Cusp patterning defect in Tabby mouse teeth and its partial rescue by FGF.
Tabby is a mouse mutant characterized by deficient development of the ectodermal organs: teeth, hair, and a subset of glands. Ectodysplasin, the protein encoded by the Tabby gene, was recently identified as a novel TNF-like transmembrane protein but little is known about its function. We have examined the Tabby tooth phenotype in detail by analysis of the adult and embryonic teeth. Tabby first molars had an obvious defect in cusp patterning as the number of cusps was reduced and the buccal and lingual cusps were joined. The disturbance in development was first visible morphologically in the bud stage molar. The primary enamel knot in a cap stage Tabby tooth expressed all enamel knot markers analyzed but was smaller than wild type and the first pair of developing secondary enamel knots was fused. We propose that the Tabby tooth phenotype is due to growth retardation during early stages of development which leads to reduced signaling from the primary enamel knot, followed by deficient growth of the dental epithelium and lack of formation of the last developing secondary enamel knots. The ectodysplasin transcripts were expressed in the outer enamel epithelium and dental lamina. When cultured in vitro Tabby bud/cap stage molars formed fewer cusps than wild-type controls. This phenotype was not rescued by exogenously added EGF despite the previously proposed link between Tabby and EGF. Instead FGF-10 partially restored morphogenesis and stimulated the development of additional tooth cusps in cultured Tabby molars.


Current and emerging strategies for treating hepatic encephalopathy.
Hepatic encephalopathy (HE) is caused by liver impairment and has a multitude of symptoms in affected patients, including change in level of consciousness, intellectual function, and neuromuscular function. Pharmacologic therapy includes use of nonabsorbable disaccharides (lactulose and lactitol), and antibiotics such as neomycin, paromycin, metronidazole, and rifaximin. Probiotics, acarbose, and drugs such as L-carnitine and flumazenil, may also be helpful in treating HE.


Carbon nanotube/graphene nanocomposite as efficient counter electrodes in dye-sensitized solar cells.
We demonstrated the replacement of the Pt catalyst normally used in the counter electrode of a dye-sensitized solar cell (DSSC) by a nanocomposite of dry spun carbon multi-walled nanotube (MWNT) sheets with graphene flakes (Gr-F). The effectiveness of this counter electrode on the reduction of the triiodide in the iodide/triiodide redox (I(-)/I(3)(-)) redox reaction was studied in parallel with the use of the dry spun carbon MWNT sheets alone and graphene flakes used independent of each other. This nanocomposite deposited onto fluorinated tin-oxide-coated glass showed improved catalytic behavior and power conversion efficiency (7.55%) beyond the use of the MWNTs alone (6.62%) or graphene alone (4.65%) for the triiodide reduction reaction in DSSC. We also compare the use of the carbon MWNT/Gr-F composite counter electrode with a DSSC using the standard Pt counter electrode (8.8%). The details of increased performance of graphene/MWNT composite electrodes as studied are discussed in terms of increased catalytic activity permitted by sharp atomic edges that arise from the structure of graphene flakes or the defect sites in the carbon MWNT and increased electrical conductivity between the carbon MWNT bundles by the graphene flakes.


Unveiling the complexity of the maize transcriptome by single-molecule long-read sequencing.
Zea mays is an important genetic model for elucidating transcriptional networks. Uncertainties about the complete structure of mRNA transcripts limit the progress of research in this system. Here, using single-molecule sequencing technology, we produce 111,151 transcripts from 6 tissues capturing ∼70% of the genes annotated in maize RefGen_v3 genome. A large proportion of transcripts (57%) represent novel, sometimes tissue-specific, isoforms of known genes and 3% correspond to novel gene loci. In other cases, the identified transcripts have improved existing gene models. Averaging across all six tissues, 90% of the splice junctions are supported by short reads from matched tissues. In addition, we identified a large number of novel long non-coding RNAs and fusion transcripts and found that DNA methylation plays an important role in generating various isoforms. Our results show that characterization of the maize B73 transcriptome is far from complete, and that maize gene expression is more complex than previously thought.


Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma.
Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results with the rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide (RT-PEPC) regimen in patients with recurrent mantle cell lymphoma (MCL). RT-PEPC included induction (Months 1-3) of rituximab 4 times weekly, daily thalidomide (50 mg), and PEPC followed by maintenance thalidomide (100 mg), oral PEPC titrated to the neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies, including tumor angiogenic phenotyping, plasma vascular endothelial growth factor (VEGF), and circulating endothelial cells. Twenty-five patients were enrolled, and 22 were evaluable. The median age was 68 years (range, 52-81 years), 24 patients (96%) had stage III or IV disease, 18 patients (72%) had an International Prognostic Index (IPI) score of 3 to 5, and 20 patients (80%) had high-risk Mantle Cell International Prognostic Index (MIPI) scores. Patients had received a median of 2 previous therapies (range, 1-7 previous therapies), and 15 patients (60%) had progressed on bortezomib. At a median follow-up of 38 months, the overall response rate was 73% (complete response [CR]/unconfirmed CR rate, 32%; partial response [PR] rate, 41%; n = 22 patients), and the median progression-free survival was 10 months. Four CRs were ongoing (> or =6 months, > or =31 months, > or =48 months, and > or =50 months). Toxicities included grade 1 and 2 fatigue, rash, neuropathy, and cytopenias, including grade 1 and 2 thrombocytopenia (64%) and grade 3 and 4 neutropenia (64%). Two thromboses and 5 episodes of grade 3 or 4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGF A and VEGF receptor 1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF levels and circulating endothelial cells trended down with treatment. RT-PEPC had significant and durable activity in MCL with manageable toxicity and maintained QoL. Novel, low-intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients.


Further analysis of the relationship between the epidemiological and hormonal aspects of 6 human neoplasias with special emphasis on the presentation of the topological features of oncogene activation tumor suppressor gene inactivation of individual neoplasias.
The purpose of this study was to test the validity of the steroid carcinogenesis hypothesis by comparatively investigating the endocrinological and epidemiological aspects of cancers of the breast, uterine cervix, endometrium, stomach, esophagus and ovary. The emphasis of this study was placed on the extraction of the information on the topological feature of oncogene activation-tumor suppressor gene inactivation for each of 6 neoplasias using the data stock of the age-adjusted incidence rates (AAIRs) of 19 neoplasias from 47 population units of the world. Our investigation was started on the basis of the recognition that the world statistics data of cancer risk should include information on the interaction of oncogene activation-tumor suppressor gene inactivation for each human neoplasia, and that the sophisticated application of statistical analysis technics may allow us to assess separately the implications of oncogene activation and tumor suppressor gene inactivation in the genesis of a given neoplasia. In designing mathematical strategies, we had in mind the premise that oncogene activation and tumor suppressor gene inactivation represent 2 distinct entities in the world of chemistry, and that they should have each their own equilibrium models with 2 distinct equilibrium points. The details of the mathematical principles and procedures are presented in the text. The results were as follows: i) There was a good agreement of results between the observed value and the expected value of thermodynamics as regards the location of the equilibrium point in both instances - a finding to support the validity of our mathematical strategies. ii) One of our mathematical strategies (the use of the original coordinates and its variant coordinates in parallel) was found to be useful for assessing separately the implication of oncogene activation (the original coordinates) and that of tumor suppressor gene inactivation (the variant coordinates). iii) The correlation study of the endocrinological data with the epidemiological data in breast cancer strongly suggests the possibility that sex steroid may play a cardinal role in the oncogene activation at the initiation step of breast carcinogenesis. iv) Evidence is available to indicate that glucocorticoid under certain circumstances may play a crucial role in the process of tumor suppressor gene inactivation at the promotion step of breast carcinogenesis. v) The philosophical distinction between the steroid carcinogenesis theory and the random mutation criminal theory of carcinogenesis is discussed in the light of recent information on chemical carcinogenesis.


Priapism.
Priapism is a prolonged, painful, penile erection that fails to subside despite orgasm. An erection lasting longer than 4-6 h is considered to be priapic; nevertheless, pain does not usually ensue until 6-8 h have elapsed. Priapism is considered a failure of the detumescence mechanism, which may be due to excess release of contractile neurotransmitters, obstruction of draining venules, malfunction of the intrinsic detumescence mechanism, or prolonged relaxation of intracavernosal smooth muscle. There are essentially two main types of priapism: high flow (non-ischemic) and low flow (ischemic). Low flow priapism is the more common form, and it is associated with a decrease in venous outflow and vascular stasis that, in turn, cause tissue hypoxia and acidosis. This form of priapism is usually quite painful because of tissue ischemia. Penile blood aspirated from cavernous spaces appears dark in color. Immediate treatment is necessary or penile fibrosis will ensue. High flow priapism is usually due to trauma, although, on rare occasions it has been idiopathic or due to sickle cell disease. The hallmark of this type of priapism is an increase in arterial inflow in the setting of normal venous outflow. Aspirated penile blood is noted to be bright red and has a high pO(2). This form of priapism is not usually painful because it is non-ischemic. Treatment is dependent on the wishes of the patient but is not mandatory. International Journal of Impotence Research (2000) 12, Suppl 4, S133-S139.


Metformin Induces Growth Inhibition and Cell Cycle Arrest by Upregulating MicroRNA34a in Renal Cancer Cells.
BACKGROUND Metformin is a widely used biguanide drug for the treatment of type 2 diabetes. It has been revaluated as a potential anti-cancer drug with promising activity in various tumors. However, the precise mechanisms underlying the suppression of cancer cells by metformin remain not well understood. MATERIAL AND METHODS In this study, human renal cell carcinoma cell line ACHN was used to investigate the anti-proliferation effect of metformin. A cell counting kit-8 assay was used to detect the cell viability. The cell cycle distribution and apoptosis were analyzed by flow cytometry. The expression of cyclin D1 and p27KIP1 was detected by Western blot. The underlying mechanism involving miRNA34a was further investigated by quantitative RT-PCR and transfection with miRNA inhibitor specific for miRNA34a in ACHN, 769-P, and A498 cells. RESULTS Metformin could significantly inhibit the proliferation of ACHN cells in a dose- and time-dependent manner. In addition, the results showed that metformin induced G0/G1 phase arrest and delayed entry into S phase in ACHN cells. It was shown that metformin downregulates the expression of cyclin D1 and increases the p27KIP1 level. Furthermore, metformin increased ACHN cell death. Lastly, miRNA34a was found to be upregulated by metformin in ACHN, 769-P, and A498 cells. Subsequently, it was demonstrated that inhibition of miRNA34a could partially attenuate the suppressive effect of metformin on renal cancer cell proliferation. CONCLUSIONS The study data revealed that metformin induced cell growth inhibition and cell cycle arrest partially by upregulating miRNA34a in renal cancer cells.


Cryptanshinone Inhibits the Glycolysis and Inhibits Cell Migration Through PKM2/β-Catenin Axis in Breast Cancer.
Breast cancer is one of the most prevalent gynecologic malignancies worldwide. Despite the high sensitivity in response to chemotherapy, drug resistance occurred frequently in clinical treatment. Cryptotanshinone (CTS) is a herbal medicine and has been identified as an anti-inflammatory and anti-oxidative drug. In vitro assays, including the cell proliferation assay, colony formation assay, Western blot analysis, transwell migration/invasion assays, and cell scratch assay were used to explore the biological activities and working mechanism of CTS. Breast cancer cells were also transfected with PKM2 expressing vectors to define the molecular mechanisms involved in CTS-mediated anti-tumor activity. We found that CTS shows anti-proliferative effects and decreases the clonogenic ability of breast cancer cells. We also found that CTS inhibited the migration and invasion activity of MCF-7 and MDA-MB-231 cells by different analyzed methods. CTS also downregulated the levels of glycolysis-related proteins, such as PKM2, LDHA, and HK2. In addition, overexpression of PKM2 recovered CTS-mediated suppression of cell proliferation, colony formation, and cell mobility of breast cancer cells. We also found PKM2 was significantly overexpressed in tumor tissues and invasive ductal breast carcinoma compared to normal tissues and patients with high PKM2 expression had worse overall survival and metastasis-free survival outcomes. CTS inhibited the proliferation, migration, and invasion of breast cancer cells. The involved mechanism may refer to the downregulation of the PKM2/β-catenin axis.


Characterisation of the interaction of the C-terminus of the dopamine D2 receptor with neuronal calcium sensor-1.
NCS-1 is a member of the neuronal calcium sensor (NCS) family of EF-hand Ca(2+) binding proteins which has been implicated in several physiological functions including regulation of neurotransmitter release, membrane traffic, voltage gated Ca(2+) channels, neuronal development, synaptic plasticity, and learning. NCS-1 binds to the dopamine D2 receptor, potentially affecting its internalisation and controlling dopamine D2 receptor surface expression. The D2 receptor binds NCS-1 via a short 16-residue cytoplasmic C-terminal tail. We have used NMR and fluorescence spectroscopy to characterise the interactions between the NCS-1/Ca(2+) and D2 peptide. The data show that NCS-1 binds D2 peptide with a K(d) of ∼14.3 µM and stoichiometry of peptide binding to NCS-1 of 2:1. NMR chemical shift mapping confirms that D2 peptide binds to the large, solvent-exposed hydrophobic groove, on one face of the NCS-1 molecule, with residues affected by the presence of the peptide spanning both the N and C-terminal portions of the protein. The NMR and mutagenesis data further show that movement of the C-terminal helix 11 of NCS-1 to fully expose the hydrophobic groove is important for D2 peptide binding. Molecular docking using restraints derived from the NMR chemical shift data, together with the experimentally-derived stoichiometry, produced a model of the complex between NCS-1 and the dopamine receptor, in which two molecules of the receptor are able to simultaneously bind to the NCS-1 monomer.


The efficacy of nystatin combined with topical microbial agents in the treatment of burn wound sepsis.
Pilot in vitro studies demonstrated that nystatin combined with Silvadene (silver sulfadiazine 1% [Marion Laboratories, Inc., Kansas City Mo.]) or Furacin in a 1:1 ratio was equally effective against Candida albicans and ATCC strains of Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, but Sulfamylon (Winthrop Pharmaceuticals, Winthrop, N.Y.) combined with nystatin demonstrated an antagonistic response. Therefore we examined the susceptibility to nystatin of 165 clinical isolates, both gram-positive and gram-negative, to nystatin combined with Silvadene or Sulfamylon and 144 isolates to nystatin and Furacin. Both Silvadene and Furacin combined with nystatin were equally effective against the microorganisms as were the individual drugs. Conversely, Sulfamylon combined with nystatin lost its antimicrobial capability (93.3% resistance, p less than 0.001). On the basis of the in vitro results, 93 patients with acute burns were treated with the appropriate topical antimicrobials from April 1988 to September 1988. Of the 93 patients treated, 90 had neither a major systemic bacterial nor a Candida sepsis, and none of these patients had associated localized burn wound sepsis during their hospital stays. These 90 patients were discharged without any documented signs of infection. The average burnsize was greater than or equal to 29.44% total body surface area. These data suggest that the antimicrobial properties of nystatin, when combined with Silvadene and Furacin, remain effective. Consequently, such combinations have been effective in controlling both local and systemic Candida and bacterial burn wound sepsis.


Proximal humeral fracture as a risk factor for subsequent hip fractures.
With the aging of the world's population, the social and economic implications of osteoporotic fractures are at epidemic proportions. This study was performed to test the hypothesis that a proximal humeral fracture is an independent risk factor for a subsequent hip fracture and that the risk of the subsequent hip fracture is highest within the first five years after the humeral fracture. A cohort of 8049 older white women with no history of a hip or humeral fracture who were enrolled in the Study of Osteoporotic Fractures was followed for a mean of 9.8 years. The risk of hip fracture after an incident humeral fracture was estimated with use of age-adjusted Cox proportional hazards regression analysis with time-varying variables; women without a humeral fracture were the reference group. Cox regression analysis was used to evaluate the timing between the proximal humeral and subsequent hip fracture. Risk factors were determined on the basis of a review of the current literature, and we chose the variables that were most predictive and easily ascertained in a clinical setting. Three hundred and twenty-one women sustained a proximal humeral fracture, and forty-four of them sustained a subsequent hip fracture. After adjustment for age and bone mineral density, the hazard ratio for hip fracture for subjects with a proximal humeral fracture relative to those without a proximal humeral fracture was 1.83 (95% confidence interval = 1.32 to 2.53). After multivariate adjustment, this risk appeared attenuated but was still significant (hazard ratio = 1.57; 95% confidence interval = 1.12 to 2.19). The risk of a subsequent hip fracture after a proximal humeral fracture was highest within one year after the proximal humeral fracture, with a hazard ratio of 5.68 (95% confidence interval = 3.70 to 8.73). This association between humeral and hip fracture was not significant after the first year, with hazard ratios of 0.87 (95% confidence interval = 0.48 to 1.59) between one and five years after the humeral fracture and 0.58 (95% confidence interval = 0.22 to 1.56) after five years. In this cohort of older white women, a proximal humeral fracture independently increased the risk of a subsequent hip fracture more than five times in the first year after the humeral fracture but was not associated with a significant increase in the hip fracture risk in subsequent years.


Low dose rate prostate brachytherapy.
Low dose rate (LDR) prostate brachytherapy is an evidence based radiation technique with excellent oncologic outcomes. By utilizing direct image guidance for radioactive source placement, LDR brachytherapy provides superior radiation dose escalation and conformality compared to external beam radiation therapy (EBRT). With this level of precision, late grade 3 or 4 genitourinary or gastrointestinal toxicity rates are typically between 1% and 4%. Furthermore, when performed as a same day surgical procedure, this technique provides a cost effective and convenient strategy. A large body of literature with robust follow-up has led multiple expert consensus groups to endorse the use of LDR brachytherapy as an appropriate management option for all risk groups of non-metastatic prostate cancer. LDR brachytherapy is often effective when delivered as a monotherapy, although for some patients with intermediate or high-risk disease, optimal outcome are achieved in combination with supplemental EBRT and/or androgen deprivation therapy (ADT). In addition to reviewing technical aspects and reported clinical outcomes of LDR prostate brachytherapy, this article will focus on the considerations related to appropriate patient selection and other aspects of its use in the treatment of prostate cancer.


Scattering and cloaking of binary hyper-particles in metamaterials.
We derive the d-dimensional scattering cross section for homogeneous and composite hyper-particles inside a metamaterial. The polarizability of the hyper-particles is expressed in multi-dimensional form and is used in order to examine various scattering characteristics. We introduce scattering bounds that display interesting results when d --> ∞ and in particular consider the special limit of hyper-particle cloaking in some detail. We demonstrate cloaking via resonance for homogeneous particles and show that composite hyper-particles can be used in order to obtain electromagnetic cloaking with either negative or all positive constitutive parameters respectively. Our approach not only considers cloaking of particles of integer dimension but also particles with non-integer dimension such as fractals. Theoretical results are compared to full-wave numerical simulations for two interacting hyper-particles in a medium.


Five-year histological and serological follow-up of operationally tolerant pediatric liver transplant recipients enrolled in WISP-R.
Pediatric liver transplant recipients arguably have the most to gain and the most to lose from discontinuing immunosuppression (IS). Whereas IS undoubtedly exerts a cumulative toll, there is concern that insufficient or no IS may contribute to allograft deterioration. Twelve pediatric recipients of parental living donor liver grafts, identified as operationally tolerant through complete IS withdrawal (WISP-R; NCT00320606), were followed for a total of 5 years (1 year of IS withdrawal and 4 years off IS) with serial liver tests and autoantibody and alloantibody assessments. Liver biopsies were performed 2 and 4 years off IS, and, at these time points, immunoglobulin G (IgG) subclass and C1q binding activity for donor-specific antibodies (DSAs) were determined. There were no cases of chronic rejection, graft loss, or death. Allografts did not exhibit progressive increase in inflammation or fibrosis. Smooth-muscle actin expression by stellate cells and CD34 expression by liver sinusoidal endothelial cells remained stable, consistent with the absence of progressive graft injury. Three subjects never exhibited DSA. However, 3 subjects showed intermittent de novo class I DSA, 4 subjects showed persistent de novo class II DSA, and 5 subjects showed persistent preexisting class II DSA. Class II DSA was predominantly against donor DQ antigens, often of high mean fluorescence intensity, rarely of the IgG3 subclass, and often capable of binding C1q. Operationally tolerant pediatric liver transplant recipients maintain generally stable allograft histology in spite of apparently active humoral allo-immune responses. The absence of increased inflammation or progressive fibrosis suggests that a subset of liver allografts seem resistant to the chronic injury that is characteristic of antibody-mediated damage. (Hepatology 2017;65:647-660).


Factors associated with uptake of vaccination against pandemic influenza: a systematic review.
In June 2009 a global influenza pandemic was declared by the World Health Organisation. A vaccination programme against H1N1 influenza was introduced in many countries from September 2009, but there was low uptake in both the general population and health professionals in many, though not all, countries. To examine the psychological and demographic factors associated with uptake of vaccination during the 2009 pandemic. A systematic literature review searching Web of Science and PubMed databases up to 24 January 2011. 37 articles met the study inclusion criteria. Using the framework of Protection Motivation Theory the review found that both the degree of threat experienced in the 2009 pandemic influenza outbreak and perceptions of vaccination as an effective coping strategy were associated with stronger intentions and higher uptake of vaccination. Appraisal of threat resulted from both believing oneself to be at risk from developing H1N1 influenza and concern and worry about the disease. Appraisal of coping resulted from concerns about the safety of the vaccine and its side effects. There was evidence of an influence of social pressure in that people who thought that others wanted them to be vaccinated were more likely to do so and people getting their information about vaccination from official health sources being more likely to be vaccinated than those relying on unofficial sources. There was also a strong influence of past behaviour, with those having been vaccinated in the past against seasonal influenza being more likely to be vaccinated against pandemic influenza. Demographic factors associated with higher intentions and uptake of vaccination were: older age, male gender, being from an ethnic minority and, for health professionals, being a doctor. Interventions designed to increase vaccination rates could be developed and implemented in advance of a pandemic. Strategies to improve uptake of vaccination include interventions which highlight the risk posed by pandemic influenza while simultaneously offering tactics to ameliorate this risk (e.g. vaccination). Perceived concerns about vaccination can be tackled by reducing the omission bias (a perception that harm caused by action is worse than harm caused by inaction). In addition, interventions to increase seasonal influenza vaccination in advance of a future pandemic may be an effective strategy.


Nuclear localization of HBD-1 in human keratinocytes.
Human defensins and cathelicidins are a family of cationic antimicrobial peptides (AMPs), which play multiple roles in both innate and adaptive immune systems. They have direct antimicrobial activity against several microorganisms including burn pathogens. The majority of components of innate and adaptive immunity either express naturally occurring defensins or are otherwise chemoattracted or functionally affected by them. They also enhance adaptive immunity and wound healing and alter antibody production. All mechanisms to explain multiple functions of AMPs are not clearly understood. Prior studies to localize defensins in normal and burned skin using deconvolution fluorescence scanning microscopy indicate localization of defensins in the nucleus, perinuclear regions, and cytoplasm. The objective of this study is to further confirm the identification of HBD-1 in the nucleus by deconvolution microscopic studies involving image reconstruction and wire frame modeling. Our study demonstrated the presence of intranuclear HBD-1 in keratinocytes throughout the stratum spinosum by costaining with the nuclear probe DAPI. In addition, HBD-1 sequence does show some homology with known cationic nuclear localization signal sequences. To our knowledge, this is the first report to localize HBD-1 in the nuclear region, suggesting a role for this peptide in gene expression and providing new data that may help determine mechanisms of defensin functions.


Co-occurrence of Type 1 Diabetes and Celiac Disease Autoimmunity.
Few birth cohorts have prospectively followed development of type 1 diabetes (T1D) and celiac disease (CD) autoimmunities to determine timing, extent of co-occurrence, and associated genetic and demographic factors. In this prospective birth cohort study, 8676 children at high genetic risk of both diseases were enrolled and 5891 analyzed in median follow-up of 66 months. Along with demographic factors and HLA-DR-DQ, genotypes for HLA-DPB1 and 5 non-HLA loci conferring risk of both T1D and CD were analyzed. Development of persistent islet autoantibodies (IAs) and tissue transglutaminase autoantibodies (tTGAs), as well as each clinical disease, was evaluated quarterly from 3 to 48 months of age and semiannually thereafter. IAs alone appeared in 367, tTGAs alone in 808, and both in 90 children. Co-occurrence significantly exceeded the expected rate. IAs usually, but not always, appeared earlier than tTGAs. IAs preceding tTGAs was associated with increasing risk of tTGAs (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.15-1.91). After adjusting for country, sex, family history, and all other genetic loci, significantly greater co-occurrence was observed in children with a T1D family history (HR: 2.80), HLA-DR3/4 (HR: 1.94) and single-nucleotide polymorphism rs3184504 at SH2B3 (HR: 1.53). However, observed co-occurrence was not fully accounted for by all analyzed factors. In early childhood, T1D autoimmunity usually precedes CD autoimmunity. Preceding IAs significantly increases the risk of subsequent tTGAs. Co-occurrence is greater than explained by demographic factors and extensive genetic risk loci, indicating that shared environmental or pathophysiological mechanisms may contribute to the increased risk.


Intestinal transit, deoxycholic acid and the cholesterol saturation of bile--three inter-related factors.
There is considerable evidence that the level of deoxycholic acid in the bile influences biliary cholesterol saturation. Deoxycholic acid is formed in the colon and absorbed slowly. Hence changes in colonic transit rate might influence biliary deoxycholic acid and the cholesterol saturation of bile. When 14 constipated subjects took standardised senna tablets for six weeks in a dose sufficient to lower mean whole gut transit time from 134 to 54 hours, deoxycholic acid as a proportion of biliary bile acids fell from 25.9 +/- 8.6 to 17.2 +/- 8.3% (p less than 0.0001) and deoxycholic acid pool measured by isotope dilution fell from 0.64 +/- 0.34 to 0.45 +/- 0.29 g (p less than 0.0001). In those subjects (n = 8) whose bile was initially supersaturated with cholesterol, the saturation index fell from 1.40 +/- 0.22 to 1.20 +/- 0.19 (p = 0.02). Conversely, when 12 normal volunteers took loperamide capsules sufficient to cause symptomatic constipation and to prolong mean transit-time from 48 to 103 hours, the deoxycholic acid pool increased from 0.40 +/- 0.24 to 0.57 +/- 0.17 g (p = 0.008). The percentage deoxycholic acid did not alter significantly, because the estimated total bile acid pool expanded (from 1.98 +/- 0.61 to 2.81 +/- 0.48 g; p less than 0.001), presumably because of loperamide slowing down small bowel transit. Despite this expansion of the bile acid pool, loperamide increased the cholesterol saturation index from 1.10 +/- 0.31 to 1.20 +/- 0.32 (p = 0.01). Changes in colonic transit rate alter the size of the deoxycholic acid pool and bile cholesterol saturation. These findings suggest that constipation or slow colonic transit might increase the chance of supersaturated bile and hence of gall stones.


Room-temperature distance measurements of immobilized spin-labeled protein by DEER/PELDOR.
Nitroxide spin labels are used for double electron-electron resonance (DEER) measurements of distances between sites in biomolecules. Rotation of gem-dimethyls in commonly used nitroxides causes spin echo dephasing times (Tm) to be too short to perform DEER measurements at temperatures between ∼80 and 295 K, even in immobilized samples. A spirocyclohexyl spin label has been prepared that has longer Tm between 80 and 295 K in immobilized samples than conventional labels. Two of the spirocyclohexyl labels were attached to sites on T4 lysozyme introduced by site-directed spin labeling. Interspin distances up to ∼4 nm were measured by DEER at temperatures up to 160 K in water/glycerol glasses. In a glassy trehalose matrix the Tm for the doubly labeled T4 lysozyme was long enough to measure an interspin distance of 3.2 nm at 295 K, which could not be measured for the same protein labeled with the conventional 1-oxyl-2,2,5,5-tetramethyl-3-pyrroline-3-(methyl)methanethio-sulfonate label.


Teriparatide improves volumetric bone mineral density and fine bone structure in the UIV+1 vertebra, and reduces bone failure type PJK after surgery for adult spinal deformity.
We conducted a prospective comparative study of the effect of teriparatide therapy for preventing vertebral-failure-type PJK after reconstructive surgery for adult spinal deformity. Prophylactic teriparatide improved the volumetric bone mineral density and fine bone structure of the vertebra above the upper-instrumented vertebra and reduced the incidence of vertebral-failure-type PJK. Proximal junctional kyphosis (PJK) is a complication after corrective surgery for spinal deformity. This study sought to determine whether teriparatide (TP) is an effective prophylactic against PJK type 2 (vertebral fracture) in surgically treated patients with adult spinal deformity (ASD). Forty-three patients who started TP therapy immediately after surgery and 33 patients who did not receive TP were enrolled in this prospective case series. These patients were female, over 50, surgically treated for ASD, and followed for at least 2 years. Preoperative and postoperative standing whole-spine X-rays and dual-energy X-ray absorptiometry scans, and multidetector CT images obtained before and 6 months after surgery were used to analyze the bone strength in the vertebra above the upper-instrumented vertebra (UIV+1). Mean age was 67.9 years. After 6 months of treatment, mean hip-bone mineral density (BMD) increased from 0.721 to 0.771 g/cm2 in the TP group and decreased from 0.759 to 0.729 g/cm2 in the control group. This percent BMD change between groups was significant (p < 0.05). The volumetric BMD (326 to 366 mg/cm3) and bone mineral content (BMC) (553 to 622 mg) at UIV+1 were also significantly increased in TP group. The bone volume/tissue volume ratio increased from 46 to 54 % in the TP group, and the trabecular bone thickness and number increased by 14 and 5 %, respectively. At the 2-year follow-up, the PJK type 2 incidence was significantly lower in the TP group (4.6 %) than in the control group (15.2 %; p = .02). Prophylactic TP treatment improved the volumetric BMD and fine bone structure at UIV+1 and reduced the PJK-type 2 incidence.


The blindness, deafness and madness of King George III: psychiatric interactions.
Recent research has thrown considerable doubt on the claim that King George III suffered from variegate porphyria, but indicates that he suffered recurrent attacks of mania as part of his bipolar disorder. George III's last episode of ill health occurred during the final decade of his life (1810-20). This has been diagnosed as chronic mania with an element of dementia. During this period the king was blind and possibly deaf, which may have contributed to his psychiatric condition. His blindness was due to bilateral cataracts; serious consideration was given at the time to surgery, but this was not carried out. The possible contribution of the king's blindness to his illness is discussed with respect to the roles of his medical attendants. It was also claimed that George III showed progressive deafness and this claim has been re-examined. However, the medical reports by the attending physicians and psychiatrists (mad doctors) do not support this claim.


Providing gender-affirming hormone therapy through primary care: service users.
INTRODUCTION Primary health care providers are playing an increasingly important role in providing gender-affirming health care for gender diverse people. This article explores the experiences of a primary care-based pilot clinic providing gender-affirming hormone therapy in Wellington, New Zealand. AIM To evaluate service users' and health professionals' experiences of a pilot clinic at Mauri Ora (Victoria University of Wellington's Student Health and Counselling Service) that provided gender-affirming hormones through primary care. METHODS In-depth interviews were conducted with four (out of six) service users and four health professionals about their perspectives on the clinic. Interviews were transcribed verbatim and analysed using thematic analysis. RESULTS Three themes were identified in service users' interviews, who discussed receiving affirming care due to the clinic's accessibility, relationship-centred care and timeliness. Three themes were identified in the health professionals' interviews, who described how the clinic involves partnership, affirms users' gender and agency, and is adaptable to other primary care settings. Both service users and health professionals discussed concerns about the lack of adequate funding for primary care services and the tensions between addressing mental health needs and accessing timely care. DISCUSSION The experiences of service users and health professionals confirm the value of providing gender-affirming hormone therapy in primary care. Models based in primary care are likely to increase accessibility, depathologise gender diversity and reduce wait times.


A Scalable Approach to Probabilistic Latent Space Inference of Large-Scale Networks.
We propose a scalable approach for making inference about latent spaces of large networks. With a succinct representation of networks as a bag of triangular motifs, a parsimonious statistical model, and an efficient stochastic variational inference algorithm, we are able to analyze real networks with over a million vertices and hundreds of latent roles on a single machine in a matter of hours, a setting that is out of reach for many existing methods. When compared to the state-of-the-art probabilistic approaches, our method is several orders of magnitude faster, with competitive or improved accuracy for latent space recovery and link prediction.


Subtalar joint axis location and rotational equilibrium theory of foot function.
A new theory of foot function based on the spatial location of the subtalar joint axis in relation to the weightbearing structures of the plantar foot is proposed. The theory relies on the concept of subtalar joint rotational equilibrium to explain how externally generated forces, such as ground reaction force, and internally generated forces, such as ligamentous and tendon tensile forces and joint compression forces, affect the mechanical behavior of the foot and lower extremity. The biomechanical effect of variations among individuals in the spatial location of the subtalar joint axis are explored, along with their clinical consequences, to offer an additional theory of foot function, which may improve on existing podiatric biomechanics theory.


Histopathologic and immunohistochemical characterization of Nipah virus infection in the guinea pig.
Mortality rate in humans infected with Nipah virus (NiV) has been reported as high as 92%. Humans infected with NiV show a widespread multisystemic vasculitis with most severe clinical and pathologic manifestations in the brain, lungs, and spleen. The purpose of this study was to study pathologic and immunohistochemical findings in guinea pigs infected with NiV. Of 28 animals inoculated intraperitoneally, only 2 survived the infection, and most died between 4 and 8 days postinoculation (dpi). Viral antigen with minimal pathologic changes was first detected 2 dpi in lymph nodes and spleen. More severe changes were noted in these organs 4-8 dpi, where pathologic damage had a vasocentric distribution and viral antigen was abundant in vascular endothelium, tunica media, adventitia, as well as in macrophages lining sinuses. The urinary bladder, uterus, and ovaries were also affected with necrosis and acute inflammation. In these organs, immunohistochemical positive staining was intense in blood vessels, epithelial cells, and ovarian follicles. Approximately 50% of the animals that died or were euthanized in extremis had evidence of viral antigen and histopathologic changes in brain, especially involving meninges and ependymal cells, with lesser changes in the neural parenchyma. A unifying feature of the damage for all affected tissues was necrosis and inflammation of the vasculature, chiefly in arterioles, capillaries, and venules. Inoculation of guinea pigs intraperitoneally with NiV produces a disease with considerable resemblance to the disease in humans, but with reduced pulmonary involvement and marked infection of urinary bladder and the female reproductive tract.


Feasibility and Acceptability of Using a Mobile Phone App for Characterizing Auditory Verbal Hallucinations in Adolescents With Early-Onset Psychosis: Exploratory Study.
Auditory verbal hallucinations (AVH) are the most frequent symptom in early-onset psychosis (EOP) and a risk factor for increased suicide attempts in adolescents. Increased knowledge of AVH characteristics can lead to better prediction of risk and precision of diagnosis and help identify individuals with AVH who need care. As 98% of Norwegian adolescents aged 12 to 16 years own a mobile phone, the use of mobile phone apps in symptom assessment and patient communication is a promising new tool. However, when introducing new technology to patients, their subjective experiences are crucial in identifying risks, further development, and potential integration into clinical care. The objective was to explore the feasibility and acceptability of a newly developed mobile phone app in adolescents with EOP by examining compliance with the app and user experiences. Indication of validity was explored by examining associations between AVH dimensions, which were correlated and analyzed. Three adolescents with EOP and active AVH were enrolled. Real-time AVH were logged on an iPod touch using the experience sampling method (ESM), for seven or more consecutive days. The app included five dimensions of AVH characteristics and was programmed with five daily notifications. Feasibility and acceptability were examined using the mean response rate of data sampling and by interviewing the participants. Validity was assessed by examining associations between the AVH dimensions using nonparametric correlation analysis and by visual inspection of temporal fluctuations of the AVH dimensions. One participant was excluded from the statistical analyses but completed the interview and was included in the examination of acceptability. The sampling period of the two participants was mean 12 (SD 6) days with overall completed sampling rate of 74% (SD 30%), indicating adequate to high compliance with the procedure. The user experiences from the interviews clustered into four categories: (1) increased awareness, (2) personal privacy, (3) design and procedure, and (4) usefulness and clinical care. One participant experienced more commenting voices during the sampling period, and all three participants had concerns regarding personal privacy when using electronic devices in symptom assessment. The AVH dimensions of content, control, and influence showed moderate to strong significant correlations with all dimensions (P<.001). Days of data sampling showed weak to moderate correlations with localization (P<.001) and influence (P=.03). Visual inspection indicated that the app was able to capture fluctuations within and across days for all AVH dimensions. This study demonstrates the value of including patients' experiences in the development and pilot-testing of new technology. Based on the small sample size, the use of mobile phones with ESM seems feasible for patients with EOP, but the acceptability of using apps should be considered. Further investigation with larger samples is warranted before definitive conclusions are made.


Rapid evolution of binding specificities and expression patterns of inhibitory CD33-related Siglecs in primates.
Siglecs are sialic acid-binding Ig-like lectins that recognize sialoglycans via amino-terminal V-set domains. CD33-related Siglecs (CD33rSiglecs) on innate immune cells recognize endogenous sialoglycans as "self-associated molecular patterns" (SAMPs), dampening immune responses via cytosolic immunoreceptor tyrosine-based inhibition motifs that recruit tyrosine phosphatases. However, sialic acid-expressing pathogens subvert this mechanism through molecular mimicry. Meanwhile, endogenous host SAMPs must continually evolve to evade other pathogens that exploit sialic acids as invasion targets. We hypothesized that these opposing selection forces have accelerated CD33rSiglec evolution. We address this by comparative analysis of major CD33rSiglec (Siglec-3, Siglec-5, and Siglec-9) orthologs in humans, chimpanzees, and baboons. Recombinant soluble molecules displaying ligand-binding domains show marked quantitative and qualitative interspecies differences in interactions with strains of the sialylated pathogen, group B Streptococcus, and with sialoglycans presented as gangliosides or in the form of sialoglycan microarrays, including variations such as N-glycolyl and O-acetyl groups. Primate Siglecs also show quantitative and qualitative intra- and interspecies variations in expression patterns on leukocytes, both in circulation and in tissues. Taken together our data explain why the CD33rSiglec-encoding gene cluster is undergoing rapid evolution via multiple mechanisms, driven by the need to maintain self-recognition by innate immune cells, while escaping 2 distinct mechanisms of pathogen subversion.


Porous calcium phosphate glass microspheres for orthobiologic applications.
Orthobiologics is a rapidly advancing field utilising cell-based therapies and biomaterials to enable the body to repair and regenerate musculoskeletal tissues. This paper reports on a cost-effective flame spheroidisation process for production of novel porous glass microspheres from calcium phosphate-based glasses to encapsulate and deliver stem cells. Careful selection of the glass and pore-forming agent, along with a manufacturing method with the required processing window enabled the production of porous glass microspheres via a single-stage manufacturing process. The morphological and physical characterisation revealed porous microspheres with tailored surface and interconnected porosity (up to 76 ± 5%) with average pore size of 55 ± 8 µm and surface areas ranging from 0.34 to 0.9 m2 g-1. Furthermore, simple alteration of the processing parameters produced microspheres with alternate unique morphologies, such as with solid cores and surface porosity only. The tuneable porosity enabled control over their surface area, degradation profiles and hence ion release rates. Furthermore, cytocompatibility of the microspheres was assessed using human mesenchymal stem cells via direct cell culture experiments and analysis confirmed that they had migrated to within the centre of the microspheres. The novel microspheres developed have huge potential for tissue engineering and regenerative medicine applications. This manuscript highlights a simple cost-effective one-step process for manufacturing porous calcium phosphate-based glass microspheres with varying control over surface pores and fully interconnected porosity via a flame spheroidisation process. Moreover, a simple alteration of the processing parameters can produce microspheres which have a solid core with surface pores only. The tuneable porosity enabled control over their surface area, degradation profiles and hence ion release rates. The paper also shows that stem cells not only attach and proliferate but more importantly migrate to within the core of the porous microspheres, highlighting applications for bone tissue engineering and regenerative medicine.


Exercise and the brain: insight in new therapeutic modalities.
Physical exercise influences the central dopaminergic, noradrenergic and serotonergic systems. A number of studies have examined brain noradrenaline (NA), serotonin (5-hydroxytryptamine, or 5-HT) and dopamine (DA) with exercise. Although there are great discrepansies in experimental protocols, the results indicate that there is evidence in favour of changes in synthesis and metabolism of monoamines during exercise. The last five to ten years the microdialysis technique is used to explore neurotransmitter release during exercise. Microdialysis can collect virtually any substance from the brains of freely moving animals with a limited amount of tissue trauma. It allows the measurement of local neurotransmitter release in combination with on-going behavioral changes such as exercise. Microdialysis probes were implanted in different brain areas to monitor diverse aspects of locomotion (striatum, hippocampus, nucleus accumbens, frontal cortex, spinal cord), food reward (hypothalamus, hippocampus, cerebral cortex), thermoregulation (hypothalamus),... Although the relationship between physical activity and mood has long been recognized, the use of exercise training as a treatment for clinical depression has been the focus of rigourous study only recently. The available evidence provides considerable support for the value of exercise in reducing depressive symptoms both in healthy and clinical populations. Subsequently, many studies have shown that environmental stimulation such as 'enriched environment' and spontaneous activity elicits various plastic responses in the adult brain of rats. Several molecular systems such as neurotrophic factors, could potentially participate in the benefits of exercise on the brain. Several experiments indicate that voluntary wheel running in rats increases both cell proliferation and recruitment of new neurons in several brain areas. Exercise is a powerful tool to stimulate several brain processes, and it is becoming clear that therapeutic effects of exercise are not only good for cardiovascular and other diseases, but that exercise is also good for the brain.


One-Year Outcomes in Caregivers of Critically Ill Patients.
Few resources are available to support caregivers of patients who have survived critical illness; consequently, the caregivers' own health may suffer. We studied caregiver and patient characteristics to determine which characteristics were associated with caregivers' health outcomes during the first year after patient discharge from an intensive care unit (ICU). We prospectively enrolled 280 caregivers of patients who had received 7 or more days of mechanical ventilation in an ICU. Using hospital data and self-administered questionnaires, we collected information on caregiver and patient characteristics, including caregiver depressive symptoms, psychological well-being, health-related quality of life, sense of control over life, and effect of providing care on other activities. Assessments occurred 7 days and 3, 6, and 12 months after ICU discharge. The caregivers' mean age was 53 years, 70% were women, and 61% were caring for a spouse. A large percentage of caregivers (67% initially and 43% at 1 year) reported high levels of depressive symptoms. Depressive symptoms decreased at least partially with time in 84% of the caregivers but did not in 16%. Variables that were significantly associated with worse mental health outcomes in caregivers were younger age, greater effect of patient care on other activities, less social support, less sense of control over life, and less personal growth. No patient variables were consistently associated with caregiver outcomes over time. In this study, most caregivers of critically ill patients reported high levels of depressive symptoms, which commonly persisted up to 1 year and did not decrease in some caregivers. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT00896220.).


Changes in the built environment and changes in the amount of walking over time: longitudinal results from the multi-ethnic study of atherosclerosis.
Lack of longitudinal research hinders causal inference on the association between the built environment and walking. In the present study, we used data from 6,027 adults in the Multi-Ethnic Study of Atherosclerosis who were 45-84 years of age at baseline to investigate the association of neighborhood built environment with trends in the amount of walking between 2000 and 2012. Walking for transportation and walking for leisure were assessed at baseline and at 3 follow-up visits (median follow-up = 9.15 years). Time-varying built environment measures (measures of population density, land use, number of destinations, bus access, and street connectivity) were created using geographic information systems. We used linear mixed models to estimate the associations between baseline levels of and a change in each built environment feature and a change in the frequency of walking. After adjustment for potential confounders, we found that higher baseline levels of population density, area zoned for retail, social destinations, walking destinations, and street connectivity were associated with greater increases in walking for transportation over time. Higher baseline levels of land zoned for residential use and distance to buses were associated with less pronounced increases (or decreases) in walking for transportation over time. Increases in the number of social destinations, the number of walking destinations, and street connectivity over time were associated with greater increases in walking for transportation. Higher baseline levels of both land zoned for retail and walking destinations were associated with greater increases in leisure walking, but no changes in built environment features were associated with leisure walking. The creation of mixed-use, dense developments may encourage adults to incorporate walking for transportation into their everyday lives.


Impact of early methadone initiation in critically injured burn patients: a pilot study.
Numerous studies have identified strategies to reduce mechanical ventilation duration by targeting appropriate sedation levels. However, applicability of these strategies to critically injured patients with burn injury has not been established. At our medical center, methadone is commonly used early in the care of burn patients to treat background pain and limit the development of opioid tolerance. The aim of this study is to evaluate the effect of early methadone initiation in critically injured burn patients requiring mechanical ventilation. This retrospective study compared patients who received early methadone with patients who did not while mechanically ventilated with the primary outcome of ventilator-free days in a 28-day period. Those who received methadone within 4 days of intubation and remained ventilated for 2 days after the first dose were included in the methadone group. Propensity scores were used to match up to three control patients to each methadone patient. Seventy patients (18 methadone and 52 matched control patients) were included in the final evaluation. Patients in the methadone group averaged 16.5 ventilator-free days compared with 11.5 in the control group (P = .03). There was no statistical difference in the duration of intensive care unit or hospital length of stay between groups. Our results suggest that early methadone initiation may have a significant effect on ventilator outcomes in critically injured patients with burn injury. However, further research is warranted.


Cost-effectiveness of adding rituximab to splenectomy and romiplostim for treating steroid-resistant idiopathic thrombocytopenic purpura in adults.
Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease in which the platelet count falls to <100 × 10(9)/L. Corticosteroids are recommended as the first-line treatment, splenectomy is recommended as the second-line treatment, and thrombopoietin receptor agonists (TPO-RAs) and rituximab are recommended as the third-line treatments for ITP in Japanese ITP treatment guidelines. However, in Japan, rituximab is not eligible for reimbursement for the treatment of ITP. The cost-effectiveness of ITP treatment has not been investigated in Japan. Therefore, in this study, the cost-effectiveness of adding rituximab treatment to the existing treatments indicated for ITP in Japan, namely splenectomy and the TPO-RA romiplostim, was investigated based on the scenario that rituximab is eligible for reimbursement in Japan as a treatment for ITP. The efficacy endpoint was set as the number of years with a platelet count ≥30 × 10(9)/L. The analysis was conducted from the healthcare payer's perspective. If the first treatment is ineffective or relapse occurs, then the patient is given the following treatment. The analyzed treatment order consisted of three patterns: splenectomy-romiplostim (sequence 1), splenectomy-romiplostim-rituximab (sequence 2), and splenectomy-rituximab-romiplostim (sequence 3). A Markov model was built for ITP, and the analysis period was set as 2 years. The discount rate was an annual rate of 2%. Sensitivity analyses of the efficacy of splenectomy, romiplostim, and rituximab; treatment cost; and romiplostim dose were performed. The expected costs per patient over a 2-year period for sequences 1, 2, and 3 were USD 40,980, USD 39,822, and USD 33,551, respectively. The expected years with a platelet count ≥30 × 10(9)/L for the three sequences were 1.75, 1.79, and 1.78 years, respectively. The sensitivity analyses illustrated that the results of the base case analysis were robust. Adding rituximab to standard treatment for ITP (sequences 2-3) is less costly and marginally more effective than standard therapy in adults. According to the study results, if rituximab is reimbursed for the treatment of ITP in Japan, medical expenses are expected to decline.


Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP.
Gap junctions, composed of proteins from the connexin family, are the only channels that directly connect the cytoplasm of adjacent cells to allow for the intercellular transfer of small hydrophilic molecules. Gap junctional communication is essential for proper development and health in animals and humans. Whereas the study of biological molecules that pass through gap junctions is extremely important, the identification of endogenous transjunctional metabolites is challenging. To help address this problem, we have developed a layered culture system to identify and quantitate the transfer of endogenous molecules that pass between cells through gap junctions. Using these techniques, we have identified several endogenous molecules that showed differential transfer between channels composed of Cx32 versus Cx43. For example, adenosine passed about 12-fold better through channels formed by Cx32. In contrast, AMP and ADP passed about 8-fold better, and ATP greater than 300-fold better, through channels formed by Cx43. Thus, addition of phosphate to adenosine appears to shift its relative permeability from channels formed by Cx32 to channels formed by Cx43. This suggests functional consequence because the energy status of a cell could be controlled via connexin expression and channel formation.


Interferometric comparison of displacements by electronic speckle pattern interferometry.
Using the image waves from two similar objects as, respectively, object wave and reference wave in an electronic speckle pattern interferometer (ESPI) setup, it is possible to obtain interference patterns that indicate the amount of relative displacement between the two objects. Experimental results demonstrating direct interferometric subtraction and addition of vibration patterns are presented. Possible applications of the technique are also discussed.


The Global Fund Secretariat's suspension of funding to Uganda: how could this have been avoided?
In August 2005, the Global Fund to fight AIDS, Tuberculosis and Malaria (the Global Fund) Secretariat suspended its five grants to Uganda following a PricewaterhouseCoopers audit report that exposed gross mismanagement in the Project Management Unit. How could this have been avoided? How can other countries avoid a similar pitfall? We argue that if a legitimate and fair decision-making process were used, the suspension of funding to Uganda could have been avoided, and that this lesson should be applied to other countries. The "accountability for reasonableness" framework of relevance, publicity, revisions and enforcement would help in implementing legitimate and fair decision-making processes, which would improve effectiveness, accountability and transparency in the implementation of Global Fund programmes, preventing future suspension of funding to any Global Fund projects.


Tumor volume change after chemotheraphy as a predictive factor of disease free survival for osteosarcoma.
Change in tumor volume after chemotherapy appears to have a prognostic significance for the outcome of osteosarcoma. A newly developed volume measurement method based on three-dimensional summation with a proved reproducibility was utilized to measure osteosarcoma tumor volume. This retrospective analysis included 38 patients with biopsy- proven, nonsurface, skeletal high-grade osteosarcoma. The treatment was started by using three cycles of preoperative chemotherapy with cisplastin (100 mg/m2) and adriamycin (30 mg/m2). The tumor volume was measured before and after preoperative chemotherapy using three-dimensional magnetic resonance image measurement. The percentage of tumor necrosis was assessed by pathologic exam. After three cycle of postoperative chemotherapy, the patients were followed up at regular interval. For the 23 good responder patients, the mean survival time was 73.2 months (95% confidence interval 61.9-84.5 months), and for the 15 poor responder patients, the mean survival time was 50.8 months (95% confidence interval 38.6-63.1 months) (p<0.05). For the 14 patients with increased tumor volume after chemotherapy, the mean survival time was 47.5 months (range: 36.3-58.6 months) and for the 24 patients with stable or decreased tumor volume, the mean survival time was 74.3 months (range: 63.79-84.88 months) (p<0.05). Among the various factors, histopathologic response and tumor volume change after chemotherapy predicted disease free survival (p<0.05). Change in the tumor volume that was measured with a reproducible method and the histopathologic response after chemotherapy were the important predictors of disease free survival for osteosarcoma patients.


Detergency and Its Implications for Oil Emulsion Sieving and Separation.
Separating petroleum hydrocarbons from water is an important problem to address in order to mitigate the disastrous effects of hydrocarbons on aquatic ecosystems. A rational approach to address the problem of marine oil-water separation is to disperse the oil with the aid of surfactants in order to minimize the formation of large slicks at the water surface and to maximize the oil-water interfacial area. Here we investigate the fundamental wetting and transport behavior of such surfactant-stabilized droplets and the flow conditions necessary to perform sieving and separation of these stabilized emulsions. We show that, for water-soluble surfactants, such droplets are completely repelled by a range of materials (intrinsically underwater superoleophobic) due to the detergency effect; therefore, there is no need for surface micro-/nanotexturing or chemical treatment to repel the oil and prevent fouling of the filter. We then simulate and experimentally investigate the effect of emulsion flow rate on the transport and impact behavior of such droplets on rigid meshes to identify the minimum pore opening (w) necessary to filter a droplet with a given diameter (d) in order to minimize the pressure drop across the mesh-and therefore maximize the filtering efficiency, which is strongly dependent on w. We define a range of flow conditions and droplet sizes where minimum droplet deformation is to be expected and therefore find that the condition of w ≈ d is sufficient for efficient separation. With this new understanding, we demonstrate the use of a commercially available filter-without any additional surface engineering or functionalization-to separate oil droplets (d < 100 μm) from a surfactant-stabilized emulsion with a flux of ∼11,000 L m-2 h-1 bar-1. We believe these findings can inform the design of future oil separation materials.


mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila.
Dosage compensation is a regulatory process that insures that males and females have equal amounts of X-chromosome gene products. In Drosophila, this is achieved by a 2-fold enhancement of X-linked gene transcription in males, relative to females. The enhancement of transcription is mediated by the activity of a group of regulatory genes characterized by the male-specific lethality of their loss-of-function alleles. The products of these genes form a complex that is preferentially associated with numerous sites on the X chromosome in somatic cells of males but not of females. Binding of the dosage compensation complex is correlated with a significant increase in the presence of a specific histone isoform, histone 4 acetylated at Lys16, on this chromosome. Experimental results and sequence analysis suggest that an additional gene, males-absent on the first (mof), encodes a putative acetyl transferase that plays a direct role in the specific histone acetylation associated with dosage compensation. The predicted amino acid sequence of MOF exhibits a significant level of similarity to several other proteins, including the human HIV-1 Tat interactive protein Tip60, the human monocytic leukemia zinc finger protein MOZ and the yeast silencing proteins SAS3 and SAS2.


Initial application of a geometric QA tool for integrated MV and kV imaging systems on three image guided radiotherapy systems.
Several linacs with integrated kilovoltage (kV) imaging have been developed for delivery of image guided radiation therapy (IGRT). High geometric accuracy and coincidence of kV imaging systems and megavoltage (MV) beam delivery are essential for successful image guidance. A geometric QA tool has been adapted for routine QA for evaluating and characterizing the geometric accuracy of kV and MV cone-beam imaging systems. The purpose of this work is to demonstrate the application of methodology to routine QA across three IGRT-dedicated linac platforms. It has been applied to a Varian Trilogy (Varian Medical Systems, Palo Alto, CA), an Elekta SynergyS (Elekta, Stockholm, Sweden), and a Brainlab Vero (Brainlab AG, Feldkirchen, Germany). Both the Trilogy and SynergyS linacs are equipped with a retractable kV x-ray tube and a flat panel detector. The Vero utilizes a rotating, rigid ring structure integrating a MV x-ray head mounted on orthogonal gimbals, an electronic portal imaging device (EPID), two kV x-ray tubes, and two fixed flat panel detectors. This dual kV imaging system provides orthogonal radiographs, CBCT images, and real-time fluoroscopic monitoring. Two QA phantoms were built to suit different field sizes. Projection images of a QA phantom were acquired using MV and kV imaging systems at a series of gantry angles. Software developed for this study was used to analyze the projection images and calculate nine geometric parameters for each projection. The Trilogy was characterized five times over one year, while the SynergyS was characterized four times and the Vero once. Over 6500 individual projections were acquired and analyzed. Quantitative geometric parameters of both MV and kV imaging systems, as well as the isocenter consistency of the imaging systems, were successfully evaluated. A geometric tool has been successfully implemented for calibration and QA of integrated kV and MV across a variety of radiotherapy platforms. X-ray source angle deviations up to 0.8 degrees, and detector center offsets up to 3 mm, were observed for three linacs, with the exception of the Vero, for which a significant center offset of one kV detector (prior to machine commissioning) was observed. In contrast, the gimbal-based MV source positioning of the Vero demonstrated differences between observed and expected source positions of less than 0.2 mm, both with and without gimbal rotation. This initial application of this geometric QA tool shows promise as a universal, independent tool for quantitative evaluation of geometric accuracies of both MV and integrated kV imaging systems across a range of platforms. It provides nine geometric parameters of any imaging system at every gantry angle as well as the isocenter coincidence of the MV and kV image systems.


Perturbed path integrals in imaginary time: Efficiently modeling nuclear quantum effects in molecules and materials.
Nuclear quantum effects (NQE), which include both zero-point motion and tunneling, exhibit quite an impressive range of influence over the equilibrium and dynamical properties of molecules and materials. In this work, we extend our recently proposed perturbed path-integral (PPI) approach for modeling NQE in molecular systems [I. Poltavsky and A. Tkatchenko, Chem. Sci. 7, 1368 (2016)], which successfully combines the advantages of thermodynamic perturbation theory with path-integral molecular dynamics (PIMD), in a number of important directions. First, we demonstrate the accuracy, performance, and general applicability of the PPI approach to both molecules and extended (condensed-phase) materials. Second, we derive a series of estimators within the PPI approach to enable calculations of structural properties such as radial distribution functions (RDFs) that exhibit rapid convergence with respect to the number of beads in the PIMD simulation. Finally, we introduce an effective nuclear temperature formalism within the framework of the PPI approach and demonstrate that such effective temperatures can be an extremely useful tool in quantitatively estimating the "quantumness" associated with different degrees of freedom in the system as well as providing a reliable quantitative assessment of the convergence of PIMD simulations. Since the PPI approach only requires the use of standard second-order imaginary-time PIMD simulations, these developments enable one to include a treatment of NQE in equilibrium thermodynamic properties (such as energies, heat capacities, and RDFs) with the accuracy of higher-order methods but at a fraction of the computational cost, thereby enabling first-principles modeling that simultaneously accounts for the quantum mechanical nature of both electrons and nuclei in large-scale molecules and materials.


Circulating biomarkers in renal cell carcinoma: the link between microRNAs and extracellular vesicles, where are we now?
Renal cell carcinoma (RCC) is a lethal urological cancer, with incidence and mortality rates increasing by 2-3% per decade. The lack of standard screening tests contributes to the fact that one-third of patients are diagnosed with locally invasive or metastatic disease. Moreover, 20-40% of RCC patients submitted to surgical nephrectomy will develop metastasis. MicroRNAs (miRNAs) are small non-coding RNAs responsible for gene regulation at a post-transcriptional level. It is accepted that they are deregulated in cancer and can influence tumor development. Thus, miRNAs are promising RCC biomarkers, since they can be detected using non-invasive methods. They are highly stable and easier to quantify in circulating biofluids. The elevated miRNA stability in circulating samples may be the consequence of their capacity to circulate inside of extracellular microvesicles (EMVs), for example, the exosomes. The EMVs are bilayered membrane vesicles secreted by all cell types. They can be released in the interstitial space or into circulating biofluids, which allows the travelling, binding and entrance of these vesicles in receptor cells. This type of cell communication can shuttle bioactive molecules between cells, allowing the horizontal transference of genetic material. In this review, we focus on circulating miRNAs (miR-210, miR-1233, miR-221, miR-15a, miR-451, miR-508, miR-378) in the biofluids of RCC patients and attempt to establish the diagnostic and prognostic accuracy, their synergic effects, and the pathways involved in RCC biology.


Family-Rated Pediatric Health Status Is Associated With Unplanned Health Services Use.
Self-rated health is a common self-reported health measure associated with morbidity, mortality, and health care use. The objective was to investigate the association of family-rated health status (FRH) in pediatric care with administrative indicators, patient and respondent features, and unplanned health services use. Data were taken from Child-Hospital Consumer Assessment of Healthcare Providers and Systems surveys collected between 2015 and 2019 in Alberta, Canada and linked with administrative health records. Three analyses were performed: correlation to assess association between administrative indicators of health status and FRH, logistic regression to assess respondent and patient characteristics associated with FRH, and automated logistic regression to assess the association between FRH and unplanned health services use within 90 days of discharge. A total of 6236 linked surveys were analyzed. FRH had small but significant associations with administrative indicators. Models of FRH had better fit with patient and respondent features. Respondent relationship to child, child age, previous hospitalizations, and number of comorbidities were significantly associated with ratings of FRH. Automated models of unplanned services use included FRH as a feature, and poor ratings of health were associated with increased odds of emergency department visits (adjusted odds ratio: 2.15, 95% confidence interval: 1.62-2.85) and readmission (adjusted odds ratio: 2.48, 95% confidence interval: 1.62-2.85). FRH is a simple, single-item global rating of health for pediatric populations that provides accessible and useful information about pediatric health care needs. The results of this article serve as a reminder that family members are valuable sources of information that can improve care and potentially prevent unplanned health services use.


Val66Met BDNF gene polymorphism influences human motor cortex plasticity in acute stroke.
BDNF gene polymorphism impacts human motor cortex function and plasticity. Using transcranial magnetic stimulation (TMS), we investigated whether BDNF polymorphism influences cortical plastic changes in acute stroke. Twenty patients were recruited within 10 days of their first-ever ischemic stroke and genotyped for BDNF polymorphism. Blinded to the latter, we evaluated the excitability of the affected and unaffected hemisphere by measuring resting and active motor threshold and motor-evoked potential amplitude under baseline conditions and after intermittent theta burst stimulation, a protocol of repetitive TMS inducing LTP-like activity. We also computed laterality indexes to assess inter-hemispheric excitability imbalance. Demographics, threshold and amplitude of motor-evoked potentials did not differ between those with (8 patients) and without polymorphism. Excitability of the unaffected hemisphere was significantly higher than the excitability of the affected hemisphere as probed by each measure. This imbalance was exaggerated in those without polymorphism; laterality indexes of rest motor thresholds were 0.016 ± 0.050 and 0.139 ± 0.028 for patients with and without polymorphism [t = 2.270, P = 0.036]. Exaggerated hemispheric imbalance also persisted after intermittent theta burst stimulation, which failed to induce any difference between groups. Our results suggest that inter-hemispheric imbalance with greater excitability over unaffected hemisphere, is several times stronger in stroke patients without, as opposed to with, polymorphism.


Acute isoniazid intoxication: seizures, acidosis and coma.
Isoniazid (INH) is the most widely used of the antituberculosis drugs. An acute overdose is potentially fatal and is characterized by the clinical triad of repetitive seizures unresponsive to the usual anticonvulsants, metabolic acidosis with a high anion gap and coma. The diagnosis of INH overdose should be considered in any patient who presents with an unexplained metabolic acidosis and convulsions. The cornerstone of therapy consists in pyridoxine (vitamin B6) and the dose should be equal to the amount of INH ingested. When conservative therapy fails or in case of renal insufficiency, dialysis must be considered. Severe central nervous toxicity can also be caused by chronic ingestion of higher than therapeutic doses of INH. In those cases pyridoxine-therapy can be useful as well. In the present paper a case of acute overdose of INH is reported, followed by a review of the literature.


ToxGen: an improved reference database for the identification of type B-trichothecene genotypes in Fusarium.
Type B trichothecenes, which pose a serious hazard to consumer health, occur worldwide in grains. These mycotoxins are produced mainly by three different trichothecene genotypes/chemotypes: 3ADON (3-acetyldeoxynivalenol), 15ADON (15-acetyldeoxynivalenol) and NIV (nivalenol), named after these three major mycotoxin compounds. Correct identification of these genotypes is elementary for all studies relating to population surveys, fungal ecology and mycotoxicology. Trichothecene producers exhibit enormous strain-dependent chemical diversity, which may result in variation in levels of the genotype's determining toxin and in the production of low to high amounts of atypical compounds. New high-throughput DNA-sequencing technologies promise to boost the diagnostics of mycotoxin genotypes. However, this requires a reference database containing a satisfactory taxonomic sampling of sequences showing high correlation to actually produced chemotypes. We believe that one of the most pressing current challenges of such a database is the linking of molecular identification with chemical diversity of the strains, as well as other metadata. In this study, we use the Tri12 gene involved in mycotoxin biosynthesis for identification of Tri genotypes through sequence comparison. Tri12 sequences from a range of geographically diverse fungal strains comprising 22 Fusarium species were stored in the ToxGen database, which covers descriptive and up-to-date annotations such as indication on Tri genotype and chemotype of the strains, chemical diversity, information on trichothecene-inducing host, substrate or media, geographical locality, and most recent taxonomic affiliations. The present initiative bridges the gap between the demands of comprehensive studies on trichothecene producers and the existing nucleotide sequence databases, which lack toxicological and other auxiliary data. We invite researchers working in the fields of fungal taxonomy, epidemiology and mycotoxicology to join the freely available annotation effort.


Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC.
The Trk receptors and their neurotrophin ligands control development and maintenance of the nervous system. The crystal structures of the ligand binding domain of TrkA, TrkB, and TrkC were solved and refined to high resolution. The domains adopt an immunoglobulin-like fold, but crystallized in all three instances as dimers with the N-terminal strand of each molecule replaced by the same strand of a symmetry-related mate. Models of the correctly folded domains could be constructed by changing the position of a single residue, and the resulting model of the binding domain of TrkA is essentially identical with the bound structure as observed in a complex with nerve growth factor. An analysis of the existing mutagenesis data for TrkA and TrkC in light of these structures reveals the structural reasons for the specificity among the Trk receptors, and explains the underpinnings of the multi-functional ligands that have been reported. The overall structure of all three domains belongs to the I-set of immunoglobulin-like domains, but shows several unusual features, such as an exposed disulfide bridge linking two neighboring strands in the same beta-sheet. For all three domains, the residues that deviate from the standard fingerprint pattern common to the I-set family fall in the region of the ligand binding site observed in the complex. Therefore, identification of these deviations in the sequences of other immunoglobulin-like domain-containing receptors may help to identify their ligand binding site even in the absence of structural or mutagenesis data.


Targeting S. mutans biofilms: a perspective on preventing dental caries.
The prevalence of biofilm diseases, and dental caries in particular, have encouraged extensive research on S. mutans biofilms, including methods of preventing its formation. Numerous small molecules with specific anti-biofilm activity against this pathogen have been isolated and synthesized. Generally, these molecules can be characterized into three categories: sucrose-dependent anti-adhesion, sucrose-independent anti-adhesion and cellular signaling interference. This review aims to provide an overview of the current small molecule strategies used for targeting S. mutans biofilms, and a perspective of the future for the field.


An Early Years Toolbox for Assessing Early Executive Function, Language, Self-Regulation, and Social Development: Validity, Reliability, and Preliminary Norms.
Several methods of assessing executive function (EF), self-regulation, language development, and social development in young children have been developed over previous decades. Yet new technologies make available methods of assessment not previously considered. In resolving conceptual and pragmatic limitations of existing tools, the Early Years Toolbox (EYT) offers substantial advantages for early assessment of language, EF, self-regulation, and social development. In the current study, results of our large-scale administration of this toolbox to 1,764 preschool and early primary school students indicated very good reliability, convergent validity with existing measures, and developmental sensitivity. Results were also suggestive of better capture of children's emerging abilities relative to comparison measures. Preliminary norms are presented, showing a clear developmental trajectory across half-year age groups. The accessibility of the EYT, as well as its advantages over existing measures, offers considerably enhanced opportunities for objective measurement of young children's abilities to enable research and educational applications.


Pathways to colonoscopy in the South: seeds of health disparities.
We aimed to highlight sociodemographic differences in how patients access colonoscopy. We invited all eligible patients (n = 2500) from 2 academy-affiliated colonoscopy centers in Alachua County, Florida (1 free standing, 1 hospital based), to participate in a precolonoscopy survey (September 2011-October 2013); patients agreeing to participate (n = 1841, response rate = 73.6%) received a $5.00 gift card. We found sociodemographic differences in referral pathway, costs, and reasons associated with obtaining the procedure. Patients with the ideal pathway (referred by their regular doctor for age-appropriate screening) were more likely to be Black (compared with other minorities), male, high income, employed, and older. Having the colonoscopy because of symptoms was associated with being female, younger, and having lower income. We found significant differences for 1 previously underestimated barrier, having a spouse to accompany the patient to the procedure. Patients' facilitators and barriers to colonoscopy differed by sociodemographics in our study, which implies that interventions based on a single facilitator will not be effective for all subgroups of a population.


The Application of Pulsed Electromagnetic Fields (PEMFs) for Bone Fracture Repair: Past and Perspective Findings.
Bone fractures are one of the most commonly occurring injuries of the musculoskeletal system. A highly complex physiological process, fracture healing has been studied extensively. Data from in vivo, in vitro and clinical studies, have shown pulsed electromagnetic fields (PEMFs) to be highly influential in the fracture repair process. Whilst the underlying mechanisms acting to either inhibit or advance the physiological processes are yet to be defined conclusively, several non-invasive point of use devices have been developed for the clinical treatment of fractures. With the complexity of the repair process, involving many components acting at different time steps, it has been a challenge to determine which PEMF exposure parameters (i.e., frequency of field, intensity of field and dose) will produce the most optimal repair. In addition, the development of an evidence-backed device comes with challenges of its own, with many elements (including process of exposure, construct materials and tissue densities) being highly influential to the field exposed. The objective of this review is to provide a broad recount of the applications of PEMFs in bone fracture repair and to then demonstrate what is further required for enhanced therapeutic outcomes.


Knock-out of nexilin in mice leads to dilated cardiomyopathy and endomyocardial fibroelastosis.
Cardiomyopathy is one of the most common causes of chronic heart failure worldwide. Mutations in the gene encoding nexilin (NEXN) occur in patients with both hypertrophic and dilated cardiomyopathy (DCM); however, little is known about the pathophysiological mechanisms and relevance of NEXN to these disorders. Here, we evaluated the functional role of NEXN using a constitutive Nexn knock-out (KO) mouse model. Heterozygous (Het) mice were inter-crossed to produce wild-type (WT), Het, and homozygous KO mice. At birth, 32, 46, and 22 % of the mice were WT, Het, and KO, respectively, which is close to the expected Mendelian ratio. After postnatal day 6, the survival of the Nexn KO mice decreased dramatically and all of the animals died by day 8. Phenotypic characterizations of the WT and KO mice were performed at postnatal days 1, 2, 4, and 6. At birth, the relative heart weights of the WT and KO mice were similar; however, at day 4, the relative heart weight of the KO group was 2.3-fold higher than of the WT group. In addition, the KO mice developed rapidly progressive cardiomyopathy with left ventricular dilation and wall thinning and decreased cardiac function. At day 6, the KO mice developed a fulminant DCM phenotype characterized by dilated ventricular chambers and systolic dysfunction. At this stage, collagen deposits and some elastin deposits were observed within the left ventricle cavity, which resembles the features of endomyocardial fibroelastosis (EFE). Overall, these results further emphasize the role of NEXN in DCM and suggest a novel role in EFE.


A naturalistic home observational approach to children's language, cognition, and behavior.
Although early life experiences of language and parenting are critical for children's development, large home observation studies of both domains are scarce in the psychological literature, presumably because of their considerable costs to the participants and researchers. Here, we used digital audio-recorders to unobtrusively observe 107 children, aged 2.03 to 3.99 years (M = 2.77, SD = 0.55), and their families over 3 days (M = 15.06 hr per day, SD = 1.87). The recording software estimated the total number of words that a child heard over the course of a day. In addition, we transcribed six 5-min excerpts per family (i.e., 30 min overall) to extract estimates of children's and their parents' lexical diversity, positive and critical parenting, and children's internalizing and externalizing behaviors. We found that home language input (i.e., number of words and lexical diversity) was positively associated with children's cognitive ability and lexical diversity but not with their behaviors. In addition, we observed that home language input varied as much within as between families across days (intraclass correlation = .47). By comparison, parenting predicted children's behavioral outcomes but was not related to their cognitive or lexical ability. Overall, our findings suggest that home language input affects child development in cognition and language, while positive and parenting informs their behavioral development. Furthermore, we demonstrated that digital audio-recordings are useful tools for home observation studies that seek to disentangle the complex relationships between early life home environments and child development. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Incidence of and risk factors for complications associated with halo-vest immobilization: a prospective, descriptive cohort study of 239 patients.
Since high rates of serious complications, such as death and pneumonia, during halo-vest immobilization have been reported, there has been a tendency of restraint with regard to the use of the halo vest. However, the rate of complications in a high-volume center with sufficient experience is unknown. Our objective was to determine the incidence of and risk factors associated with complications during halo-vest immobilization. During a five-year period, a prospective cohort study was performed in a single, level-I trauma center that was also a tertiary referral center for spinal disorders. Data from all patients undergoing halo-vest immobilization were collected prospectively, and every complication was recorded. The primary outcome was the presence or absence of complications. Univariate regression analysis and regression modeling were used to analyze the results. In 239 patients treated with halo-vest immobilization, twenty-six major, seventy-two intermediate, and 121 minor complications were observed. Fourteen patients (6%) died during the treatment, although only one death was related directly to the immobilization and three were possibly related directly to the immobilization. Twelve patients (5%) acquired pneumonia during halo-vest immobilization. Patients older than sixty-five years did not have an increased risk of pneumonia (p = 0.543) or halo vest-related mortality (p = 0.467). Halo vest-related complications ranged from three patients (1%) with incorrect initial placement of the halo vest to twenty-nine patients (12%) with a pin-site infection. Pin-site infection was significantly related to pin penetration through the outer table of the skull (odds ratio, 4.34; 95% confidence interval, 1.22 to 15.51; p = 0.024). In 164 trauma patients treated only with halo-vest immobilization, cervical fractures with facet joint involvement or dislocations were significantly related to radiographic loss of alignment during follow-up (odds ratio, 2.81; 95% confidence interval, 1.06 to 7.44; p = 0.031). There are relatively low rates of mortality and pneumonia during halo-vest immobilization, and elderly patients do not have an increased risk of pneumonia or death related to halo-vest immobilization. Nevertheless, the total number of minor complications is substantial. This study confirms that awareness of and responsiveness to minor complications can prevent subsequent development of serious morbidities and perhaps reduce mortality.


Drug delivering technology for endovascular management of infrainguinal peripheral artery disease.
Endovascular intervention has become a well-recognized treatment modality for peripheral artery disease; however, mid- and long-term outcomes have been plagued by limited durability. Plain balloon angioplasty and bare-metal stents have historically suffered from high restenosis rates leading to the need for frequent repeat revascularization procedures. The innovation of locally administered, drug-delivering balloons and stents has been a direct result of technological innovations directed toward prevention and treatment of this limitation. Over the last 5 years, numerous clinical trials investigating the use of drug-coated stents and drug-coated balloons indicate a significant improvement in endovascular treatment durability and outcomes. This review provides an up-to-date assessment of the current evidence for the use of drug-coated stents and drug-coated balloons in the treatment of femoropopliteal and infrapopliteal peripheral artery disease. Additionally, it provides an overview of the development of this technology, highlights landmark ongoing and completed clinical trials, examines evidence to support the use of drug-coated technologies in combination with other modalities, and examines promising new technological developments. Last, it summarizes the challenges and safety concerns that have delayed U.S. Food and Drug Administration approval of these devices.


Apoptotic effects of non-edible parts of Punica granatum on human multiple myeloma cells.
Multiple myeloma is of great concern since existing therapies are unable to cure this clinical condition. Alternative therapeutic approaches are mandatory, and the use of plant extracts is considered interesting. Punica granatum and its derived products were suggested as potential anticancer agents due to the presence of bioactive compounds. Thus, polypenolic-rich extracts of the non-edible parts of P. granatum were investigated for their antiproliferative and apoptotic effects on U266 multiple myeloma cells. We demonstrated that there were dose-dependent decreases in the proliferation of U266 cells in response to P. granatum extracts. Also, exposure to the extracts triggered apoptosis with significant increases in loss of mitochondrial membrane potential in U266 cells exposed to the leaves and stem extracts, while the flower extract resulted in slight increases in loss of MMP. These results were confirmed by Annexin-V analysis. These results documented the cytotoxic and apoptotic effects of P. granatum extracts on human U266 multiple myeloma cells via disruption of mitochondrial membrane potential and increasing cell cycle arrest. The data suggest that the extracts can be envisaged in cancer chemoprevention and call for further exploration into the potential application of these plant parts.


Piracetam promotes mossy fiber synaptic reorganization in rats withdrawn from alcohol.
Prolonged alcohol intake affects the morphology of the hippocampal formation of the rat and the resulting alterations do not reverse after withdrawal. Actually, an increase of the degenerative activity might occur in this condition. This unexpected observation prompted us to test the efficacy of neuronoprotective drugs during withdrawal. Because in a previous study we found that piracetam, a cyclic derivative of GABA, once added during withdrawal impedes hippocampal cell loss, we decided to evaluate the effect of this compound at the synaptic level. Using unbiased stereological techniques, we estimated the total number of contacts between mossy fibers and CA3 pyramids, as well as the volume and the surface area of the respective pre- and postsynaptic compartments. We found that in piracetam-treated withdrawn rats the number of synapses was higher than that observed in nonpiracetam-treated and alcohol-fed animals. The mechanisms leading to the synaptic reorganization took place at the mossy fiber level. The postsynaptic compartment does not seem to participate in the reorganization. It is suggested that the role of piracetam in this process might depend on the protective effect that this compound has upon glutamatergic receptors.


Evaluation of effectiveness of wavelet based denoising schemes using ANN and SVM for bearing condition classification.
The wavelet based denoising has proven its ability to denoise the bearing vibration signals by improving the signal-to-noise ratio (SNR) and reducing the root-mean-square error (RMSE). In this paper seven wavelet based denoising schemes have been evaluated based on the performance of the Artificial Neural Network (ANN) and the Support Vector Machine (SVM), for the bearing condition classification. The work consists of two parts, the first part in which a synthetic signal simulating the defective bearing vibration signal with Gaussian noise was subjected to these denoising schemes. The best scheme based on the SNR and the RMSE was identified. In the second part, the vibration signals collected from a customized Rolling Element Bearing (REB) test rig for four bearing conditions were subjected to these denoising schemes. Several time and frequency domain features were extracted from the denoised signals, out of which a few sensitive features were selected using the Fisher's Criterion (FC). Extracted features were used to train and test the ANN and the SVM. The best denoising scheme identified, based on the classification performances of the ANN and the SVM, was found to be the same as the one obtained using the synthetic signal.