Symplekin, a polyadenylation factor, prevents MOZ and MLL activity on HOXA9 in hematopoietic cells.
MOZ and MLL encoding a histone acetyltransferase and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. We have previously shown that MOZ and MLL cooperate to activate HOXA9 gene expression in hematopoietic stem/progenitors cells. To dissect the mechanism of action of this complex, we decided to identify new proteins interacting with MOZ. We found that the scaffold protein Symplekin that supports the assembly of polyadenylation machinery was identified by mass spectrometry. Symplekin interacts and co-localizes with both MOZ and MLL in immature hematopoietic cells. Its inhibition leads to a decrease of the HOXA9 protein level but not of Hoxa9 mRNA and to an over-recruitment of MOZ and MLL onto the HOXA9 promoter. Altogether, our results highlight the role of Symplekin in transcription repression involving a regulatory network between MOZ, MLL and Symplekin.


Cal-B-catalyzed alkoxycarbonylation of a-ring stereoisomeric synthons of 1alpha,25-dihydroxyvitamin D3 and 1alpha,25-dihydroxy-19-nor-previtamin D3: a comparative study. first regioselective chemoenzymatic synthesis of 19-nor-A-ring carbonates.
A comparative study of alkoxycarbonylation processes of both 19-nor-A-ring and A-ring stereoisomers of 1alpha,25-dihydroxyvitamin D3 analogues catalyzed by Candida antarctica lipase B (CAL-B) has been described. The presence of the methyl group in the A-ring at C-2, as in 3-6, has a determining role in the regioselectivity of the biocatalysis, mainly allowing the hydroxyl group at C-5 position to react. For the 19-nor-A-ring stereoisomers 7-10, which lack the C-2 methyl group, the configurations at C-3 and C-5 have a high influence in the selectivity exhibited by CAL-B. Thus, each couple of enantiomers showed opposing regioselectivities depending on the C-3 configuration. When C-3 possesses an (S)-configuration, enzymatic alkoxycarbonylations took place at the C-5-(R) or C-5-(S) hydroxyl groups. However, if the chiral centers at C-3 are (R), CAL-B alkoxycarbonylated the C-3-(R) hydroxyl group independently of the configuration at C-5. The corresponding carbonates are useful A-ring precursors of 1alpha,25-dihydroxyvitamin D3 analogues, selectively modified at the C-1 or C-3 positions. In addition, an improved synthesis of cis A-ring synthons 5 and 6 is described using a Mitsunobu methodology.


Itinerary of high density lipoproteins in endothelial cells.
High density lipoprotein (HDL) and its main protein component apolipoprotein A-I (ApoA-I) have multiple anti-atherogenic functions. Some of them are exerted within the vessel wall, so that HDL needs to pass the endothelial barrier. To elucidate their itinerary through endothelial cells (ECs), we labelled ApoA-I and HDL either fluorescently or with 1.4 nm nanogold and investigated their cellular localization by using immunofluorescent microscopy (IFM) and electron microscopy (EM). HDL as well as ApoA-I is taken up by ECs into the same route of intracellular trafficking. Time kinetics and pulse chase experiments revealed that HDL is trafficked through different vesicles. HDL partially co-localized with LDL, albumin, and transferrin. HDL did not co-localize with clathrin and caveolin-1. Fluorescent HDL was recovered at small proportions in early endosomes and endosome to trans-golgi network vesicles but not at all in recycling endosomes, in late endosomes or lysosomes. EM identified HDL mainly in large filled vesicles which however upon IFM did not colocalize with markers of multivesicular bodies or autophagosomes. The uptake or cellular distribution of HDL was altered upon pharmacological interference with cytochalasine D, colchicine and dynasore. Blockage of fluid phase uptake with Amiloride or EIPA did not reduce the uptake of HDL. Neither did we observe any co-localization of HDL with dextran as the marker of fluid phase uptake. In conclusion, HDL and ApoA-I are internalized and trafficked by endothelial cells through a non-classical endocytic route.


Activity and expression of progesterone metabolizing 5alpha-reductase, 20alpha-hydroxysteroid oxidoreductase and 3alpha(beta)-hydroxysteroid oxidoreductases in tumorigenic (MCF-7, MDA-MB-231, T-47D) and nontumorigenic (MCF-10A) human breast cancer cells.
Recent observations indicate that human tumorous breast tissue metabolizes progesterone differently than nontumorous breast tissue. Specifically, 5alpha-reduced metabolites (5alpha-pregnanes, shown to stimulate cell proliferation and detachment) are produced at a significantly higher rate in tumorous tissue, indicating increased 5alpha-reductase (5alphaR) activity. Conversely, the activities of 3alpha-hydroxysteroid oxidoreductase (3alpha-HSO) and 20alpha-HSO enzymes appeared to be higher in normal tissues. The elevated conversion to 5alpha-pregnanes occurred regardless of estrogen (ER) or progesterone (PR) receptor levels. To gain insight into these differences, the activities and expression of these progesterone converting enzymes were investigated in a nontumorigenic cell line, MCF-10A (ER- and PR-negative), and the three tumorigenic cell lines, MDA-MB-231 (ER- and PR-negative), MCF-7 and T-47D (ER- and PR-positive). For the enzyme activity studies, either whole cells were incubated with [14C]progesterone for 2, 4, 8, and 24 hours, or the microsomal/cytosolic fraction was incubated for 15-60 minutes with [3H]progesterone, and the metabolites were identified and quantified. Semi-quantitative RT-PCR was employed to determine the relative levels of expression of 5alphaR type1 (SRD5A1), 5alphaR type 2 (SRD5A2), 20alpha-HSO (AKR1C1), 3alpha-HSO type 2 (AKR1C3), 3alpha-HSO type 3 (AKR1C2) and 3beta-HSO (HSD3B1/HSD3B2) in the four cell lines using 18S rRNA as an internal control. The relative 5alpha-reductase activity, when considered as a ratio of 5alpha-pregnanes/4-pregnenes, was 4.21 (+/- 0.49) for MCF-7 cells, 6.24 (+/- 1.14) for MDA-MB-231 cells, 4.62 (+/- 0.43) for T-47D cells and 0.65 (+/- 0.07) for MCF-10A cells, constituting approximately 6.5-fold, 9.6-fold and 7.1 fold higher conversion to 5alpha-pregnanes in the tumorigenic cells, respectively, than in the nontumorigenic MCF-10A cells. Conversely, the 20alpha-HSO and 3alpha-HSO activities were significantly higher (p < 0.001) in MCF-10A cells than in the other three cell types. In the MCF-10A cells, 20alpha-HSO activity was 8-14-fold higher and the 3alpha-HSO activity was 2.5-5.4-fold higher than in the other three cell types. The values of 5alphaR:20alpha-HSO ratios were 16.9-32.6-fold greater and the 5alphaR:3alpha-HSO ratios were 5.2-10.5-fold greater in MCF-7, MDA-MB-231 and T-47D cells than in MCF-10A cells. RT-PCR showed significantly higher expression of 5alphaR1 (p < 0.001), and lower expression of 20alpha-HSO (p < 0.001), 3alpha-HSO2 (p < 0.001), 3alpha-HSO3 (p < 0.001) in MCF-7, MDA-MB-231 and T-47D cells than in MCF-10A cells. The findings provide the first evidence that the 5alphaR activity (leading to the conversion of progesterone to the cancer promoting 5alpha-pregnanes) is significantly higher in the tumorigenic MCF-7, MDA-MB-231 and T-47D breast cell lines than in the nontumorigenic MCF-10A cell line. The higher 5alphaR activity coincides with significantly greater expression of 5alphaR1. On the other hand, the activities of 20alpha-HSO and 3alpha-HSO are higher in the MCF-10A cells than in MCF-7, MDA-MB-231 and T-47D cells; these differences in activity correlate with significantly higher expression of 20alpha-HSO, 3alpha-HSO2 and 3alpha-HSO3 in MCF-10A cells. Changes in progesterone metabolizing enzyme expression (resulting in enzyme activity changes) may be responsible for stimulating breast cancer by increased production of tumor-promoting 5alpha-pregnanes and decreased production of anti-cancer 20alpha--and 3alpha-4-pregnenes.


Effectiveness and sustainability of deprescribing for hospitalized older patients near end of life: a systematic review.
Introduction: Polypharmacy is prevalent in hospitals and deprescribing strategies for older people are strongly promoted. However, evidence of their feasibility and sustainability among patients receiving end of life care is lacking. The objective of this review was to ascertain effectiveness and post-discharge sustainability of hospital-initiated deprescribing strategies in older people near the end of life. Areas covered: The authors searched for controlled trials, with low risk of bias and measures of effectiveness post-discharge. Intervention description, duration, and healthcare provider engagement were investigated for their impact on reduction of number of medications, proportions of patients prescribed inappropriate medications, returns to emergency, hospital admission and adverse events. Expert opinion: Limited evidence suggests hospital-initiated deprescribing interventions may reduce prescribing inappropriateness among older terminal patients in the short term, but evidence beyond 3 months is lacking for significant prevention of adverse events or health service utilization. Heterogeneity precluded meta-analysis, and short follow-up periods precluded quantitative assessment of sustainability. Trials of older people with terminal conditions with larger sample sizes and longer follow-up periods are needed to confirm the effectiveness and sustainability of deprescribing at the end of life. Objective tools to reliably identify near end-of-life status would be useful in selecting target groups for these interventions.


Regional patterns in foliar (15)N across a gradient of nitrogen deposition in the northeastern US.
Recent studies have demonstrated that natural abundance (15)N can be a useful tool for assessing nitrogen saturation, because as nitrification and nitrate loss increase, delta(15)N of foliage and soil also increases. We measured foliar delta(15)N at 11 high-elevation spruce-fir stands along an N deposition gradient in 1987-1988 and at seven paired northern hardwood and spruce-fir stands in 1999. In 1999, foliar delta(15)N increased from -5.2 to -0.7 per thousand with increasing N deposition from Maine to NY. Foliar delta(15)N decreased between 1987-1988 and 1999, while foliar %N increased and foliar C:N decreased at most sites. Foliar delta(15)N was strongly correlated with N deposition, and was also positively correlated with net nitrification potential and negatively correlated with soil C:N ratio. Although the increase in foliar %N is consistent with a progression towards N saturation, other results of this study suggest that, in 1999, these stands were further from N saturation than in 1987-1988.


I-gel Versus LMA-Fastrach Supraglottic Airway for Flexible Bronchoscope-Guided Tracheal Intubation Using a Parker (GlideRite) Endotracheal Tube: A Randomized Controlled Trial.
The I-gel (IG) supraglottic airway device is a reliable way to establish an airway. Its large ventilation lumen allows for easy passage of an endotracheal tube. With the use of a flexible bronchoscope, the IG offers a good visualization of the laryngeal inlet. This prospective randomized study aims to compare the success rate of flexible bronchoscope-guided tracheal intubation using either the IG or the LMA-Fastrach (FT) laryngeal masks. One hundred twenty patients requiring general anesthesia were randomized to 1 of the 2 study groups: IG or FT. After anesthesia induction, the assigned laryngeal mask was inserted to obtain adequate ventilation. We then proceeded to a flexible bronchoscope-guided intubation through the supraglottic device. Tracheal intubation and laryngeal mask insertion success rates were noted, as well as the time required for these manipulations. The view of the laryngeal inlet was graded for each intubation attempt. Sixty patients were assigned to each study group. The intubation success rates were similar between the IG and the FT groups (100 % vs 95.0 % at first attempt; P = 0.12). The times required for tracheal intubation were significantly lower in the IG group (30 ± 11 seconds vs 50 ± 21 seconds; P < 0.0001). Glottic visualization was better in the IG group, with a significantly higher percentage of grade 1 visualization (63.3% vs 3.3%; P < 0.0001) and a lower percentage of grade 3 visualization (1.7% vs 60.0%; P < 0.0001), than that in the FT group. The use of the IG supraglottic airway device as a conduit for flexible bronchoscope-guided tracheal intubation results in a success rate equivalent to the use of the LMA-FT. However, the IG allows for shorter intubation times and a better visualization of the glottic opening compared with the LMA-FT.


PCR experion automated electrophoresis system to detect Listeria monocytogenes in foods.
Listeria monocytogenes is frequently found as a contaminant in raw and ready-to-eat foods. The ability of L. monocytogenes to multiply at refrigeration temperatures and to grow in a wide range of pH values is of particular concern for food safety. According to the European Union regulation on microbiological criteria for foodstuffs, L. monocytogenes must be absent in some categories of ready-to-eat foods. The standard microbiological method for L. monocytogenes detection in foods (ISO 11290-1: 1996 (ISO, International Organization for Standardization)) is cost and time consuming. Developments of rapid, cost-effective and automated diagnostic methods to detect food-borne pathogens in foods continue to be a major concern for the industry and public health. The aim of this study was the development of a rapid, sensitive and specific molecular detection method for L. monocytogenes. To this purpose, we have applied a capillary electrophoresis method to a PCR protocol (PCR-EES (EES, experion automated electrophoresis system)) for detecting L. monocytogenes in food. In particular, a microfluidic chip-based automated electrophoresis system (experion automated electrophoresis system, Bio-Rad Laboratories, USA) was used for the rapid and automatic analysis of the amplicons. Fifty naturally contaminated samples were analysed with this method and the results were compared with those obtained with ISO method. Moreover, the microfluidic chip-based automated electrophoresis system was compared with classical gel electrophoresis (PCR-CGE). The results showed that after 24 h of culture enrichment, the PCR-EES showed a relative accuracy of 100% with ISO, while using PCR-CGE decreased it down to 96%. After 48 h of enrichment, both PCR-EES and PCR-CGE showed an accuracy of 100% with ISO.


Blood selenium levels and contribution of food groups to selenium intake in adolescent girls in Iceland.
Significant changes have been reported in dietary habits and food availability in Iceland that would be expected to compromise selenium intake and status, especially among young people. These include substantial decreases in the consumption of fish and milk, as well as the selenium content of imported wheat. The aim of this study was to assess selenium in the diet and whole blood of adolescent girls, as well as define the most important foods contributing to intake and blood concentrations of selenium. The subjects were 96 randomly selected girls, aged 16-20, who answered a validated food frequency questionnaire (FFQ) for dietary assessment. Selenium intake from each food group was calculated in µg/day. Blood samples were collected for measurement of whole blood selenium. Mean dietary selenium was 51±25 µg/day. Milk/dairy products, including cheese, contributed 36±14% of total dietary selenium; fish 18±12%; and bread/cereal products 13±6%. Mean whole blood selenium was 117±12 µg/l (range 90-208); nearly 90% of subjects were above the optimal level of 100 µg/l. Fish and bread/cereal products were the only foods significantly correlated with selenium in blood (r=0.32; P=0.002 and r=0.22; P=0.04, respectively) while no correlation was found with milk and dairy products in spite of their greater contribution to total selenium intake. In this population of Icelandic adolescent girls, selenium intake and status seem acceptable. Judging from associations between intake and blood levels, fish and cereals may be the most important contributors to blood selenium.


Chromosome transplantation as a novel approach for correcting complex genomic disorders.
Genomic disorders resulting from large rearrangements of the genome remain an important unsolved issue in gene therapy. Chromosome transplantation, defined as the perfect replacement of an endogenous chromosome with a homologous one, has the potential of curing this kind of disorders. Here we report the first successful case of chromosome transplantation by replacement of an endogenous X chromosome carrying a mutation in the Hprt genewith a normal one in mouse embryonic stem cells (ESCs), correcting the genetic defect. The defect was also corrected by replacing the Y chromosome with an X chromosome. Chromosome transplanted clones maintained in vitro and in vivo features of stemness and contributed to chimera formation. Genome integrity was confirmed by cytogenetic and molecular genome analysis. The approach here proposed, with some modifications, might be used to cure various disorders due to other X chromosome aberrations in induced pluripotent stem (iPS) cells derived from affected patients.


Quantifying fire-specific smoke exposure and health impacts.
Rapidly changing wildfire regimes across the Western United States have driven more frequent and severe wildfires, resulting in wide-ranging societal threats from wildfires and wildfire-generated smoke. However, common measures of fire severity focus on what is burned, disregarding the societal impacts of smoke generated from each fire. We combine satellite-derived fire scars, air parcel trajectories from individual fires, and predicted smoke PM2.5 to link source fires to resulting smoke PM2.5 and health impacts experienced by populations in the contiguous United States from April 2006 to 2020. We quantify fire-specific accumulated smoke exposure based on the cumulative population exposed to smoke PM2.5 over the duration of a fire and estimate excess asthma-related emergency department (ED) visits as a result of this exposure. We find that excess asthma visits attributable to each fire are only moderately correlated with common measures of wildfire severity, including burned area, structures destroyed, and suppression cost. Additionally, while recent California fires contributed nearly half of the country's smoke-related excess asthma ED visits during our study period, the most severe individual fire was the 2007 Bugaboo fire in the Southeast. We estimate that a majority of smoke PM2.5 comes from sources outside the local jurisdictions where the smoke is experienced, with 87% coming from fires in other counties and 60% from fires in other states. Our approach could enable broad-scale assessment of whether specific fire characteristics affect smoke toxicity or impact, inform cost-effectiveness assessments for allocation of suppression resources, and help clarify the growing transboundary nature of local air quality.


Gonadal supporting cells acquire sex-specific chromatin landscapes during mammalian sex determination.
Cis-regulatory elements are critical for the precise spatiotemporal regulation of genes during development. However, identifying functional regulatory sites that drive cell differentiation in vivo has been complicated by the high numbers of cells required for whole-genome epigenetic assays. Here, we identified putative regulatory elements during sex determination by performing ATAC-seq and ChIP-seq for H3K27ac in purified XX and XY gonadal supporting cells before and after sex determination in mice. We show that XX and XY supporting cells initiate sex determination with similar chromatin landscapes and acquire sex-specific regulatory elements as they commit to the male or female fate. To validate our approach, we identified a functional gonad-specific enhancer downstream of Bmp2, an ovary-promoting gene. This work increases our understanding of the complex regulatory network underlying mammalian sex determination and provides a powerful resource for identifying non-coding regulatory elements that could harbor mutations that lead to Disorders of Sexual Development.


ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer's disease.
In sporadic Alzheimer's disease (sAD) specific regions, layers and neurons accumulate hyperphosphorylated Tau (pTau) and degenerate early while others remain unaffected even in advanced disease. ApoER2-Dab1 signaling suppresses Tau phosphorylation as part of a four-arm pathway that regulates lipoprotein internalization and the integrity of actin, microtubules, and synapses; however, the role of this pathway in sAD pathogenesis is not fully understood. We previously showed that multiple ApoER2-Dab1 pathway components including ApoE, Reelin, ApoER2, Dab1, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 accumulate together within entorhinal-hippocampal terminal zones in sAD, and proposed a unifying hypothesis wherein disruption of this pathway underlies multiple aspects of sAD pathogenesis. However, it is not yet known whether ApoER2-Dab1 disruption can help explain the origin(s) and early progression of pTau pathology in sAD. In the present study, we applied in situ hybridization and immunohistochemistry (IHC) to characterize ApoER2 expression and accumulation of ApoER2-Dab1 pathway components in five regions known to develop early pTau pathology in 64 rapidly autopsied cases spanning the clinicopathological spectrum of sAD. We found that (1) these selectively vulnerable neuron populations strongly express ApoER2; and (2) multiple ApoER2-Dab1 components representing all four arms of this pathway accumulate in abnormal neurons and neuritic plaques in mild cognitive impairment (MCI) and sAD cases and correlate with histological progression and cognitive deficits. Multiplex-IHC revealed that Dab1, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 accumulate together within many of the same ApoER2-expressing neurons and in the immediate vicinity of ApoE/ApoJ-enriched extracellular plaques. Collective findings reveal that pTau is only one of many ApoER2-Dab1 pathway components that accumulate in multiple neuroanatomical sites in the earliest stages of sAD and provide support for the concept that ApoER2-Dab1 disruption drives pTau-associated neurodegeneration in human sAD.


Antiarrhythmics After Ablation of Atrial Fibrillation (5A Study).
Atrial arrhythmias are common early after atrial fibrillation (AF) ablation. We hypothesized that empirical antiarrhythmic drug (AAD) therapy for 6 weeks after AF ablation would reduce the occurrence of atrial arrhythmias. We randomized consecutive patients with paroxysmal AF undergoing ablation to empirical antiarrhythmic therapy (AAD group) or no antiarrhythmic therapy (no-AAD group) for the first 6 weeks after ablation. In the no-AAD group, only atrioventricular nodal blocking agents were prescribed. All patients wore a transtelephonic monitor for 4 weeks after discharge and were reevaluated at 6 weeks. The primary end point of the study was a composite of (1) atrial arrhythmias lasting more than 24 hours; (2) atrial arrhythmias associated with severe symptoms requiring hospital admission, cardioversion, or initiation/change of antiarrhythmic drug therapy; and (3) intolerance to antiarrhythmic agent requiring drug cessation. Of 110 enrolled patients (age 55+/-9 years, 71% male), 53 were randomized to AAD and 57 to no-AAD. There was no difference in baseline characteristics between groups. During the 6 weeks after ablation, fewer patients reached the primary end point in the AAD compared with the no-AAD group (19% versus 42%; P=0.005). There remained fewer events in the AAD group (13% versus 28%; P=0.05) when only end points of AF >24 hours, arrhythmia-related hospitalization, or electrical cardioversion were compared. AAD treatment during the first 6 weeks after AF ablation is well tolerated and reduces the incidence of clinically significant atrial arrhythmias and need for cardioversion/hospitalization for arrhythmia management.


Use of a Rapid Diagnostic for Chlamydia trachomatis and Neisseria gonorrhoeae for Women in the Emergency Department Can Improve Clinical Management: Report of a Randomized Clinical Trial.
In emergency departments (EDs), diagnosis and treatment of Chlamydia trachomatis and Neisseria gonorrhoeae are challenging. We conducted a randomized clinical trial to assess rapid C trachomatis and N gonorrhoeae testing on overtreatment and undertreatment of women evaluated for C trachomatis and N gonorrhoeae. Women undergoing pelvic examinations and C trachomatis and N gonorrhoeae testing (n=254) were randomized to control or rapid test groups. The control group received standard-of-care C trachomatis and N gonorrhoeae nucleic acid amplification tests of endocervical specimens, with 2- to 3-day turnaround times. For the rapid test group, clinicians collected an extra endocervical swab for GeneXpert C trachomatis and N gonorrhoeae rapid testing, in addition to the standard-of-care nucleic acid amplification test swab. Rapid results were immediately provided, and all patients were treated according to providers' clinical judgment. In the rapid test group, 7.9% of patients had positive test results for C trachomatis; 3.9% had positive test results for N gonorrhoeae. In the control standard-of-care group, 10.2% of patients had positive nucleic acid amplification test results for C trachomatis; 5.5% had positive results for N gonorrhoeae. Undertreatment for both C trachomatis and N gonorrhoeae in the ED was 0% for the rapid test group and 43.8% for the control standard-of-care group. Clinicians overtreated 46.5% of uninfected standard-of-care control patients for C trachomatis compared with 23.1% of uninfected rapid test patients. For patients uninfected with N gonorrhoeae, clinicians overtreated 46.7% of standard-of-care control patients compared with 25.4% of rapid test patients. The length of stay did not differ significantly between groups. Rapid C trachomatis and N gonorrhoeae testing in the ED led to a significant reduction in overtreatment for women without infections compared with the standard-of-care control group. Additionally, in the rapid test group there was significant improvement in appropriate treatment for patients with infections.


Diagnostic host gene signature for distinguishing enteric fever from other febrile diseases.
Misdiagnosis of enteric fever is a major global health problem, resulting in patient mismanagement, antimicrobial misuse and inaccurate disease burden estimates. Applying a machine learning algorithm to host gene expression profiles, we identified a diagnostic signature, which could distinguish culture-confirmed enteric fever cases from other febrile illnesses (area under receiver operating characteristic curve > 95%). Applying this signature to a culture-negative suspected enteric fever cohort in Nepal identified a further 12.6% as likely true cases. Our analysis highlights the power of data-driven approaches to identify host response patterns for the diagnosis of febrile illnesses. Expression signatures were validated using qPCR, highlighting their utility as PCR-based diagnostics for use in endemic settings.


Immediate supracrestal implant placement with immediate temporization in the anterior dentition: a retrospective study of 31 implants in 26 patients with up to 5.5-years follow-up.
To assess the stability of the peri-implant bone, the peri-implant soft tissues and the esthetic success of immediately placed implants. In this retrospective study, scalloped-shaped implants were placed immediately and 1.5 mm supracrestally after single-tooth extraction. All implants were immediately restored with an implant-supported temporary crown. Clinical and radiographic parameters were assessed on the day of tooth extraction with subsequent implant placement and temporization, after 6 months at delivery of the final crown, and after 1, after 3, and up to 5 years after crown delivery. All 31 implants were clinically successful and in function during the observation period (mean 3.4 years). The peri-implant soft tissues were clinically healthy as indicated by a low mean plaque (below 0.5) and sulcus bleeding index (below 0.24) values. The distance between the implant shoulder and the first visible bone-to-implant contact (DIBrx) was measured at the mesial and distal aspects of each implant using periapical radiographs. Mean values for DIBrx of 1.73 ± 0.59 mm directly after implant placement and 2.25 ± 0.66 mm after the observation period demonstrated stable peri-implant bone levels. The mean distance from the implant shoulder to the gingival margin on the labial aspect (DIM vestibular) was 2.21 ± 1.09 mm directly after implant placement. Respective values at 1 year, at 3 years and at 5 years after crown delivery remained stable thus demonstrating little if any gingival recession. The assessed mean values for the pink (PES) and white (WES) esthetic score (0 = 0-33% score, 1 = 34-66% score, 2 = 67-100% score) were 8/4 directly after implant placement and 9/10 after 1.5-5.5 years of observation. After an observation time of 1.5-5.5 years all implants demonstrated very stable soft tissue levels with little if any recession on mesial, distal and labial aspects and an esthetic score that was reasonable directly after temporization and developed toward maximum scores over time.


The poly dA strand of poly dA.poly dT adopts an A-form in solution: a UV resonance Raman study.
The study by resonance Raman spectroscopy with a 257 nm excitation wave-length of adenine in two single-stranded polynucleotides, poly rA and poly dA, and in three double-stranded polynucleotides, poly dA.poly dT, poly(dA-dT).poly(dA-dT) and poly rA.poly rU, allows one to characterize the A-genus conformation of polynucleotides containing adenine and thymine bases. The characteristic spectrum of the A-form of the adenine strand is observed, except small differences, for poly rA, poly rA.poly rU and poly dA.poly dT. Our results prove that it is the adenine strand which adopts the A-family conformation in poly dA.poly dT.


Resistance of ex vivo expanded CD3+CD56+ T cells to Fas-mediated apoptosis.
A variety of malignancies express Fas ligand (FasL), which can induce apoptosis in effector lymphocytes and may limit the success of cellular immunotherapy. Our laboratory has been investigating a population of ex vivo activated T cells, termed cytokine-induced killer (CIK) cells. These cells share functional and phenotypic properties with natural killer cells and a subset of cytolytic cells have the phenotype CD3+CD56+. CIK cells expand in culture, have significant antitumor activity and are presently being tested in phase I/II clinical trials. In this study, we investigated the sensitivity of CIK cells to Fas-mediated apoptosis. Fas engagement leads to apoptosis in small numbers of CIK cells and does not significantly influence antitumor cytotoxicity. CIK cells will undergo apoptosis following Fas engagement when protein synthesis is inhibited, suggesting the expression of antiapoptotic genes. Evaluation of antiapoptotic gene transcripts shows an upregulation in the expression of cFLIP, Bcl-2, Bcl-xL, DAD1 and survivin. Resistance to Fas-mediated apoptosis may come about through an in vitro selection for Fas resistance, since CIK cells synthesize FasL and supernatant from CIK cultures contains biologically active soluble FasL, which can be inhibited with Fas:Fc. These results indicate that CIK cells are a suitable form of immunotherapy against FasL-positive tumors.


Specific inhibition of the Akt1 pleckstrin homology domain by D-3-deoxy-phosphatidyl-myo-inositol analogues.
Activation of Akt (protein kinase B), a Ser/Thr protein kinase that promotes cell survival, has been linked to tumorigenesis. Akt is activated by phosphorylation after binding of its pleckstrin homology (PH) domain to plasma membrane phosphatidyl-myo-inositol-3-phosphates, formed by phosphoinositide-3-kinase. We report a novel strategy to inhibit Akt activation based on the use of D-3-deoxy-phosphatidyl-myo-inositols (DPIs) that cannot be phosphorylated on the 3-position of the myo-inositol ring. We have studied the DPIs, DPI 1-[(R)-2,3-bis(hexadecanoyloxy)propyl hydrogen phosphate], its ether lipid derivative DPI 1-[(R)-2-methoxy-3-octadecyloxypropyl hydrogen phosphate] (DPIEL), and its carbonate derivative DPI 1-[(R)-2-methoxy-3-octadecyloxypropyl carbonate]. We demonstrate in platelet-derived growth factor-stimulated mouse NIH3T3 cells that the DPIs bind to the PH domain of Akt, trapping it in the cytoplasm and thus preventing Akt activation. DPIEL did not inhibit myristylated-Akt, a constitutively active membrane-bound Akt expressed in NIH3T3 cells, and cell growth was not inhibited, unlike in wild-type NIH3T3 cells. Molecular modeling and docking studies show that DPIEL binds with much higher affinity to Akt's PH domain as compared with DPI and DPI 1-[(R)-2-methoxy-3-octadecyloxypropyl carbonate]. This study shows that the DPIs are a novel class of growth inhibitory agents with a novel mechanism of action through binding to the PH domain of Akt and inhibition of Akt activation.


Genetic consequences of breaking migratory traditions in barnacle geese Branta leucopsis.
Cultural transmission of migratory traditions enables species to deal with their environment based on experiences from earlier generations. Also, it allows a more adequate and rapid response to rapidly changing environments. When individuals break with their migratory traditions, new population structures can emerge that may affect gene flow. Recently, the migratory traditions of the Barnacle Goose Branta leucopsis changed, and new populations differing in migratory distance emerged. Here, we investigate the population genetic structure of the Barnacle Goose to evaluate the consequences of altered migratory traditions. We used a set of 358 single nucleotide polymorphism (SNP) markers to genotype 418 individuals from breeding populations in Greenland, Spitsbergen, Russia, Sweden and the Netherlands, the latter two being newly emerged populations. We used discriminant analysis of principal components, FST , linkage disequilibrium and a comparison of geneflow models using migrate-n to show that there is significant population structure, but that relatively many pairs of SNPs are in linkage disequilibrium, suggesting recent admixture between these populations. Despite the assumed traditions of migration within populations, we also show that genetic exchange occurs between all populations. The newly established nonmigratory population in the Netherlands is characterized by high emigration into other populations, which suggests more exploratory behaviour, possibly as a result of shortened parental care. These results suggest that migratory traditions in populations are subject to change in geese and that such changes have population genetic consequences. We argue that the emergence of nonmigration probably resulted from developmental plasticity.


The evolution of self-control.
Cognition presents evolutionary research with one of its greatest challenges. Cognitive evolution has been explained at the proximate level by shifts in absolute and relative brain volume and at the ultimate level by differences in social and dietary complexity. However, no study has integrated the experimental and phylogenetic approach at the scale required to rigorously test these explanations. Instead, previous research has largely relied on various measures of brain size as proxies for cognitive abilities. We experimentally evaluated these major evolutionary explanations by quantitatively comparing the cognitive performance of 567 individuals representing 36 species on two problem-solving tasks measuring self-control. Phylogenetic analysis revealed that absolute brain volume best predicted performance across species and accounted for considerably more variance than brain volume controlling for body mass. This result corroborates recent advances in evolutionary neurobiology and illustrates the cognitive consequences of cortical reorganization through increases in brain volume. Within primates, dietary breadth but not social group size was a strong predictor of species differences in self-control. Our results implicate robust evolutionary relationships between dietary breadth, absolute brain volume, and self-control. These findings provide a significant first step toward quantifying the primate cognitive phenome and explaining the process of cognitive evolution.


Effects of Weight-Loss Medications on Cardiometabolic Risk Profiles: A Systematic Review and Network Meta-analysis.
We performed a systematic review and network meta-analysis to evaluate the overall and comparative effects of weight-loss medications approved by the Food and Drug Administration for long-term use on cardiometabolic risk profiles of obese adults. We performed a systematic literature review through February 28, 2017 to identify randomized clinical trials of the effects of Food and Drug Administration-approved weight-loss medications (ie, orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide) administered to obese adults for 1 year or more, compared with placebo or another active agent. Outcomes of interest included changes in blood glucose (fasting blood glucose [FBG] and hemoglobin A1c), cholesterol profile (low-density lipoprotein and high-density lipoproteins), blood pressure (BP; systolic/diastolic), and waist circumference (WC). We performed pair-wise and network meta-analyses with outcomes reported as weighted and standardized mean differences. Quality of evidence was rated using GRADE (Grading of Recommendations Assessment, Development and Evaluation). In a meta-analysis of 28 randomized controlled trials (29,018 participants; median body mass index, 36.1 kg/m2), we associated weight-loss medications with a modest decrease in FBG (weighted mean difference, 4.0 mg/dL; 95% confidence interval, -4.4 to -3.6 mg/dL) and WC (weighted mean difference, reduction of 3.3 cm; 95% confidence interval, -3.5 to -3.1 cm), without clinically meaningful changes in systolic/diastolic BP or cholesterol profile vs placebo (standardized mean difference <0.2); effects varied among drugs. Phentermine-topiramate use was associated with a substantial decrease in WC and a modest decrease in FBG, hemoglobin A1c, and BP, and had minimal effect on cholesterol. Liraglutide use was associated with a substantial decrease in FBG, hemoglobin A1c, and WC, and a minimal effect on BP and cholesterol. Naltrexone-bupropion use was associated with moderate increase in high-density lipoprotein cholesterol, but had a minimal effect on FBG and WC. Orlistat use was associated with a decrease in low-density lipoprotein and high-density lipoprotein cholesterol. No drug improved all cardiometabolic risk factors. In a systematic review and network meta-analysis, we found Food and Drug Administration-approved weight-loss medications to have only modest positive effects on cardiometabolic risk profile. Further research is needed to evaluate the long-term cardiometabolic benefits of these medications. CRD42016039486.


Prescribed drug therapy and near-fatal asthma attacks.
Inhaled fenoterol has been associated with an increased risk of death in severe asthmatics, when compared to other adrenoceptor agonists. It is plausible that fenoterol may also increase the risk of near-fatal attacks. We have conducted a case-control study to investigate this hypothesis. The cases comprised Intensive Care Unit (ICU) admissions for asthma in the Wellington region during 1977-1988. For each of these cases, two age-matched controls were selected from asthma admissions to the same hospital during the same period. For the 155 cases and 305 controls, information on prescribed drug therapy was collected from the hospital admission records. The relative risk of a near-fatal asthma attack in patients prescribed inhaled fenoterol was 2.00 (95% confidence interval (CI) 1.35-2.97). An increased risk was also observed for oral theophylline (odds ratio (OR) = 1.88; 95% CI 1.26-2.79). For the 65 cases and 104 controls who had a previous admission for asthma in the previous 12 months, information relating to the previous admission was also collected; an increased risk was once again observed for inhaled fenoterol (OR = 2.18; 95% CI 1.10-4.33) and for oral theophylline (OR = 1.18; 95% CI 0.99-3.57). No other asthma drugs showed significantly increased risks. Although the ICU admission cases had generally been prescribed more asthma drugs than the hospital admission controls, and appeared to have more severe asthma, it is possible that the findings reported here are influenced by confounding by severity. We nevertheless estimate that our findings are consistent with the hypothesis that fenoterol increases the risk of near-fatal asthma attacks, and that they complement previous findings on fatal asthma attacks.(ABSTRACT TRUNCATED AT 250 WORDS)


Distances to emergency department and to primary care provider's office affect emergency department use in children.
Patients of all ages use emergency departments (EDs) for primary care. Several studies have evaluated patient and system characteristics that influence pediatric ED use. However, the issue of proximity as a predictor of ED use has not been well studied. The authors sought to determine whether ED use by pediatric Medicaid enrollees was associated with the distance to their primary care providers (PCPs), distance to the nearest ED, and distance to the nearest children's hospital. This historical cohort study included 26,038 children age 18 and under, assigned to 332 primary care practices affiliated with a Medicaid health maintenance organization (HMO). Predictor variables were distance from the child's home to his or her PCP site, distance from home to the nearest ED, and distance from home to the nearest children's hospital. The outcome variable was each child's ED use. A negative binomial model was used to determine the association between distance variables and ED use, adjusted for age, sex, and race, plus medical and primary care site characteristics previously found to influence ED use. Distance variables were divided into quartiles to test for nonlinear associations. On average, children made 0.31 ED visits/person/year. In the multivariable model, children living greater than 1.19 miles from the nearest ED had 11% lower ED use than those living within 0.5 miles of the nearest ED (risk ratio [RR] = 0.89, 95% CI = 0.81 to 0.99). Children living between 1.54 and 3.13 miles from their PCPs had 13% greater ED use (RR = 1.13, 95% CI = 1.03 to 1.24) than those who lived within 0.7 miles of their PCP. Geographical variables play a significant role in ED utilization in children, confirming the importance of system-level determinants of ED use and creating the opportunity for interventions to reduce geographical barriers to primary care.


The estimated rate of depressed mood in US adults: recent evidence for a peak in later life.
The main aim of this study is to add new evidence on the descriptive epidemiology of depressed mood, and to investigate suspected determinants for depressed mood in adulthood. The data are from a continuing survey of a nationally representative sample of adult household residents in the United States, conducted in 1995 and 1996, totaling 26,883 respondents. Multiple logistic regression procedures yielded estimated associations. We found that an estimated 1.9% of adult females and 1.0% of adult males experience a spell of sustained depressed mood during a span of approximately 2 weeks duration (i.e. point prevalence). For most of these cases, this is not the first spell. Among women, the smoothed curve for the prevalence estimates shows a peak in the youngest age stratum and decreases across age strata before 60 years, and has a slight secondary peak thereafter. In contrast, for males, the prevalence estimates of depression show no peak in the older age strata. Evidence from logistic regression analyses supports the inference of this later life peak in frequency of depressed mood among women. These new findings add to a growing body of epidemiological evidence on age and depression, and provoke new questions about the possibly etiological relationships involving social structural characteristics of local neighborhoods in combination with individual-level risk factors that have received primary attention in recent psychiatric epidemiology. These findings point to the need for further etiological research, including studies of relationships between social structural characteristics of local neighborhoods and the occurrence of spells of depressed mood, as well as clinical implications for depression mood in late life.


Residential pesticides and childhood leukemia: a systematic review and meta-analysis.
It is a systematic review and meta-analysis of previous observational epidemiologic studies examining the relationship between residential pesticide exposures during critical exposure time windows (preconception, pregnancy, and childhood) and childhood leukemia. Searches of Medline and other electronic databases were performed (1950-2009). Study selection, data abstraction, and quality assessment were performed by two independent reviewers. Random effects models were used to obtain summary odds ratios (ORs) and 95% confidence intervals (Cis). Of the 17 identified studies, 15 were included in the meta-analysis. Exposures during pregnancy to unspecified residential pesticides insecticides, and herbicides were positively associated with childhood leukemia. Exposures during childhood to unspecified residential pesticides and insecticides were also positively associated with childhood leukemia, but there was no association with herbicides. Positive associations were observed between childhood leukemia and residential pesticide exposures. Further work is needed to confirm previous findings based on self-report, to examine potential exposure-response relationships, and to assess specific pesticides and toxicologically related subgroups of pesticides in more detail.


Effect of palivizumab prophylaxis on subsequent recurrent wheezing in preterm infants.
Palivizumab effectively prevents severe respiratory syncytial virus (RSV) disease in preterm infants. Our objective was to test whether palivizumab prophylaxis given to preterm infants during the first RSV season reduces the incidence of subsequent recurrent wheezing up to 3 years of life. We conducted an observational prospective multicenter (52 registered hospitals in Japan) case-control study in preterm infants with a gestational age between 33 and 35 weeks followed for 3 years. During the 2007-2008 RSV season, the decision to administer palivizumab was made based on standard medical practice. In April 2008, 52 hospitals were recruited. Study participants were prospectively followed to the age of 3 years. Parents of study subjects reported the infants' physician's assessment of recurrent wheezing, used a report card and a novel mobile phone-based reporting system by using the Internet. The primary end point was the incidence of physician-diagnosed recurrent wheezing. Of 444 preterm infants enrolled, 349 received palivizumab during the first 6 months of life and 95 infants did not. Physician-diagnosed recurrent wheezing was observed in 6.4% and 18.9% of infants in the treated and untreated groups, respectively (P < .001). This difference remained significant after adjustment for known risk factors of recurrent wheezing (P < .001). Palivizumab prophylaxis administered to preterm infants 33 to 35 weeks' gestational age is associated with a significantly lower incidence of recurrent wheezing during the first 3 years of life.


Specializations of the granular prefrontal cortex of primates: implications for cognitive processing.
The biological underpinnings of human intelligence remain enigmatic. There remains the greatest confusion and controversy regarding mechanisms that enable humans to conceptualize, plan, and prioritize, and why they are set apart from other animals in their cognitive abilities. Here we demonstrate that the basic neuronal building block of the cerebral cortex, the pyramidal cell, is characterized by marked differences in structure among primate species. Moreover, comparison of the complexity of neuron structure with the size of the cortical area/region in which the cells are located revealed that trends in the granular prefrontal cortex (gPFC) were dramatically different to those in visual cortex. More specifically, pyramidal cells in the gPFC of humans had a disproportionately high number of spines. As neuron structure determines both its biophysical properties and connectivity, differences in the complexity in dendritic structure observed here endow neurons with different computational abilities. Furthermore, cortical circuits composed of neurons with distinguishable morphologies will likely be characterized by different functional capabilities. We propose that 1. circuitry in V1, V2, and gPFC within any given species differs in its functional capabilities and 2. there are dramatic differences in the functional capabilities of gPFC circuitry in different species, which are central to the different cognitive styles of primates. In particular, the highly branched, spinous neurons in the human gPFC may be a key component of human intelligence.


Methods for synthesizing the macromolecular constituents of smart nanosized carriers for controlled drug delivery.
Smart multifunctional polymeric nanocarriers able to respond to physicochemical changes in their environment or to external stimuli represent a new paradigm in the field of pharmaceutical formulations for controlled drug delivery. The introductory part of the present review deals with this new concept and presents the main advantages resulting from the use of such nanovehicles instead of conventional, much larger drug delivery systems. The access to drug nanocarriers based on smart supramolecular polymeric materials is primarily limited by the available polymerization methods capable to produce polymers with low polydispersity index, as well as much more complex macromolecular architectures with strictly controlled chemical composition, such as block copolymers and star or graft polymers or copolymers. This article reviews the state-of-the art in controlled/"living" free radical polymerization techniques as well as ring opening polymerization methods. Nitroxide mediated free radical polymerization (NMP), atom transfer radical polymerization (ATRP), reversible addition-fragmentation chain-transfer polymerization (RAFT), single electron transfer-living radical polymerization (SET-LRP), single electron transfer-nitroxide radical coupling reaction (SET-NRC), cationic ring opening polymerization (CROP), anionic ring opening polymerization (AROP), and metal catalyzed ring opening polymerization are described, highlighting their mechanistic details and their synthetic potential as well as their limitations. The final part of the article is dedicated to a special type of unimolecular, monodisperse nanocarriers - the dendrimers. Both divergent and convergent approaches to dendrimer synthesis are described along with the therapeutic applications taking advantage of the unique branched tree-like globular structure of dendrimers to treat cancer.


The role of Rab3A in neurotransmitter release.
The small GTP-binding protein Rab3A is a Rab family member that is abundant in brain synaptic vesicles. Here we show that mice in which the rab3A gene has been mutated by homologous recombination do not express Rab3A but are viable and fertile. Electrophysiological recordings in hippocampal CA1 pyramidal cells indicate that most of their synaptic parameters are also normal, although synaptic depression after short trains of repetitive stimuli (15-30 stimuli at 14 Hz) is significantly increased. Levels of the Rab3A-binding protein rabphilin are decreased by 70%, but expression of more than 20 other synaptic proteins is unchanged. No compensatory changes were detected in other GTP-binding proteins or in proteins that interact with Rab3. Rab3A thus appears not to be essential for synaptic vesicle exocytosis but to play a role in the recruitment of synaptic vesicles for exocytosis during repetitive stimulation.


A decade of clinical development of PARP inhibitors in perspective.
Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce tumour-specific vulnerabilities that can be exploited therapeutically. In 2009, a first-in-man clinical trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib clinically validated the synthetic lethal interaction between inhibition of PARP1, a key sensor of DNA damage, and BRCA1/BRCA2 deficiency. In this review, we summarize a decade of PARP inhibitor clinical development, a work that has resulted in the registration of several PARP inhibitors in breast (olaparib and talazoparib) and ovarian cancer (olaparib, niraparib and rucaparib, either alone or following platinum chemotherapy as maintenance therapy). Over the past 10 years, our knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and we summarise this work here. We also discuss opportunities for expanding the precision medicine approach with PARP inhibitors, identifying a wider population who could benefit from this drug class. This includes developing and validating better predictive biomarkers for patient stratification, mainly based on homologous recombination defects beyond BRCA1/BRCA2 mutations, identifying DNA repair deficient tumours in other cancer types such as prostate or pancreatic cancer, or by designing combination therapies with PARP inhibitors.


PEGylated liposome IHL-305 markedly improved the survival of ovarian cancer peritoneal metastasis in mouse.
Advanced ovarian cancer is characterized by peritoneal metastasis and the accumulation of ascites. Peritoneal metastasis of ovarian cancer is a major cause of the negative treatment outcome, as these metastases are resistant to most chemotherapy regimens. The aim of this study was to clarify aggressive pathology of peritoneal metastasis and examine the therapeutic efficacy of a liposomal agent in the model. A human cancer cell line ES-2 of ovarian clear cell carcinoma, known as a chemotherapy-resistant cancer, was cultured in nonadherent plate to form spheroid and single cell suspension was transplanted into mouse peritoneal cavity. The epidermal growth factor receptor (EGFR) pathways in the cellular aggregates were analyzed both spheroid and ascites. The pharmacokinetics and therapeutic efficacy of CPT-11 (45 mg/kg) and IHL-305 (45 mg/kg), an irinotecan-encapsulated liposome, were examined by intravenous administration. Established peritoneal metastasis model showed an accumulation of ascites. The activation of EGFR and Akt was demonstrated in cellular aggregates both in the spheroid and ascites. In ascites samples, the area under the curve of SN-38, the activated form of CPT-11, was 3.8 times higher from IHL-305-treated mice than from CPT-11-treated mice. IHL-305 prolonged the survival time and decreased the accumulation of ascites and tumor metastasis. The median survival time were 22, 37 and 54 days in the control, CPT-11-treated, and IHL-305-treated mice, respectively. EGFR/Akt pathway contributes to the aggressive progression in ES-2 peritoneal metastasis model and effective delivery into ascites of IHL-305 was thought to useful treatment for ovarian cancer with peritoneal metastasis.


Biopharmacological considerations for accelerating drug development of deguelin, a rotenoid with potent chemotherapeutic and chemopreventive potential.
Deguelin is a rotenoid compound that exists in abundant quantities in the bark, roots, and leaves of the Leguminosae family of plants. An analysis of evidence from both in vitro and in vivo studies suggests that deguelin displays potent anticancer activity against multiple cancer types and exhibits chemopreventive potential in Akt-inducible transgenic mouse models. Deguelin appears to impede carcinogenesis by enhancing cell apoptosis and hindering malignant transformation and tumor cell propagation. Crucial oncogenic pathways likely targeted by deguelin include the epithelial-to-mesenchymal transition; angiogenesis-related pathways; and the phosphoinositide 3-kinase/Akt, Wnt, epidermal growth factor receptor, c-Met, and hedgehog signal transduction cascades. This review article provides a comprehensive summary of current preclinical research featuring deguelin as a leading chemotherapeutic and chemopreventive compound, and it highlights the importance of identifying companion molecular biomarkers and performing systemic pharmacokinetic studies for accelerating the process of developing deguelin as a clinical anticancer agent.


LDAHash: Improved Matching with Smaller Descriptors.
SIFT-like local feature descriptors are ubiquitously employed in computer vision applications such as content-based retrieval, video analysis, copy detection, object recognition, photo tourism, and 3D reconstruction. Feature descriptors can be designed to be invariant to certain classes of photometric and geometric transformations, in particular, affine and intensity scale transformations. However, real transformations that an image can undergo can only be approximately modeled in this way, and thus most descriptors are only approximately invariant in practice. Second, descriptors are usually high dimensional (e.g., SIFT is represented as a 128-dimensional vector). In large-scale retrieval and matching problems, this can pose challenges in storing and retrieving descriptor data. We map the descriptor vectors into the Hamming space in which the Hamming metric is used to compare the resulting representations. This way, we reduce the size of the descriptors by representing them as short binary strings and learn descriptor invariance from examples. We show extensive experimental validation, demonstrating the advantage of the proposed approach.


The effect of inhaled menthol on upper airway resistance in humans: a randomized controlled crossover study.
Menthol (l-menthol) is a naturally-occurring cold receptor agonist commonly used to provide symptomatic relief for upper airway congestion. Menthol can also reduce the sensation of dyspnea. It is unclear whether the physiological action of menthol in dyspnea reduction is through its cold receptor agonist effect or whether associated mechanical changes occur in the upper airway. To determine whether menthol inhalation alters upper airway resistance in humans. A randomized, sham-controlled, single-blinded crossover study of inhaled menthol on upper airway resistance during semirecumbent quiet breathing in healthy subjects was conducted. Ten healthy participants (eight female) with a mean (± SD) age of 21±1.6 years completed the study. Nasal resistance before testing was similar on both occasions. No differences were found in respiratory frequency (mean ± SEM) (menthol 17.0±1.1 cmH2O⁄L⁄s; sham 16.9±0.9 cmH2O⁄L⁄s), minute ventilation (menthol 7.7±0.5 cmH2O⁄L⁄s; sham 7.9±0.5 cmH2O⁄L⁄s) or total inspiratory time⁄total breath time (menthol 0.4±0.1 cmH2O⁄L⁄s; sham 0.4±0.1 cmH2O⁄L⁄s). The upper airway resistance was similar during menthol (3.47±0.32 cmH2O⁄L⁄s) and sham (3.27±0.28 cmH2O⁄L⁄s) (P=0.33) inhalation. Inhalation of menthol does not alter upper airway resistance in awake human subjects.


A Systematic Review of Glucose Transport Alterations in Alzheimer's Disease.
Introduction: Alzheimer's disease (AD) is characterized by cerebral glucose hypometabolism. Hypometabolism may be partly due to reduced glucose transport at the blood-brain barrier (BBB) and across astrocytic and neuronal cell membranes. Glucose transporters (GLUTs) are integral membrane proteins responsible for moving glucose from the bloodstream to parenchymal cells where it is metabolized, and evidence indicates vascular and non-vascular GLUTs are altered in AD brains, a process which could starve the brain of glucose and accelerate cognitive decline. Here we review the literature on glucose transport alterations in AD from human and rodent studies. Methods: Literature published between 1st January 1946 and 1st November 2020 within EMBASE and MEDLINE databases was searched for the terms "glucose transporters" AND "Alzheimer's disease". Human and rodent studies were included while reviews, letters, and in-vitro studies were excluded. Results: Forty-three studies fitting the inclusion criteria were identified, covering human (23 studies) and rodent (20 studies). Post-mortem studies showed consistent reductions in GLUT1 and GLUT3 in the hippocampus and cortex of AD brains, areas of the brain closely associated with AD pathology. Tracer studies in rodent models of AD and human AD also exhibit reduced uptake of glucose and glucose-analogs into the brain, supporting these findings. Longitudinal rodent studies clearly indicate that changes in GLUT1 and GLUT3 only occur after amyloid-β pathology is present, and several studies indicate amyloid-β itself may be responsible for GLUT changes. Furthermore, evidence from human and rodent studies suggest GLUT depletion has severe effects on brain function. A small number of studies show GLUT2 and GLUT12 are increased in AD. Anti-diabetic medications improved glucose transport capacity in AD subjects. Conclusions: GLUT1 and GLUT3 are reduced in hippocampal and cortical regions in patients and rodent models of AD, and may be caused by high levels of amyloid-β in these regions. GLUT3 reductions appear to precede the onset of clinical symptoms. GLUT2 and GLUT12 appear to increase and may have a compensatory role. Repurposing anti-diabetic drugs to modify glucose transport shows promising results in human studies of AD.


Bioinspired imprinted PHEMA-hydrogels for ocular delivery of carbonic anhydrase inhibitor drugs.
Hydrogels with high affinity for carbonic anhydrase (CA) inhibitor drugs have been designed trying to mimic the active site of the physiological metallo-enzyme receptor. Using hydroxyethyl methacrylate (HEMA) as the backbone component, zinc methacrylate, 1- or 4-vinylimidazole (1VI or 4VI), and N-hydroxyethyl acrylamide (HEAA) were combined at different ratios to reproduce in the hydrogels the cone-shaped cavity of the CA, which contains a Zn(2+) ion coordinated to three histidine residues. 4VI resembles histidine functionality better than 1VI, and, consequently, pHEMA-ZnMA(2) hydrogels bearing 4VI moieties were those with the greatest ability to host acetazolamide or ethoxzolamide (2 to 3 times greater network/water partition coefficient) and to sustain the release of these antiglaucoma drugs (50% lower release rate estimated by fitting to the square root kinetics). The use of acetazolamide as template during polymerization did not enhance the affinity of the network for the drugs. In addition to the remarkable improvement in the performance as controlled release systems, the biomimetic hydrogels were highly cytocompatible and possessed adequate oxygen permeability to be used as medicated soft contact lenses or inserts. The results obtained highlight the benefits of mimicking the structure of the physiological receptors for the design of advanced drug delivery systems.


Point-of-Care Lung Ultrasound Pattern in Healthy Parturients: Prevalence of Pulmonary Interstitial Syndrome Following Vaginal Delivery, Elective and Unplanned Intrapartum Cesarean Delivery.
Pregnancy-related cardiovascular physiologic changes increase the likelihood of pulmonary edema, with the risk of fluid extravasating into the pulmonary interstitium being potentially at a maximum during the early postpartum period. Data on the impact of labor and peripartum hemodynamic strain on lung ultrasound (LUS) are limited, and the prevalence of subclinical pulmonary interstitial syndrome in peripartum women is poorly described. The primary aim of this exploratory study was to estimate the prevalence of pulmonary interstitial syndrome in healthy term parturients undergoing vaginal (VD), elective (eCD), and unplanned intrapartum cesarean deliveries (uCD). Secondary aims were to estimate the prevalence of positive lung regions (≥3 B-lines on LUS per region) and to assess the associations between positive lung regions and possible contributing factors. In this prospective observational cohort study, healthy women at term undergoing VD, eCD, or uCD were enrolled. Following international consensus recommendations, a LUS examination was performed within 4 hours after delivery applying an 8-region technique. Pulmonary interstitial syndrome was defined by the presence of 2 or more positive lung regions per hemithorax. Ultrasound studies were reviewed by 2 blinded reviewers and assessed for interobserver reliability. Seventy-five women were assessed (n = 25 per group). No pulmonary interstitial syndrome was found in the VD and eCD groups (each 0 of 25; 0%, 95% confidence interval [CI], 0-13.7). Pulmonary interstitial syndrome was found in 2 of 25 (8%, 95% CI, 1-26) women undergoing an uCD (P = .490 for VD versus uCD and P = .490 for eCD versus uCD). In 1 woman, this correlated clinically with the development of pulmonary edema. One or more positive lung regions were present in 5 of 25 (20%), 6 of 25 (24%), and 11 of 25 (44%) parturients following VD, eCD, and uCD, respectively (P = .136). Positive lung regions were predominantly found in lateral lung regions. The number of positive lung regions showed a weak correlation with patient age (r = 0.25, 95% CI, 0.05-0.47; P = .033). No significant association was found between LUS pattern and parity, duration of labor, labor augmentation, labor induction, estimated total intravenous fluid intake, or net intravenous fluid intake. Although many focal areas of increased extravascular lung water (20%-44% prevalence) can be identified on LUS, the overall prevalence of pulmonary interstitial syndrome was 2.7% (2 of 75; 95% CI, 0.3-9.3) among healthy term parturients soon after delivery. Focal areas of positive lung water regions were weakly correlated with maternal age.


Functional compartmentation of the Golgi apparatus of plant cells : immunocytochemical analysis of high-pressure frozen- and freeze-substituted sycamore maple suspension culture cells.
The Golgi apparatus of plant cells is engaged in both the processing of glycoproteins and the synthesis of complex polysaccharides. To investigate the compartmentalization of these functions within individual Golgi stacks, we have analyzed the ultrastructure and the immunolabeling patterns of high-pressure frozen and freeze-substituted suspension-cultured sycamore maple (Acer pseudoplatanus L.) cells. As a result of the improved structural preservation, three morphological types of Golgi cisternae, designated cis, medial, and trans, as well as the trans Golgi network, could be identified. The number of cis cisternae per Golgi stack was found to be fairly constant at approximately 1, whereas the number of medial and trans cisternae per stack was variable and accounted for the varying number of cisternae (3-10) among the many Golgi stacks examined. By using a battery of seven antibodies whose specific sugar epitopes on secreted polysaccharides and glycoproteins are known, we have been able to determine in which types of cisternae specific sugars are added to N-linked glycans, and to xyloglucan and polygalacturonic acid/rhamnogalacturonan-I, two complex polysaccharides. The findings are as follows. The beta-1,4-linked d-glucosyl backbone of xyloglucan is synthesized in trans cisternae, and the terminal fucosyl residues on the trisaccharide side chains of xyloglucan are partly added in the trans cisternae, and partly in the trans Golgi network. In contrast, the polygalacturonic/rhamnogalacturonan-I backbone is assembled in cis and medial cisternae, methylesterification of the carboxyl groups of the galacturonic acid residues in the polygalacturonic acid domains occurs mostly in medial cisternae, and arabinose-containing side chains of the polygalacturonic acid domains are added to the nascent polygalacturonic acid/rhamnogalacturonan-I molecules in the trans cisternae. Double labeling experiments demonstrate that xyloglucan and polygalacturonic acid/rhamnogalacturonan-I can be synthesized concomitantly within the same Golgi stack. Finally, we show that the xylosyl residue-linked beta-1,2 to the beta-linked mannose of the core of N-linked glycans is added in medial cisternae. Taken together, our results indicate that in sycamore maple suspension-cultured cells, different types of Golgi cisternae contain different sets of glycosyl transferases, that the functional organization of the biosynthetic pathways of complex polysaccharides is consistent with these molecules being processed in a cis to trans direction like the N-linked glycans, and that the complex polysaccharide xyloglucan is assembled exclusively in trans Golgi cisternae and the trans Golgi network.


Assessment of Transition Readiness in Adolescents with Sickle Cell Disease and their Caretakers, A single institution experience.
Sickle Cell Disease (SCD) is associated with high child mortality and birth incidence in sub-Saharan Africa. Improved SCD medical services in Ghana aims to enhance survival into adulthood, creating emerging need for transition from pediatric to adult care. Anticipating transition for adolescents with SCD, we sought to understand patient and caretaker perspectives on transition to adult care within Ghana. Structured interviews were conducted with a sample of patients ages 12-15 years and accompanying adults at Ghana's Komfo Anokye Teaching Hospital Sickle Cell Clinic (KATH SCC) covering four areas: SCD medical knowledge, symptom self-management, psychosocial impact, and transition preparation. In total, 46 children (mean age 13 years) paired with 46 adults were interviewed. Most children and caretakers had some knowledge about SCD and disease management. At least one-third lacked knowledge about SCD as an inherited condition. Youth were significantly more concerned about family burden and social stigmatization than adults. Most were unaware that patients are expected to switch care to adult medical providers by age 15 years, but were willing to transfer if needed. Our clinic-based assessment at KATH SCC identified needs of adolescents and caretakers for education and counseling about disease, self-management, transition, family burden, and stigmatization. These findings provide insights into perspectives and educational gaps of families treated for SCD. Results suggest consideration of transition planning for adolescents with SCD and their caretakers in Ghana. Generalizability of our findings and practical methods to address needs for transition within Africa remain to be tested.


Desmosomes and cytoskeletal architecture in epithelial differentiation: cell type-specific plaque components and intermediate filament anchorage.
Among the diverse kinds of intercellular, plaque-bearing, cadherin-containing junctions, desmosomes (maculae adhaerentes) represent a major type characterized by the presence of specific transmembrane glycoproteins, i.e. desmosomal cadherins of the desmoglein and desmocollin categories, and the cytoplasmic plaque proteins, desmoplakin I and plakoglobin. Recent studies, however, have shown that the composition of desmosomes is not identical in the various normal and tumorous desmosome-forming tissues and cell cultures, including diverse forms of epithelia and carcinomas, meningothelia and meningiomas, myocardium and the lymph node follicle reticulum. Desmosomes can differ in their specific complement of desmogleins, Dsg1-3, and desmocollins, Dsc1a-3b, as well as in the additional presence and in their relative amounts of certain accessory plaque proteins such as desmoplakin II and plakophilin 1, a basic member of the larger plakoglobin family of proteins ("band 6 protein"). Assembly and function of desmosomes are effected by the interaction of the specific complement of desmosomal cadherins with certain cytoplasmic proteins. In particular, the cytoplasmic portions ("tails") of the desmosomal cadherins contain certain domains and amino acid sequence motifs, identified by mutagenesis and transfection assays, that are essential elements in desmosome formation, notably the assembly of plaque proteins, and in the site-specific anchorage of intermediate-sized filaments (IFs) of the cytoskeleton, thereby contributing to the specific intracellular as well as supracellular, i.e. tissue, architecture.


The Positive Relationships of Playfulness With Indicators of Health, Activity, and Physical Fitness.
Adult playfulness is a personality trait that enables people to frame or reframe everyday situations in such a way that they experience them as entertaining, intellectually stimulating, or personally interesting. Earlier research supports the notion that playfulness is associated with the pursuit of an active way of life. While playful children are typically described as being active, only limited knowledge exists on whether playfulness in adults is also associated with physical activity. Additionally, existing literature has not considered different facets of playfulness, but only global playfulness. Therefore, we employed a multifaceted model that allows distinguishing among Other-directed, Lighthearted, Intellectual, and Whimsical playfulness. For narrowing this gap in the literature, we conducted two studies addressing the associations of playfulness with health, activity, and fitness. The main aim of Study 1 was a comparison of self-ratings (N = 529) and ratings from knowledgeable others (N = 141). We tested the association of self- and peer-reported playfulness with self- and peer-reported physical activity, fitness, and health behaviors. There was a good convergence of playfulness among self- and peer-ratings (between r = 0.46 and 0.55, all p < 0.001). Data show that both self- and peer-ratings are differentially associated with physical activity, fitness, and health behaviors. For example, self-rated playfulness shared 3% of the variance with self-rated physical fitness and 14% with the pursuit of an active way of life. Study 2 provides data on the association between self-rated playfulness and objective measures of physical fitness (i.e., hand and forearm strength, lower body muscular strength and endurance, cardio-respiratory fitness, back and leg flexibility, and hand and finger dexterity) using a sample of N = 67 adults. Self-rated playfulness was associated with lower baseline and activity (climbing stairs) heart rate and faster recovery heart rate (correlation coefficients were between -0.19 and -0.24 for global playfulness). Overall, Study 2 supported the findings of Study 1 by showing positive associations of playfulness with objective indicators of physical fitness (primarily cardio-respiratory fitness). The findings represent a starting point for future studies on the relationships between playfulness, and health, activity, and physical fitness.


A topical azithromycin preparation for the treatment of acne vulgaris and rosacea.
Erythromycin is a common therapy for acne and rosacea. A newer macrolide, azithromycin, offers superior tissue distribution and cellular concentration and is an effective oral anti-acne agent. Topical formulations such as erythromycin have been a major clinical therapy for acne. To date, no topical solution of azithromycin is available for the treatment of acne. To prepare a stable topical 2% azithromycin formulation that could be used in an acne clinical trial to determine the efficacy of topical azithromycin in treating subjects with acne vulgaris and acne rosacea. The study was divided into two phases. In phase I, azithromycin was prepared over a range of ethanol/water concentrations to determine solubility. The stability of a 2% azithromycin in 60% ethanol/water preparation was assessed by high-pressure liquid chromatography. The temperature, light, and pH dependence of the stability was also assessed. In phase II, a single center, randomized, double-blind, treatment-controlled study compared once-nightly application of topical 2% azithromycin versus 2% erythromycin. A total of 20 subjects with moderate inflammatory acne and 20 with rosacea were examined clinically at 0, 2, 4, 8, and 12 weeks for a 12-week period. Efficacy was evaluated with the Physician's Visual Analog Scale evaluation (PVAS), the papulopustule count, and acne severity rating (in subjects with acne). In phase I, azithromycin was soluble in 60% ethanol/water. A 2% azithromycin in 60% ethanol/water solution maintained stability at room temperature for up to 26 weeks but at 37 degrees C there was some decay (16%) at 26 weeks. The stability was greatest at pH 6.8 and was unaffected by ambient light exposure. In phase II, the number of inflammatory lesions decreased in both acne and rosacea subjects treated with 2% erythromycin (7.56, p=0.03 and 4.4, p=0.01, respectively). Azithromycin was not as effective for the treatment of rosacea. Both azithromycin (p=0.01) and erythromycin (p=0.03) treatment significantly reduced the inflammatory lesion count in acne vulgaris. No significant adverse events were identified in the acne group. In patients with rosacea, transient irritation occurred in five patients. A 2% azithromycin in 60% ethanol/water solution can be prepared and is stable for at least 6 months at room temperature. The methodology and power of the study were adequate to identify improvement in acne vulgaris and rosacea. Though it appears the formulation of topical azithromycin was at least comparable with topical erythromycin, larger studies would be needed to determine whether topical azithromycin has any significant advantage over topical erythromycin.


Consumer Perception of Sustainability Attributes in Organic and Local Food.
Although sustainable food consumption is gaining growing importance on the international agenda, research on this subject is still quite fragmented and most studies analyse single aspects of sustainable food consumption with particular reference to environmental sustainability. In addition, the literature highlights the need to take account of the strong heterogeneity of consumers in studying sustainable behaviour. Identifying consumer segments with common profiles, needs and values is essential for developing effective communication strategies to promote sustainability in food consumption. Consumer segmentation based on the perception of the sustainability attributes of organic and local products was realized using descriptive data collected through a consumer online survey in southern Italy (Campania). K-means cluster analysis was performed to identify different consumer segments based on consumer perception of sustainable attributes in organic and local food. Results confirm the support of consumers for organic and local food as sustainable alternative in food choices even if occasional buying behaviour of these products still predominates. In addition, our results show that an egoistic approach prevails among consumers, who seem to attach more value to attributes related to quality and health than to environmental, social and economic sustainability. Segmentation proves the existence of three consumer segments that differ significantly in terms of perception of sustainability attributes: a large segment of individuals who seem more egocentric oriented, an environmental sustainability oriented segment and a small segment that includes sustainability oriented consumers. The existence of different levels of sensitivity to sustainability attributes in organic and local food among the identified segments could be duly considered by policy makers and other institutions in promoting sustainable consumption patterns. Consumers in the first cluster could be educated about the social and environmental benefits of organic and local consumption, beyond health and quality aspects, by promoting communication strategies aimed at creating a sense of belonging and self-identity in the change process towards sustainability. Consumers in the second cluster could be more informed about the additional social and economic benefits of organic and local consumption that goes beyond the still perceived environmental benefits. The strategic focus should be on attracting interest on the sense of belonging to the local community, in order to further promoting the short supply chain as models based on community building relationships and processes that hold people to place and share responsibility. Finally, it is worth mentioning that the increasing demand for more sustainable food products needs to be coupled with the development and adoption of innovations. In this regards, several patents have been registered for biopesticides/ insecticides and bioactive agricultural products. However, more scientific evidence of higher yields and other benefits and enabling measures that support farmers are required to broaden adoption of innovation for sustainable agro-food production.


Myocardial kinetics of Tc-99m glucarate in low flow, hypoxia, and aglycemia.
Technetium-99m glucarate is a myocardial infarct-avid imaging agent. Recent conflicting and inconclusive reports have suggested that the agent may be taken up by ischemic but viable myocardium. The purposes of this study were (1) to determine conclusively whether there is Tc-99m glucarate uptake in ischemic viable myocardium and (2) to investigate the potential mechanisms for such uptake by studying components of ischemia, namely, low flow, hypoxia, and aglycemia. Rat hearts were isolated and perfused in a modified Langendorff preparation with a crytalloid perfusate. Tc-99m glucarate was studied in control (n = 6), low-flow (n = 5), hypoxic (n = 5), and aglycemic (n = 5) conditions. The experimental protocol consisted of 20-minute baseline (12 mL/min flow) and 20-minute treatment (low flow at 1 mL/min, hypoxia, or aglycemia), followed by tracer uptake (20 minute) and washout (20 minutes). Activity was monitored with a sodium iodide detector. The tracer was delivered continuously over a 20-minute uptake period. The injected dose was 150 micro Ci (5.6 MBq). Hemodynamics were monitored throughout. Triphenyltetrazolium chloride staining was used to assess myocardial viability. There was no evidence of myocardial necrosis. Low flow tended to delay tracer uptake compared with control for the first 10 minutes, but this did not reach statistical significance. Low flow increased end fractional retention significantly compared with control (mean +/- SEM, 59.0% +/- 0.9% peak vs 41.2% +/- 1.4%, respectively; P <.05). Hypoxia resulted in a trend toward increased uptake; however, this was significant only at one early time point during the uptake phase. Retention in the hypoxia group was similar to control. Tc-99m glucarate uptake was significantly increased in aglycemia from 16 minutes to peak compared with control (1.36% +/- 0.71% injected dose per gram vs 0.91% +/- 0.37% injected dose per gram, respectively; P <.05). Aglycemia produced significantly higher end fractional retention compared with control (51.6% +/- 1.8% peak vs 41.2% +/- 1.4%, respectively; P <.05). Tc-99m glucarate myocardial retention is increased in the setting of ischemia, even in the absence of necrosis. This increased retention is not due to hypoxia. Furthermore, the retention is only partially explained by tissue hypoglycemia. Thus low flow per se appears to have a role in this increased retention, probably as a result of delayed flow-dependent washout.


Using the Courts to Shape Medicaid Policy: Olmstead v. L.C. by Zimring and Its Community Integration Legacy.
In Olmstead v. L.C. by Zimring, the United States Supreme Court addressed the relationship between the Americans with Disabilities Act (ADA), a landmark in US civil rights law, and the Medicaid program. Olmstead holds that qualified individuals with disabilities who are protected by the ADA have the right to receive publicly funded services in community-integrated treatment settings and that medically unnecessary institutionalization violates the ADA. But the Court had to wrestle with the extent to which the ADA requires state Medicaid programs to make deep and structural reforms in how long-term care services are organized, financed, and delivered. From a strictly legal perspective, Olmstead's impact has been limited by the fact that the ADA does not require fundamental alterations in public programs. Despite this fact, Olmstead remains a watershed decision in US disability law that has helped spur transformational changes in how Medicaid addresses community-based long-term care.


A prospective study of tobacco smoking and mortality in Bangladesh.
Limited data are available on smoking-related mortality in low-income countries, where both chronic disease burden and prevalence of smoking are increasing. Using data on 20,033 individuals in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh, we prospectively evaluated the association between tobacco smoking and all-cause, cancer, and cardiovascular disease mortality during ∼7.6 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) for deaths from all-cause, cancer, CVD, ischemic heart disease (IHD), and stroke, in relation to status, duration, and intensity of cigarette/bidi and hookah smoking. Among men, cigarette/bidi smoking was positively associated with all-cause (HR 1.40, 95% CI 1.06 1.86) and cancer mortality (HR 2.91, 1.24 6.80), and there was a dose-response relationship between increasing intensity of cigarette/bidi consumption and increasing mortality. An elevated risk of death from ischemic heart disease (HR 1.87, 1.08 3.24) was associated with current cigarette/bidi smoking. Among women, the corresponding HRs were 1.65 (95% CI 1.16 2.36) for all-cause mortality and 2.69 (95% CI 1.20 6.01) for ischemic heart disease mortality. Similar associations were observed for hookah smoking. There was a trend towards reduced risk for the mortality outcomes with older age at onset of cigarette/bidi smoking and increasing years since quitting cigarette/bibi smoking among men. We estimated that cigarette/bidi smoking accounted for about 25.0% of deaths in men and 7.6% in women. Tobacco smoking was responsible for substantial proportion of premature deaths in the Bangladeshi population, especially among men. Stringent measures of tobacco control and cessation are needed to reduce tobacco-related deaths in Bangladesh.


Spinal trauma in Tanzania: current management and outcomes.
Spinal trauma is a major cause of disability worldwide. The burden is especially severe in low-income countries, where hospital infrastructure is poor, resources are limited, and the volume of cases is high. Currently, there are no reliable data available on incidence, management, and outcomes of spinal trauma in East Africa. The main objective of this study was to describe, for the first time, the demographics, management, costs of surgery and implants, treatment decision factors, and outcomes of patients with spine trauma in Tanzania. The authors retrospectively reviewed prospectively collected data on spinal trauma patients in the single surgical referral center in Tanzania (Muhimbili Orthopaedic Institute [MOI]) from October 2016 to December 2017. They collected general demographics and the following information: distance from site of trauma to the center, American Spinal Injury Association Impairment Scale (AIS), time to surgery, steroid use, and mechanism of trauma and AOSpine classification and costs. Surgical details and complications were recorded. Primary outcome was neurological status on discharge. The authors analyzed surgical outcome and determined predicting factors for positive outcome. A total of 180 patients were included and analyzed in this study. The mean distance from site of trauma to MOI was 278.0 km, and the time to admission was on average 5.9 days after trauma. Young males were primarily affected (82.8% males, average age 35.7 years). On admission, 47.2% of patients presented with AIS grade A. Most common mechanisms of injury were motor vehicle accidents (28.9%) and falls from height (32.8%). Forty percent of admitted patients underwent surgery. The mean time to surgery was 33.2 days; 21.4% of patients who underwent surgery improved in AIS grade at discharge (p = 0.030). Overall, the only factor associated with improvement in neurological status was undergoing surgery (p = 0.03) and shorter time to surgery (p = 0.02). This is the first study to describe the management and outcomes of spinal trauma in East Africa. Due to the lack of referral hospitals, patients are admitted late after trauma, often with severe neurological deficit. Surgery is performed but generally late in the course of hospital stay. The decision to perform surgery and timing are heavily influenced by the availability of implants and economic factors such as insurance status. Patients with incomplete deficits who may benefit most from surgery are not prioritized. The authors' results suggest that surgery may have a positive impact on patient outcome. Further studies with a larger sample size are needed to confirm our results. These results provide strong support to implement evidence-based protocols for the management of spinal trauma.


Onset of subcutaneous emphysema and pneumomediastinum after tonsillectomy: a case report.
Several complications can be related to surgical approaches of head and neck regions. Among those, there are rare conditions such as pneumomediastinum, pneumothorax and subcutaneous cervical emphysema. This study reports a case of a patient that developed pneumomediastinum, pneumothorax and subcutaneous emphysema after undergoing tonsillectomy. In order to reduce these complications in surgical approaches such as tonsillectomy, care should be taken with intubation, use of oxygen mask for positive pressure ventilation during anesthesia recovery, aggressive surgical maneuvers and use of surgical instruments that may cause deep tonsillar injuries.


Can high quality listening predict lower speakers' prejudiced attitudes?
Theorizing from humanistic and motivational literatures suggests attitude change may occur because high quality listening facilitates the insight needed to explore and integrate potentially threatening information relevant to the self. By extension, self-insight may enable attitude change as a result of conversations about prejudice. We tested whether high quality listening would predict attitudes related to speakers' prejudices and whether self-insight would mediate this effect. Study 1 (preregistered) examined scripted conversations characterized by high, regular, and poor listening quality. In Study 2, we manipulated high versus regular listening quality in the laboratory as speakers talked about their prejudiced attitudes. Finally, Study 3 (preregistered) used a more robust measure of prejudiced attitudes to test whether perceived social acceptance could be an alternative explanation to Study 2 findings. Across these studies, the exploratory (pilot study and Study 2) and confirmatory (Studies 1 & 3) findings were in line with expectations that high, versus regular and poor, quality listening facilitated lower prejudiced attitudes because it increased self-insight. A meta-analysis of the studies (N = 952) showed that the average effect sizes for high quality listening (vs. comparison conditions) on self-insight, openness to change and prejudiced attitudes were, ds = 1.19, 0.46, 0.32 95%CIs [0.73, 1.51], [0.29, 0.63] [0.12, 0.53], respectively. These results suggest that when having conversations about prejudice, high-quality listening modestly shapes prejudice following conversations about it, and underscore the importance of self-insight and openness to change in this process.


Dbh+ catecholaminergic cardiomyocytes contribute to the structure and function of the cardiac conduction system in murine heart.
The heterogeneity of functional cardiomyocytes arises during heart development, which is essential to the complex and highly coordinated cardiac physiological function. Yet the biological and physiological identities and the origin of the specialized cardiomyocyte populations have not been fully comprehended. Here we report a previously unrecognised population of cardiomyocytes expressing Dbhgene encoding dopamine beta-hydroxylase in murine heart. We determined how these myocytes are distributed across the heart by utilising advanced single-cell and spatial transcriptomic analyses, genetic fate mapping and molecular imaging with computational reconstruction. We demonstrated that they form the key functional components of the cardiac conduction system by using optogenetic electrophysiology and conditional cardiomyocyte Dbh gene deletion models. We revealed their close relationship with sympathetic innervation during cardiac conduction system formation. Our study thus provides new insights into the development and heterogeneity of the mammalian cardiac conduction system by revealing a new cardiomyocyte population with potential catecholaminergic endocrine function.


Physician and stakeholder perceptions of conflict of interest policies in oncology.
The landscape of managing potential conflicts of interest (COIs) has evolved substantially across many disciplines in recent years, but rarely are the issues more intertwined with financial and ethical implications than in the health care setting. Cancer care is a highly technologic arena, with numerous physician-industry interactions. The American Society of Clinical Oncology (ASCO) recognizes the role of a professional organization to facilitate management of these interactions and the need for periodic review of its COI policy (Policy). To gauge the sentiments of ASCO members and nonphysician stakeholders, two surveys were performed. The first asked ASCO members to estimate opinions of the Policy as it relates to presentation of industry-sponsored research. Respondents were classified as consumers or producers of research material based on demographic responses. A similar survey solicited opinions of nonphysician stakeholders, including patients with cancer, survivors, family members, and advocates. The ASCO survey was responded to by 1,967 members (1% of those solicited); 80% were producers, and 20% were consumers. Most respondents (93% of producers; 66% of consumers) reported familiarity with the Policy. Only a small proportion regularly evaluated COIs for presented research. Members favored increased transparency about relationships over restrictions on presentations of research. Stakeholders (n = 264) indicated that disclosure was "very important" to "extremely important" and preferred written disclosure (77%) over other methods. COI policies are an important and relevant topic among physicians and patient advocates. Methods to simplify the disclosure process, improve transparency, and facilitate responsiveness are critical for COI management.


TRAF1 is a negative regulator of TNF signaling. enhanced TNF signaling in TRAF1-deficient mice.
TNF receptor-associated factor 1 (TRAF1) is a unique TRAF protein because it lacks a RING finger domain and is predominantly expressed in activated lymphocytes. To elucidate the function of TRAF1, we generated TRAF1-deficient mice. TRAF1(-/-) mice are viable and have normal lymphocyte development. TRAF1(-/-) T cells exhibit stronger than wild-type (WT) T cell proliferation to anti-CD3 mAb, which persisted in the presence of IL-2 or anti-CD28 antibodies. Activated TRAF1(-/-) T cells, but not TRAF1(+/+) T cells, responded to TNF by proliferation and activation of the NF-kappa B and AP-1 signaling pathways. This TNF effect was mediated by TNFR2 (p75) but not by TNFR1 (p55). Furthermore, skin from TRAF1(-/-) mice was hypersensitive to TNF-induced necrosis. These findings suggest that TRAF1 is a negative regulator of TNF signaling.


Comparison of two anaerobic water polo-specific tests with the Wingate test.
The purpose of the current study was to compare 2 water polo-specific tests-the 14 x 25-m swims (SWIM) and the 30-second crossbar jumps (30CJ)-with a laboratory-based test of anaerobic power, the Wingate Anaerobic Test (WAnT). Thirteen elite women's water polo players (mean +/- SD: age 22.0 +/- 4.4 years, height 168.7 +/- 7.9 cm, body mass 65.9 +/- 6.1 kg, body fat 23.6 +/- 3.5 %, maximum oxygen uptake 51.4 +/- 4.5 mlxkgxmin) participated in the study. The SWIM involved 14 repeated "all-out" sprints every 30 seconds. Swimming time was recorded, and sprint velocity, mean velocity (Vmean), and the gradient of the linear regression equation (GRADIENT) were calculated. The 30CJ involved repeated in-water water polo jumps and touching the goal crossbar with both hands. The number of touches in 30 seconds was recorded. Additionally, the subjects completed a 30-second WAnT, and mean power (Mp) and fatigue index (FI) were calculated. Kendall tau (tau) rank correlation was used to examine for correlation between ranks. Significance level was set at p <or= 0.05. No significant correlation was found between any of the measures of the WAnT and the 2 sport-specific tests. It was suggested that the WAnT may not be an appropriate evaluation tool for anaerobic power assessment of water polo players, stressing the importance of sport-specific tests.