-0.38, P<0.001) in patients with 19 exon deletion and 0.47 (95% CI 0.35-0.64, P<0.001) in those with exon 21 L858R mutation. Indirect comparison revealed that the patients with exon 19 deletion had longer PFS than those with exon 21 L858R mutation (HR19 exon deletion/exon 21 L858R mutation = 0.59, 95% CI 0.38-0.92; P = 0.019). Additionally, direct meta-analysis showed similar result (HR19 exon deletion/exon 21 L858R mutation = 0.75, 95% CI 0.65 to 0.85; P<0.001) by incorporating another seven studies. For advanced NSCLC patients, exon 19 deletion might be associated with longer PFS compared to L858 mutation at exon 21 after first-line EGFR-TKIs.