Is it possible to define the ideal lips?
The lips are an essential component of the symmetry and aesthetics of the face. Cosmetic surgery to modify the lips has recently gained in popularity, but the results are in some cases disasterous. In this review, we describe the features of the ideal lips for an individual's face. The features of the ideal lips with respect to facial anatomy, important anatomical landmarks of the face, the facial proportions of the lips and ethnic and sexual differences are described. The projection and relative sizes of the upper and lower lips are as significant to lip aesthetics as the proportion of the lips to the rest of the facial structure. Robust, pouty lips are considered to be sexually attractive by both males and females. Horizontal thirds and the golden ratio describe the proportions that contribute to the beauty and attractiveness of the lips. In young Caucasians, the ideal ratio of the vertical height of the upper lip to that of the lower lip is 1:1.6. Blacks, genetically, have a greater lip volume. The shape and volume of a person's lips are of great importance in the perception of beauty by humans. The appearance of the lips in part determines the attractiveness of a person's face. In females, fuller lips in relation to facial width as well as greater vermilion height are considered to be attractive.


Virtual HDR CyberKnife SBRT for Localized Prostatic Carcinoma: 5-Year Disease-Free Survival and Toxicity Observations.
Prostate stereotactic body radiotherapy (SBRT) may substantially recapitulate the dose distribution of high-dose-rate (HDR) brachytherapy, representing an externally delivered "Virtual HDR" treatment method. Herein, we present 5-year outcomes from a cohort of consecutively treated virtual HDR SBRT prostate cancer patients. Seventy-nine patients were treated from 2006 to 2009, 40 low-risk, and 39 intermediate-risk, under IRB-approved clinical trial, to 38 Gy in four fractions. The planning target volume (PTV) included prostate plus a 2-mm volume expansion in all directions, with selective use of a 5-mm prostate-to-PTV expansion and proximal seminal vesicle coverage in intermediate-risk patients, to better cover potential extraprostatic disease; rectal PTV margin reduced to zero in all cases. The prescription dose covered >95% of the PTV (V100 ≥95%), with a minimum 150% PTV dose escalation to create "HDR-like" PTV dose distribution. Median pre-SBRT PSA level of 5.6 ng/mL decreased to 0.05 ng/mL 5 years out and 0.02 ng/mL 6 years out. At least one PSA bounce was seen in 55 patients (70%) but only 3 of them subsequently relapsed, biochemical-relapse-free survival was 100 and 92% for low-risk and intermediate-risk patients, respectively, by ASTRO definition (98 and 92% by Phoenix definition). Local relapse did not occur, distant metastasis-free survival was 100 and 95% by risk-group, and disease-specific survival was 100%. Acute and late grade 2 GU toxicity incidence was 10 and 9%, respectively; with 6% late grade 3 GU toxicity. Acute urinary retention did not occur. Acute and late grade 2 GI toxicity was 0 and 1%, respectively, with no grade 3 or higher toxicity. Of patient's potent pre-SBRT, 65% remained so at 5 years. Virtual HDR prostate SBRT creates a very low PSA nadir, a high rate of 5-year disease-free survival and an acceptable toxicity incidence, with results closely resembling those reported post-HDR brachytherapy.


Clinical Impact and Risk Factors of Portal Vein Thrombosis for Patients on Wait List for Liver Transplant.
The effect of portal vein thrombosis on the progression of liver disease is controversial, with no consensus on optimal treatment. We aimed to assess how portal vein thrombosis affects wait list outcomes, identify risk factors associated with its development while on a wait list, and assess its effects on patient and graft survival. This US-based retrospective cohort study analyzed 134 109 adult patients on wait lists for or undergoing primary orthotopic liver transplant between January 2002 and June 2014. Rate of portal vein thrombosis development, time from entry on wait list to transplant, comparisons of wait list drop-off rates between patients with versus those without portal vein thrombosis, risk factors associated with its development while on a wait list, and its effects on patient and graft survival were analyzed. We found that the rate of portal vein thrombosis at listing increased. Patients with the disease at listing were more likely to be removed from wait lists because of being too sick. Portal vein thrombosis at listing was an independent risk factor for being removed from a wait list. Of 63 265 patients who underwent primary orthotopic liver transplant, those with the disease were more likely to have higher Model for End-Stage Liver Disease scores and incidence of nonalcoholic steatohepatitis and diabetes mellitus. Portal vein thrombosis had a negative effect on patient and graft survival. Nonalcoholic steatohepatitis, body mass index, diabetes, and hepatocellular carcinoma were identified as risk factors for its development. Portal vein thrombosis represents an increasing management and outcome burden in liver transplant. Having this disease at listing and/or at time of transplant is associated with worse patient and graft survival. Nonalcoholic steatohepatitis and hepatocellular carcinoma are among the biggest risk factors for its development while on a wait list.


Massive hepatosplenomegaly caused by Penicillium marneffei associated with human immunodeficiency virus infection in a Thai patient.
A 29 year old Thai woman presented with non-specific features and examination revealed left upper zone consolidation and hepatosplenomegaly. The initial clinical differential diagnosis included tuberculosis and melioidosis. She died four days after admission, while still under investigation. Postmortem examination revealed antibodies to human immunodeficiency virus, disseminated Penicillium marneffei infection, and Salmonella enteritidis infection. Penicillium marneffei is a well described AIDS defining pathogen in South East Asia but is very rare in the UK. Appropriate antifungal treatment may be associated with a successful outcome. Increased awareness of this clinical association may enable correct diagnosis in affected patients from South East Asia presenting within the UK.


Detection of Mycobacterium tuberculosis complex DNA in CD34-positive peripheral blood mononuclear cells of asymptomatic tuberculosis contacts: an observational study.
Haematopoietic stem cells expressing the CD34 surface marker have been posited as a niche for Mycobacterium tuberculosis complex bacilli during latent tuberculosis infection. Our aim was to determine whether M tuberculosis complex DNA is detectable in CD34-positive peripheral blood mononuclear cells (PBMCs) isolated from asymptomatic adults living in a setting with a high tuberculosis burden. We did a cross-sectional study in Ethiopia between Nov 22, 2017, and Jan 10, 2019. Digital PCR (dPCR) was used to determine whether M tuberculosis complex DNA was detectable in PBMCs isolated from 100 mL blood taken from asymptomatic adults with HIV infection or a history of recent household or occupational exposure to an index case of human or bovine tuberculosis. Participants were recruited from HIV clinics, tuberculosis clinics, and cattle farms in and around Addis Ababa. A nested prospective study was done in a subset of HIV-infected individuals to evaluate whether administration of isoniazid preventive therapy was effective in clearing M tuberculosis complex DNA from PBMCs. Follow-up was done between July 20, 2018, and Feb 13, 2019. QuantiFERON-TB Gold assays were also done on all baseline and follow-up samples. Valid dPCR data (ie, droplet counts >10 000 per well) were available for paired CD34-positive and CD34-negative PBMC fractions from 197 (70%) of 284 participants who contributed data to cross-sectional analyses. M tuberculosis complex DNA was detected in PBMCs of 156 of 197 participants with valid dPCR data (79%, 95% CI 74-85). It was more commonly present in CD34-positive than in CD34-negative fractions (154 [73%] of 197 vs 46 [23%] of 197; p<0·0001). Prevalence of dPCR-detected M tuberculosis complex DNA did not differ between QuantiFERON-negative and QuantiFERON-positive participants (77 [78%] of 99 vs 79 [81%] of 98; p=0·73), but it was higher in HIV-infected than in HIV-uninfected participants (67 [89%] of 75 vs 89 [73%] of 122, p=0·0065). By contrast, the proportion of QuantiFERON-positive participants was lower in HIV-infected than in HIV-uninfected participants (25 [33%] of 75 vs 73 [60%] of 122; p<0·0001). Administration of isoniazid preventive therapy reduced the prevalence of dPCR-detected M tuberculosis complex DNA from 41 (95%) of 43 HIV-infected individuals at baseline to 23 (53%) of 43 after treatment (p<0·0001), but it did not affect the prevalence of QuantiFERON positivity (17 [40%] of 43 at baseline vs 13 [30%] of 43 after treatment; p=0·13). We report a novel molecular microbiological biomarker of latent tuberculosis infection with properties that are distinct from those of a commercial interferon-γ release assay. Our findings implicate the bone marrow as a niche for M tuberculosis in latently infected individuals. Detection of M tuberculosis complex DNA in PBMCs has potential applications in the diagnosis of latent tuberculosis infection, in monitoring response to preventive therapy, and as an outcome measure in clinical trials of interventions to prevent or treat latent tuberculosis infection. UK Medical Research Council.


Synthesis of Dispersible Mesoporous Nitrogen-Doped Hollow Carbon Nanoplates with Uniform Hexagonal Morphologies for Supercapacitors.
In this study, dispersible mesoporous nitrogen-doped hollow carbon nanoplates have been synthesized as a new anisotropic carbon nanostructure using gibbsite nanoplates as templates. The gibbsite-silica core-shell nanoplates were first prepared before the gibbsite core was etched away. Dopamine as carbon precursor was self-polymerized on the hollow silica nanoplates surface assisted by sonification, which not only favors a homogeneous polymer coating on the nanoplates but also prevents their aggregation during the polymerization. Individual silica-polydopamine core-shell nanoplates were immobilized in a silica gel in an insulated state via a silica nanocasting technique. After pyrolysis in a nanoconfine environment and elimination of silica, discrete and dispersible hollow carbon nanoplates are obtained. The resulted hollow carbon nanoplates bear uniform hexagonal morphology with specific surface area of 460 m2·g-1 and fairly accessible small mesopores (∼3.8 nm). They show excellent colloidal stability in aqueous media and are applied as electrode materials for symmetric supercapacitors. When using polyvinylimidazolium-based nanoparticles as a binder in electrodes, the hollow carbon nanoplates present superior performance in parallel to polyvinylidene fluoride (PVDF) binder.


TRPV4 and the mammalian kidney.
Transient receptor potential vanilloid 4 (TRPV4) was identified as the mammalian homologue of the Caenorhabditis elegans osmosensory channel protein, OSM-9. In mammals, TRPV4 is activated by a variety of stimuli including thermal stress, fatty acid metabolites, and hypotonicity. Two distinct mechanisms have been described through which TRPV4 may be activated by hypotonicity: one involves the Src family of nonreceptor protein tyrosine kinases, whereas a second is mediated via arachidonic acid metabolites. TRPV4 likely plays a role in systemic osmoregulation; accordingly, it is expressed in the blood-brain barrier-deficient osmosensory nuclei of the hypothalamus. TRPV4 is also abundantly expressed in the kidney, and its precisely demarcated distribution along the kidney tubule permits speculation about a physiological role in this tissue. TRPV4-expressing and TRPV4-negative tubule segments co-exist at all levels of the kidney, from the cortex through the inner medulla. It is conceivable that basolaterally expressed TRPV4 transmits signals arising in the interstitium (e.g, changing tonicity) to more-distal tubule segments where "fine-tuning" of the incipient urine takes place.


Molecular phylogenetic analyses of genus Crocodylus (Eusuchia, Crocodylia, Crocodylidae) and the taxonomic position of Crocodylus porosus.
The genus Crocodylus consists of 11 species including the largest living reptile, Crocodylus porosus. The current understanding of the intrageneric relationships between the members of the genus Crocodylus is sparse. Even though members of this genus have been included in many phylogenetic analyses, different molecular approaches have resulted in incongruent trees leaving the phylogenetic relationships among the members of Crocodylus unresolved inclusive of the placement of C. porosus. In this study, the complete mitochondrial genome sequences along with the partial mitochondrial gene sequences and a nuclear gene, C-mos were utilized to infer the intrageneric relationships among Crocodylus species with a special emphasis on the phylogenetic position of C. porosus. Four different phylogenetic methods, Neighbour Joining, Maximum Parsimony, Maximum Likelihood and Bayesian inference, were utilized to reconstruct the crocodilian phylogeny. The uncorrected pairwise distances computed in the study, show close proximity of C. porosus to C. siamensis and the tree topologies thus obtained, also consistently substantiated this relationship with a high statistical support. In addition, the relationship between C. acutus and C. intermedius was retained in all the analyses. The results of the current phylogenetic study support the well established intergeneric crocodilian phylogenetic relationships. Thus, this study proposes the sister relationship between C. porosus and C. siamensis and also suggests the close relationship of C. acutus to C. intermedius within the genus Crocodylus.


Building a Foundation for a Successful Doctoral Student Journey: A Scholarship of Teaching and Learning Investigation.
Doctoral students' program non-completion continues to be a worldwide phenomenon. Given the challenges across the globe following the 2020-22 pandemic, we need scholarly and skilled PhD and education (EdD) doctoral program graduates. A place to look for retention improvement is by studying what students learn and how they are taught in their university doctoral programs. One purpose of this case study was to describe how 12 EdD students in a program seminar responded to instruction in research and writing strategies during their first year of a four-year program. The second purpose was to examine student responses to formative assessments and describe and explain ongoing instructional adjustments using a Scholarship of Teaching and Learning (SoTL) framework within our own faculty community of practice. Analysis of surveys and student work indicated that writing and research strategies were instructive, engaging, and useful in building research and writing foundations. Analysis of multiple formative assessments helped us refine our instructional strategies during the year. Because all students completed the first high stakes program milestone (comprehensive paper) in year two, our findings suggested that the seminar's instructional strategies established a foundation for student success and timely program progress. Using multiple formative assessments over time was critical in strengthening our teaching practice as well. We recommended instructional practices associated with student research and writing skill development as well as student progress and retention.


[Immunologic status of patients with pulmonary tuberculosis and pneumonia].
A combined immunologic examination included 67 patients with concurrent lung pathology (tuberculosis with pneumonia), 64 with tuberculosis and 71 with pneumonia. The relation of the immune status to the pattern of the process was demonstrated proceeding from the findings. Pneumonia in the abatement phase had no influence on the immunologic parameters of a tuberculosis patient. Acute pneumonia combined with tuberculosis was marked by suppressed T-lymphocyte functional and specific activity, increased counts of T-suppressors and the presence of antituberculous antibodies. It was found that the newly developed diagnostic tables can be used effectively for differentiating the combined pathology from the uncomplicated tuberculosis and pneumonia.


Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma.
KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). A small subset of PDACs harbor KRAS wild-type (WT). We aim to characterize the molecular profiles of KRAS WT PDAC to uncover new pathogenic drivers and offer targeted treatments. Tumor tissue obtained from surgical or biopsy material was subjected to next-generation DNA/RNA sequencing, microsatellite instability (MSI) and mismatch repair status determination. Of the 2,483 patients (male 53.7%, median age 66 years) studied, 266 tumors (10.7%) were KRAS WT. The most frequently mutated gene in KRAS WT PDAC was TP53 (44.5%), followed by BRAF (13.0%). Multiple mutations within the DNA-damage repair (BRCA2, ATM, BAP1, RAD50, FANCE, PALB2), chromatin remodeling (ARID1A, PBRM1, ARID2, KMT2D, KMT2C, SMARCA4, SETD2), and cell-cycle control pathways (CDKN2A, CCND1, CCNE1) were detected frequently. There was no statistically significant difference in PD-L1 expression between KRAS WT (15.8%) and MT (17%) tumors. However, KRAS WT PDAC were more likely to be MSI-high (4.7% vs. 0.7%; P < 0.05), tumor mutational burden-high (4.5% vs. 1%; P < 0.05), and exhibit increased infiltration of CD8+ T cells, natural killer cells, and myeloid dendritic cells. KRAS WT PDACs exhibited gene fusions of BRAF (6.6%), FGFR2 (5.2%), ALK (2.6%), RET (1.3%), and NRG1 (1.3%), as well as amplification of FGF3 (3%), ERBB2 (2.2%), FGFR3 (1.8%), NTRK (1.8%), and MET (1.3%). Real-world evidence reveals a survival advantage of KRAS WT patients in overall cohorts as well as in patients treated with gemcitabine/nab-paclitaxel or 5-FU/oxaliplatin. KRAS WT PDAC represents 10.7% of PDAC and is enriched with targetable alterations, including immuno-oncologic markers. Identification of KRAS WT patients in clinical practice may expand therapeutic options in a clinically meaningful manner.


Transdifferentiation of neoplastic cells.
Transdifferentiation is a process in which a stable cell's phenotype changes to that of a distinctly different cell type. It occurs during certain physiological processes and leads to transition of tumor cell phenotypes. The latter process includes neoplastic epithelial-epithelial transition, neoplastic epithelial-mesenchymal transition, neoplastic mesenchymal-epithelial transition and transition between non-neural and neural neoplastic cell. This phonomenon is exemplified in some origin-debated tumors, such as carcinosarcoma, pleomorphic adenoma, synovial sarcoma, Ewing's/pPNET, and malignant fibrohistiocytoma. We propose that differentiation disturbance of cancer cells should include not only undifferentiation and dedifferentiation, but also transdifferentiation as well. Tumor cell transdifferentiation may be influenced or determined by cellular genetic instabilities, proliferation and apoptosis, as well as by extracellular matrix and growth factors.


Heterologous expression of WT and mutant photoreceptor peripherin/rds in Madin Darby canine kidney cells: an assessment of fusogenic function.
Peripherin/rds is proposed to function as a fusion protein within the rod outer segment and a fusion domain has been mapped to amino acids 311-325 within the C-terminus. To map regions within peripherin/rds required for membrane fusion a series of C-terminal mutants was analyzed. Madin Darby canine kidney cells were transiently transfected with an Xpress or FLAG epitope tagged peripherin/rds (wt) and three mutants of peripherin/rds. The mutants selected were a P296T mutant (replacement of the proline at position 296 with a threonine) and two C-terminal deletion mutants (one lacking the terminal 10 amino acids, Delta10 and one lacking the terminal 50 amino acids, Delta50). The wt protein, the P296T and Delta10 mutants were detected on SDS-PAGE as 84 kDa dimers, that resolved into 38-42 kDa monomers under reducing conditions. The Delta50 mutant showed a slightly increased mobility. The cellular localization of mutants differed from that of wt peripherin/rds. The wt Xpress-human and wt FLAG-bovine peripherin/rds were localized to both intracellular and plasma membranes. In contrast, the C-terminal deletion mutants were localized only to the intracellular membrane. The P296T mutant presented a still different pattern: initially the protein localized to intracellular membranes. Upon confluence, however, the localization appeared to become predominantly plasma membrane. To assess the fusion activity of the proteins, the cell membranes were fractionated using sucrose density gradient centrifugation and the various fractions identified based on immunoreactivity in Western blot analysis with Golgi (anti-rab 6) or plasma membrane (anti-ZO-3) specific marker proteins. All membrane fractions were assayed for fusion with ROS plasma membrane vesicles. The plasma membrane enriched fractions (isolated at densities of 1.08 and 1.125 g ml(-1)) containing tagged peripherin/rds and the Delta10 mutant promoted membrane fusion with ROS plasma membrane vesicles. In contrast, fusion was not detected with plasma membrane vesicles from mock-transfected cells or the Delta50 peripherin/rds deletion mutant. Fusion was enhanced in a less dense fraction enriched in the P296T mutant (isolated from the 1.04/1.02 interface) relative to wt. Fusion was dependent on the presence of peripherin/rds in the membranes and could be inhibited with trypsinolysis and competition studies with the bovine fusion peptide, PP-5. Peptide competition suggests that the fusion domain of human peripherin/rds is most likely identical to that characterized in bovine and corresponds to amino acid residues 312-326. The C-terminal deletion mutants have allowed us to predict the minimal region of the C-terminus necessary for fusion to include residues starting at number 335. In addition a second region important in the formation of a fusion competent peripherin/rds has been mapped to a region upstream of the fusion peptide domain.


[Women "healthcare" and obstetrics - "thoughts of farewell"].
Medicine, and so within also gynecology and obstetrics is shaped in the process of the last decade by changes of interaction between female-patient and physician in "Arbeitszeitgesetz" (law upon daily working time), the introduction of payment-system an case by case based lump-sums and intrusion (interference) of the political administration into autonomy of medical faculties. The contribution concerns with these prevailing economical required changes, interacting and beyond inter-disciplinarity. The progress in medicine by research is causing potential capacity and secondary costs explosion. Including financing of health service and decisive determinants: the demographic development of society, the change in working sphere and particularly law-dominated prenatal-medicine. This, future of medicine determining political, ethical and legal challenge must be accepted by medical professions. Solutions are pointed out.


Prognostic importance of the Controlling Nutritional Status (CONUT) score in patients undergoing cardiac resynchronisation therapy.
Malnutrition is common and associated with worse clinical outcomes in patients with heart failure (HF). The Controlling Nutritional Status (CONUT) score is an integrated index for evaluating diverse aspects of the complex mechanism of malnutrition. However, the relationship between the severity of malnutrition assessed by the CONUT score and clinical outcomes of HF patients receiving cardiac resynchronisation therapy (CRT) has not been fully clarified. Clinical records of 263 patients who underwent pacemaker or defibrillator implantation for CRT between March 2003 and October 2020 were retrospectively evaluated. The CONUT score was calculated from laboratory data obtained before CRT device implantation. Patients were divided into three groups: normal nutrition (CONUT scores 0-1, n=58), mild malnutrition (CONUT scores 2-4, n=132) and moderate or severe malnutrition (CONUT scores 5-12, n=73). The primary endpoint was all-cause mortality. The moderate or severe malnutrition group had a lower body mass index, more advanced New York Heart Association functional class, higher Clinical Frailty Scale score, lower levels of haemoglobin and higher levels of N-terminal probrain natriuretic peptide (all p<0.05). In the moderate or severe malnutrition group, the CRT response rate was significantly lower than for the other two groups (p=0.001). During a median follow-up period of 31 (10-67) months, 103 (39.1%) patients died. Kaplan-Meier analysis revealed that the moderate or severe malnutrition group had a significantly higher mortality rate (log-rank p<0.001). A higher CONUT score and CONUT score ≥5 remained significantly associated with all-cause mortality after adjusting for previously reported clinically relevant factors and the conventional risk score (VALID-CRT risk score) (all p<0.05). A higher CONUT score before CRT device implantation was strongly associated with HF severity, frailty, lower CRT response rate and subsequent long-term all-cause mortality.


Mental health data available in representative surveys conducted in Latin America and the Caribbean countries: a scoping review.
Mental health data from Latin America and the Caribbean countries (LACC) national and international surveys are essential for public health surveillance. This review aimed to identify and describe available mental health survey data in LACC, providing access details for researchers. Our study was a scoping review. The search for available mental health survey data was conducted in PubMed and through grey literature searches, and the search dates were between 26 August 2021 and 15 October 2021. Included survey data were/had (1) nationally representative, (2) the latest version available from 2012 onward, (3) collected in at least one LACC and (4) at least one mental health variable or related factor. We accepted all written languages, including Spanish and English. A total of 56 national and 13 international surveys were included, with data available on 95 mental health variables classified into 10 categories. Most national surveys were performed in upper-middle-income countries. Variables categorised as 'Substance use' and 'Violence' were the most frequent. Mexico and Colombia had the highest production in both the national and international surveys. The main target population was the adult population. However, there are several mental health topics and LACC yet unsurveyed. We identified a total of 69 representative surveys from LACCs since 2012. We categorised the available data on mental health variables into 10 categories, and provided technical details to facilitate the future selection and use of these surveys.


Stochastic multi-objective auto-optimization for resource allocation decision-making in fixed-input health systems.
The management of hospitals within fixed-input health systems such as the U.S. Military Health System (MHS) can be challenging due to the large number of hospitals, as well as the uncertainty in input resources and achievable outputs. This paper introduces a stochastic multi-objective auto-optimization model (SMAOM) for resource allocation decision-making in fixed-input health systems. The model can automatically identify where to re-allocate system input resources at the hospital level in order to optimize overall system performance, while considering uncertainty in the model parameters. The model is applied to 128 hospitals in the three services (Air Force, Army, and Navy) in the MHS using hospital-level data from 2009 - 2013. The results are compared to the traditional input-oriented variable returns-to-scale Data Envelopment Analysis (DEA) model. The application of SMAOM to the MHS increases the expected system-wide technical efficiency by 18 % over the DEA model while also accounting for uncertainty of health system inputs and outputs. The developed method is useful for decision-makers in the Defense Health Agency (DHA), who have a strategic level objective of integrating clinical and business processes through better sharing of resources across the MHS and through system-wide standardization across the services. It is also less sensitive to data outliers or sampling errors than traditional DEA methods.


Serum creatine kinase levels in pubertal, mature, pregnant, and postmenopausal women.
In order to obtain control values for the diagnosis of carriers of Duchenne muscular dystrophy, creatine kinase (CK) estimations were performed in two laboratories on 148 healthy teenage girls (of whom 38 were premenarchal and 110 postmenarchal), 133 healthy mature women, 124 pregnant women, and 37 postmenopausal women. These levels were highest in the premenarchal teenagers, and became successively lower in the postmenarchal teenagers, the mature women, and the pregnant women, so that the mean level of the pregnant women was less than half that of the teenagers. The CK levels then rose again after the menopause. If the distribution of CK levels in adult non-pregnant women had been taken as controls for teenagers who were possible carriers for Duchenne muscular dystrophy, then one third of those teenagers classified as carriers would have been so classified incorrectly.


Recent developments in d-α-tocopheryl polyethylene glycol-succinate-based nanomedicine for cancer therapy.
Cancer remains an obstacle to be surmounted by humans. As an FDA-approved biocompatible drug excipient, d-α-tocopheryl polyethylene glycol succinate (TPGS) has been widely applied in drug delivery system (DDS). Along with in-depth analyses of TPGS-based DDS, increasingly attractive results have revealed that TPGS is able to act not only as a simple drug carrier but also as an assistant molecule with various bio-functions to improve anticancer efficacy. In this review, recent advances in TPGS-based DDS are summarized. TPGS can inhibit P-glycoprotein, enhance drug absorption, induce mitochondrial-associated apoptosis or other apoptotic pathways, promote drug penetration and tumor accumulation, and even inhibit tumor metastasis. As a result, many formulations, by using original TPGS, TPGS-drug conjugates or TPGS copolymers, were prepared, and as expected, an enhanced therapeutic effect was achieved in different tumor models, especially in multidrug resistant and metastatic tumors. Although the mechanisms by which TPGS participates in such functions are not yet very clear, considering its effectiveness in tumor treatment, TPGS-based DDS appears to be one of the best candidates for future clinical applications.


The historical biogeography of Mammalia.
Palaeobiogeographic reconstructions are underpinned by phylogenies, divergence times and ancestral area reconstructions, which together yield ancestral area chronograms that provide a basis for proposing and testing hypotheses of dispersal and vicariance. Methods for area coding include multi-state coding with a single character, binary coding with multiple characters and string coding. Ancestral reconstruction methods are divided into parsimony versus Bayesian/likelihood approaches. We compared nine methods for reconstructing ancestral areas for placental mammals. Ambiguous reconstructions were a problem for all methods. Important differences resulted from coding areas based on the geographical ranges of extant species versus the geographical provenance of the oldest fossil for each lineage. Africa and South America were reconstructed as the ancestral areas for Afrotheria and Xenarthra, respectively. Most methods reconstructed Eurasia as the ancestral area for Boreoeutheria, Euarchontoglires and Laurasiatheria. The coincidence of molecular dates for the separation of Afrotheria and Xenarthra at approximately 100 Ma with the plate tectonic sundering of Africa and South America hints at the importance of vicariance in the early history of Placentalia. Dispersal has also been important including the origins of Madagascar's endemic mammal fauna. Further studies will benefit from increased taxon sampling and the application of new ancestral area reconstruction methods.


A comparison snapshot of states' small group market reform on access and enhancing valued plan features, 1999.
Small group health insurance statutes of 48 states and the District of Columbia, as of 1999, were reviewed. Reform provisions judged to have some relevance for the market are catalogued and total 74 distinct regulations. Judgment of market relevance was based on actuarial experience at a leading health insurance company. The regulations are categorized under: (1) Access improvement; (2) Pricing and Rating Reforms; (3) Improving stability of coverage; and (4) Improving valued features of plans. The nuances and variety of these regulations, adopted in various combinations by the states, are discussed. The complexity of the reform scenario suggests the need for impact studies that take into account the totality of reform. Past studies have evaluated the impact of selected major reforms in isolation, and, thus, have been inadequate to provide definitive conclusions on the reforms' impact.


Fisher waves: An individual-based stochastic model.
The propagation of a beneficial mutation in a spatially extended population is usually studied using the phenomenological stochastic Fisher-Kolmogorov-Petrovsky-Piscounov (SFKPP) equation. We derive here an individual-based, stochastic model founded on the spatial Moran process where fluctuations are treated exactly. The mean-field approximation of this model leads to an equation that is different from the phenomenological FKPP equation. At small selection pressure, the front behavior can be mapped into a Brownian motion with drift, the properties of which can be derived from the microscopic parameters of the Moran model. Finally, we generalize the model to take into account dispersal kernels beyond migration to nearest neighbors. We show how the effective population size (which controls the noise amplitude) and the diffusion coefficient can both be computed from the dispersal kernel.


EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy.
Glioma, particularly its most malignant form, glioblastoma multiforme (GBM), is the most common and aggressive malignant central nervous system tumor. The drawbacks of the current chemotherapy for GBM have aroused curiosity in the search for targeted therapies. Aberrantly overexpressed epidermal growth factor receptor (EGFR) in GBM results in poor prognosis, low survival rates, poor responses to therapy and recurrence, and therefore EGFR-targeted therapy stands out as a promising approach for the treatment of gliomas. In this context, a series of pentacyclic triterpene analogues were subjected to in vitro and in silico assays, which were conducted to assess their potency as EGFR-targeted anti-glioma agents. In particular, compound 10 was the most potent anti-glioma agent with an IC50 value of 5.82 µM towards U251 human glioblastoma cells. Taking into account its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), compound 10 exerts selective antitumor action towards Jurkat human leukemic T-cells. This compound also induced apoptosis and inhibited EGFR with an IC50 value of 9.43 µM compared to erlotinib (IC50 = 0.06 µM). Based on in vitro and in silico data, compound 10 stands out as a potential orally bioavailable EGFR-targeted anti-glioma agent endowed with the ability to cross the blood-brain barrier (BBB).


Hydrogen bonds of the imidazolium rings of ionic liquids with DMSO studied by NMR, soft X-ray spectroscopy, and SANS.
The hydrogen bonds of the imidazolium-ring H atoms of ionic liquids (ILs), 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amides ([Cnmim][TFSA], n = 2 to 12 where n represents the alkyl chain length), with the O atom of dimethyl sulfoxide (DMSO) have been elucidated using 1H, 13C, and 15N NMR spectroscopy and soft X-ray absorption and emission spectroscopy (XAS and XES). Density functional theory (DFT) calculations have been performed on an isolated DMSO molecule and two cluster models of [Cnmim]+-DMSO by hydrogen bonding to interpret the XES spectra for the [Cnmim][TFSA]-DMSO solutions. The 1H and 13C NMR chemical shifts of the imidazolium ring showed that deshielding of the ring H and C atoms is moderate as the DMSO mole fraction xDMSO increases to ∼0.8; however, it becomes more significant with further increase of xDMSO. This finding suggests that the hydrogen bonds of the three ring H atoms with the DMSO O atoms are saturated in solutions with xDMSO increased to ∼0.8. The 1H and 13C chemical shifts of the alkyl chains revealed that the electron densities of the chain H and C atoms gradually decrease with increasing xDMSO, except for the N1-bound carbon atom C7 of the chain. The 15N NMR chemical shifts showed that the imidazolium-ring N1 atom which is bound to the alkyl chain is shielded with increasing xDMSO in the range from 0 to 0.8 and is then deshielded with further increase of xDMSO. In contrast, the imidazolium ring N3 atom is simply deshielded with increasing xDMSO. Thus, the electron densities of the alkyl chain may be condensed at the C7 and N1 atoms of [Cnmim]+ by the hydrogen bonding of the ring H atoms with DMSO. The hydrogen bonding of DMSO with the ring results in low-energy shifts of the XES peaks of the O K-edge of DMSO. Small-angle neutron scattering experiments showed that [Cnmim][TFSA] and DMSO are homogeneously mixed with each other on the mesoscopic scale. This results from the strong hydrogen bonds of DMSO with the imidazolium-ring H atoms.


A Novel Surfactant-free Lipid-based Formulation for Improving Oral Bioavailability of Loratadine Using Colloidal Silicon Dioxide as Emulsifier and Solid Carrier.
The purpose of this study was to develop an innovative surfactant-free lipidbased formulation (LF) for improving oral bioavailability of loratadine based on using solid particles colloidal silicon dioxide (CSD) as emulsifier and solid carrier. Loratadine was dissolved in oil solution with the aid of co-solvent and LF formulations were prepared by a simple adsorption and milling technique. The LF Powder was evaluated in terms of angle of repose and X-ray powder diffraction. After dispersing and emulsifying in water, the particle size and morphology were also characterized. In vitro dissolution and pharmacokinetic behavior in vivo were also studied. Orthogonal design indicated that the amount of CSD in formulations had a major and significant influence on emulsification. The optimal formulation showed LF with good flowability and without crystallization or deposition of loratadine in it. After dispersing in water, an emulsion with the mean droplet size of 1.2μm was obtained. Although the dissolution of drug from LF was slower in vitro in acidic aqueous solution, pharmacokinetic studies in vivo showed that the bioavailability of loratadine increased 2.49-fold by CF compared to a commercial tablet.


Duration of diabetes and risk of ischemic stroke: the Northern Manhattan Study.
Diabetes increases stroke risk, but whether diabetes status immediately before stroke improves prediction and whether duration is important are less clear. We hypothesized that diabetes duration independently predicts ischemic stroke. Among 3298 stroke-free participants in the Northern Manhattan Study, baseline diabetes and age at diagnosis were determined. Incident diabetes was assessed annually (median, 9 years). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% CI for incident ischemic stroke using baseline diabetes, diabetes as a time-dependent covariate, and duration of diabetes as a time-varying covariate; models were adjusted for demographic and cardiovascular risk factors. Mean age was 69 ± 10 years (52% Hispanic, 21% white, and 24% black); 22% had diabetes at baseline and 10% had development of diabetes. There were 244 ischemic strokes, and both baseline diabetes (HR, 2.5; 95% CI, 1.9-3.3) and diabetes considered as a time-dependent covariate (HR, 2.4; 95% CI, 1.8-3.2) were similarly associated with stroke risk. Duration of diabetes was associated with ischemic stroke (adjusted HR, 1.03 per year with diabetes; 95% CI, 1.02-1.04). Compared to nondiabetic participants, those with diabetes for 0 to 5 years (adjusted HR, 1.7; 95% CI, 1.1-2.7), 5 to 10 years (adjusted HR, 1.8; 95% CI, 1.1-3.0), and ≥ 10 years (adjusted HR, 3.2; 95% CI, 2.4-4.5) were at increased risk. Duration of diabetes is independently associated with ischemic stroke risk adjusting for risk factors. The risk increases 3% each year, and triples with diabetes ≥ 10 years.


Duodenal wedge resection for large gastrointestinal stromal tumour presenting with life-threatening haemorrhage.
Background. Duodenal gastrointestinal stromal tumours (GISTs) are an uncommon malignancy of the gastrointestinal (GI) tract. We present a case of life-threatening haemorrhage caused by a large ulcerating duodenal GIST arising from the third part of the duodenum managed by a limited duodenal wedge resection. Case Presentation. A 61-year-old patient presented with acute life-threatening gastrointestinal bleeding. After oesophagogastroduodenoscopy failed to demonstrate the source of bleeding, a 5 cm ulcerating exophytic mass originating from the third part of the duodenum was identified at laparotomy. A successful limited wedge resection of the tumour mass was performed. Histopathology subsequently confirmed a duodenal GIST. The patient remained well at 12-month followup with no evidence of local recurrence or metastatic spread. Conclusion. Duodenal GISTs can present with life-threatening upper GI haemorrhage. In the context of acute haemorrhage, even relatively large duodenal GISTs can be treated by limited wedge resection. This is a preferable alternative to duodenopancreatectomy with lower morbidity and mortality but comparable oncological outcome.


Somatoform disorders in Caucasian and Chinese Americans.
Somatization, broadly defined as the presentation of one or more medically unexplained somatic symptoms, refers both to the presentation of somatic symptoms in diagnosable psychiatric disorders such as major depression or anxiety as well as to the presentation of such symptoms in somatoform disorders. Although no comparative data exist, somatization is considered by many clinical investigators to be more common among Chinese than Caucasian patients, but it is unclear if this occurs because somatoform disorders are more prevalent among the Chinese or because Chinese patients with major depression or anxiety more often present with somatic complaints. We examined 85 consecutive Chinese American and 85 consecutive Caucasian American patients referred for psychiatric consultation and found the following: a) True somatization was significantly more common among Chinese American patients referred for psychiatric consultation; b) The somatoform symptom profiles of the two cohorts were different: Chinese American somatizers complained predominantly of cardiopulmonary and vestibular symptoms, whereas their Caucasian counterparts had symptoms that corresponded well with the categories listed in DSM-IV; c) In both cohorts of somatizers, a concurrent psychiatric disorder, most commonly major depression, was almost always present; and d) Among the Chinese American somatizers, pseudoneurological symptoms occurred most commonly in the form of abnormal sensations, whereas abnormal motor functions were more common among Caucasian Americans. Implications of the findings with respect to pathogenesis, treatment, and classification of somatization are discussed.


Comparative genomics identifies male accessory gland proteins in five Glossina species.
Accessory gland proteins (ACPs) are important reproductive proteins produced by the male accessory glands (MAGs) of most insect species. These proteins are essential for male insect fertility, and are transferred alongside semen to females during copulation. ACPs are poorly characterized in Glossina species (tsetse fly), the principal vector of the parasite that causes life-threatening Human African Trypanosomiasis and Animal trypanosomiasis in endemic regions in Africa. The tsetse fly has a peculiar reproductive cycle because of the absence of oviposition. Females mate once and store sperm in a spermathecal, and produce a single fully developed larva at a time that pupates within minutes of exiting their uterus. This slow reproductive cycle, compared to other insects, significantly restricts reproduction to only 3 to 6 larvae per female lifespan. This unique reproductive cycle is an attractive vector control strategy entry point. We exploit comparative genomics approaches to explore the diversity of ACPs in the recently available whole genome sequence data from five tsetse fly species ( Glossina morsitans, G. austeni, G. brevipalpis, G. pallidipes and G. fuscipes). We used previously described ACPs in Drosophila melanogaster and Anopheles gambiae as reference sequences. We identified 36, 27, 31, 29 and 33 diverse ACP orthologous genes in G. austeni, G. brevipalpis, G. fuscipes, G. pallidipes and G. morsitans genomes respectively, which we classified into 21 functional classes. Our findings provide genetic evidence of MAG proteins in five recently sequenced Glossina genomes. It provides new avenues for molecular studies that evaluate potential field control strategies of these important vectors of human and animal disease.


Galuminox: Preclinical validation of a novel PET tracer for non-invasive imaging of oxidative stress in vivo.
Overproduction of reactive oxygen species (ROS) is a well-established indicator of ongoing tissue inflammation. However, there is a scarcity of molecular imaging probes capable of providing noninvasive sensitive detection of ROS for allowing longitudinal studies of disease pathology and/or monitoring therapeutic efficacy of ROS scavengers. Herein, we report synthesis and chemical characterization of a novel metalloprobe, Galuminox, a moderately fluorescent agent that detects superoxide and hydrogen peroxide generation. Using live-cell fluorescence imaging analysis, Galuminox demonstrates ability to detect superoxide and monitor effects of ROS-attenuating agents, such as Carvedilol, Dexrazoxane, and mitoTempo in lung epithelial A549 cells. Furthermore, LPS stimulation of A549 cells that either express the mitochondria targeted fluorescent protein Keima or are stained with MitoSOX, a mitochondria-specific superoxide probe, indicates preferential co-localization of Galuminox with mitochondria producing elevated amounts of superoxide. Dynamic PET/CT scans 45 min post tail-vein administration of 68Ga-Galuminox show 4-fold higher uptake and stable retention in lungs of LPS treated mice compared to their saline-only treated counterparts. Post preclinical PET imaging, quantitative biodistribution studies also correlate with 4-fold higher retention of the radiotracer in lungs of LPS treated mice compared with their saline-only treated control counterparts. Consistent with these observations, lung cells isolated from LPS-treated mice demonstrated elevated ROS production deploying CellROX, the ROS probe. Finally, Galuminox uptake correlates with histological and physiological evidence of acute lung injury as evident by polynuclear infiltration, thickening of the alveolar epithelial membranes and increased bronchioalveolar lavage protein content. Taken collectively, these data indicate that 68Ga-Galuminox tracer uptake is a measure of ROS activity in acutely injured lungs and suggests its potential utility in monitoring oxidative stress in other diseases.


Lens-forming competence in the epidermis of Xenopus laevis during development.
In larval X. laevis the capacity to regenerate a lens under the influence of inductive factors present in the vitreous chamber is restricted to the outer cornea and pericorneal epidermis (Lentogenic Area, LA). However, in early embryos, the whole ectoderm is capable of responding to inductive factors of the larval eye forming lens cells. In a previous paper, Cannata et al. (2003) demonstrated that the persistence of lens-forming competence in the LA is the result of early signals causing lens-forming bias in the presumptive LA and of late signals from the eye causing cornea development. This paper analyzes 1) the decrease of the lens-forming capacity in ectodermal regions both near LA (head epidermis) and far from LA (flank epidermis) during development, 2) the capacity of the head epidermis and flank epidermis to respond to lens-competence promoting factors released by an eye transplanted below these epidermal regions, and 3) the eye components responsible for the promoting effect of the transplanted eye. Results were obtained by implanting fragments of ectoderm or epidermis into the vitreous chamber of host tadpoles and by evaluating the percentage of implants positive to a monoclonal antibody anti-lens. These results demonstrated that the lens-forming competence in the flank region is lost at the embryonic stage 30/31 and is weakly restored by eye transplantation; however, lens-forming competence in the head region is lost at the larval stage 48 and is strongly restored by eye transplantation. The authors hypothesize that during development the head ectoderm outside the LA is attained by low levels of the same signals that attain the LA and that these signals are responsible for the maintenance of lens-forming competence in the cornea and pericorneal epidermis of the larva. In this hypothesis, low levels of these signals slacken the decrease of the lens-forming competence in the head ectoderm and make the head epidermis much more responsive than the flank epidermis to the effect of promoting factors released by a transplanted eye. Results obtained after transplantation of eyes deprived of some components indicate that the lens and the retina are the main source of these promoting factors. The immunohistochemical detection of the FGFR-2 (bek variant) protein in the epidermis of stage 53 larvae submitted to eye transplantation at stage 46 showed that the eye transplantation increased the level of FGFR-2 protein in the head epidermis but not in the flank epidermis, indicating that the lens-forming competence in X. laevis epidermis could be related to the presence of an activated FGF receptor system in the responding tissue.


Social Media, E-Health, and Medical Ethics.
Given the profound influence of social media and emerging evidence of its effects on human behavior and health, bioethicists have an important role to play in the development of professional standards of conduct for health professionals using social media and in the design of online systems themselves. In short, social media is a bioethics issue that has serious implications for medical practice, research, and public health. Here, we inventory several ethical issues across four areas at the intersection of social media and health: the impact of social networking sites on the doctor-patient relationship, the development of e-health platforms to deliver care, the use of online data and algorithms to inform health research, and the broader public health consequences of widespread social media use. In doing so, we review discussions of these topics and emphasize the need for bioethics to focus more deeply on the ways online technology platforms are designed and implemented. We argue that bioethicists should turn their attention to the ways in which consumer engagement, bias, and profit maximization shape online content and, consequently, human behavior and health. We also offer a set of recommendations and suggest future directions for addressing ethical challenges in these domains.


Human prion diseases with variant prion protein.
Recent molecular genetic studies revealed that the human prion protein (PrP) gene has a large repertoire of polymorphisms and mutations. Each variant PrP seems to correspond to a distinct type of prion diseases. We report herein that it is useful to classify prion diseases into plaque type or non-plaque type, based on the distribution of PrP in the central nervous system. The variant PrP including codon 102, codon 105, codon 129, codon 145 and insertional polymorphisms belong to the plaque type prion diseases, whereas the wild-type PrP and the variants including codon 180, codon 200, and codon 232 polymorphisms belong to the non-plaque type. The non-plaque type prion diseases showed a rapidly progressive dementia, myoclonus and periodic synchronous discharges in the electroencephalogram, and in the pathological findings diffuse grey matter PrP accumulations including the synaptic structures. The plaque type prion diseases showed a long clinical course without myoclonus and periodic synchronous discharges, and the major PrP accumulation sites were extracellular PrP plaques. The distribution of PrP deposits in the central nervous system influences the clinical and pathological aspects of prion diseases. Thus, PrP accumulations may play a central role in the pathogenesis of prion diseases.


Skin tightening-does it really exist?
Skin tightening is one of the cornerstones of skin rejuvenation and is defined as the improvement of skin laxity and crepiness of the skin. There are several energy-based devices that can produce significant skin tightening without surgery, both on and off the face. The mechanisms of skin tightening involve collagen denaturation resulting in collagen shrinkage and tissue tightening, and the wound healing response that generates new collagen and elastin. These hypothesized mechanisms of skin contraction leading to clinical skin tightening have been derived from histological, immunohistochemical, and electron microscope analysis, as well as in vitro and in vivo experiments. This review is aimed at evaluating and analyzing the literature on the proposed mechanisms for skin tightening by minimally invasive energy-based technologies.


HIV seroprevalence among patients admitted to two psychiatric hospitals.
The authors determined the seroprevalence of HIV-1 among patients admitted to two psychiatric hospitals in New York City. Patients consecutively admitted to an acute psychiatric unit in Manhattan and a large state hospital in Queens were anonymously tested for HIV-1 antibodies from December 1989 through July 1990. Test results were linked to age, gender, ethnicity, and two risk behaviors: male homosexual activity and injection drug use. Blood was obtained from 83.0% of the eligible patients. The prevalence of HIV was 5.5% (25 of 451). Black patients accounted for 38.0% of the patients tested and 76.0% of positive results (N = 19), a rate of 11.1% for this group. The rate of seropositivity was comparable in women and men. Clinicians had charted risk behavior for nine (36.0%) of the 25 HIV-positive patients. Infection control records suggested that clinicians were aware of seven (28.0%) of the positive cases. One in every 18 patients admitted to two public psychiatric hospitals in New York City was HIV positive. Clinical staff largely failed to identify HIV-positive patients. Ethnicity and a history of homosexual activity among men or use of injected drugs were strongly associated with seropositivity. This pattern of infection may be linked to needle sharing and/or sexual activity with partners who have shared needles. Future research should clarify how psychiatric illness affects risk-taking behavior, focus on improving detection by clinicians, and identify effective prevention strategies in this population.


Prevalence of hand dermatoses among Finnish farmers.
The goal of this study was to determine the prevalence and risk factors of hand dermatosis among farmers. A questionnaire survey was carried out in a geographically defined sample of the Finnish farming population between the ages of 18 and 64 years (N = 10,847). The one-year prevalence of self-reported hand and forearm dermatoses was 16% for the women and 7% for the men. These figures were similar to the prevalence of hand eczema in two large Scandinavian questionnaire surveys. The highest one-year prevalence of hand dermatoses was found for women on farms with more than nine dairy cows (20%). Atopy (both the personal history of atopic dermatitis and respiratory atopy), female gender, and, among the women, also age under 35 years were the most important risk factors for the occurrence of hand dermatosis. Work-related risk factors were handling disinfectants daily, handling silage preservatives, milking cows, and machine servicing. Occupational risk factors for hand dermatoses were found, especially for dairy farming. The results may be useful for the prevention of hand dermatoses in farming since they direct attention to related occupational hazards, and they may also aid vocational guidance for the atopic population. In order to lower the prevalence of hand dermatoses in dairy farming, both preventive and protective measures should become everyday practice in farming work.


Non-valvular Atrial Fibrillation in CKD: Role of Vitamin K Antagonists and Direct Oral Anticoagulants. A Narrative Review.
Atrial fibrillation (AF) is the most common arrhythmia in chronic kidney disease (CKD), with a close bidirectional relationship between the two entities. The presence of CKD in AF increases the risk of thromboembolic events, mortality and bleeding. Vitamin K antagonists (VKA) have been the mainstay of treatment for the prevention of thromboembolic events in AF until recently, with confirmed benefits in AF patients with stage 3 CKD. However, the risk-benefit profile of VKA in patients with AF and stages 4-5 CKD is controversial due to the lack of evidence from randomized controlled trials. Treatment with VKA in CKD patients has been associated with conditions such as poorer anticoagulation quality, increased risk of bleeding, faster progression of vascular/valvular calcification and higher risk of calciphylaxis. Direct oral anticoagulants (DOACs) have shown equal or greater efficacy in stroke/systemic embolism prevention, and a better safety profile than VKA in post-hoc analysis of the pivotal randomized controlled trials in patients with non-valvular AF and stage 3 CKD, yet evidence of its risk-benefit profile in more advanced stages of CKD is scarce. Observational studies associate DOACs with a good safety/effectiveness profile compared to VKA in non-dialysis CKD patients. Further, DOACs have been associated with a lower risk of acute kidney injury and CKD development/progression than VKA. This narrative review summarizes the evidence of the efficacy and safety of warfarin and DOACs in patients with AF at different CKD stages, as well as their effects on renal function, vascular/valvular calcification and bone health.


[Epicardial mapping in the syndrome of premature ventricular excitation. 2].
Epicardial mapping was carried out in 20 patients suffering from Wolff-Parkinson-White's syndrome with supraventricular tachycardias resistant to drug therapy. The automated mapping system elaborated at the A.N. Bakulev Cardiovascular Surgery Institute and a modified method of epicardial mapping made it possible to radically eliminate additional routes of conduction in 91% of cases.


Intracellular gradients of O2 supply to mitochondria in actively respiring single cardiomyocyte of rats.
We demonstrated in a previous study [Takahashi, E., K. Sato, H. Endoh, Z.-L. Xu, and K. Doi. Am. J. Physiol. 275 (Heart Circ. Physiol. 44): H225-H233, 1998] that significant radial gradients of intracellular PO2 may be produced in an uncoupled actively respiring, single isolated cardiomyocyte of the rat. The present study was designed to further determine whether such intracellular PO2 gradients can be a limiting factor of oxidative metabolism in uncoupled cardiomyocytes. The NAD(P)H fluorescence of a single cardiomyocyte was captured by a digital charge-coupled device camera and quantitated with a subcellular spatial resolution by a ratio-imaging technique. In the conditions that we demonstrated significant radial PO2 gradients (cells treated with 1 microM carbonyl cyanide m-chlorophenylhydrazone and superfused with 2.09% or 3.14% O2 gas at 27 degreesC), we demonstrated significant augmentation of NAD(P)H fluorescence near the core of an individual cell. The heterogeneous fluorescence pattern was not found in the control cell, whereas fluorescence intensity averaged over the cell was increased by hypoxia. These results suggest the possibility that oxidative phosphorylation near the core of actively respiring, uncoupled cardiomyocytes may be severely suppressed due to insufficient diffusional oxygen supply (hypoxic core) even if regions near the sarcolemma are adequately oxygenated.


Changes in intestinal fluid and mucosal immune responses to cholera toxin in Giardia muris infection and binding of cholera toxin to Giardia muris trophozoites.
The effect of Giardia muris infection on the diarrheal response and gut mucosal antibody response to cholera toxin was examined in mice. The results obtained showed that the fluid accumulation in intestinal loops exposed to cholera toxin was increased in mice infected with a low number (5 X 10(4) ) of G. muris cysts compared with the response in noninfected mice. This effect was associated with a marked reduction in absorption of oral rehydration fluid from the intestine. In contrast, mice infected with a high dose (2 X 10(5) ) of cysts showed a marked decrease in fluid accumulation in response to the toxin. This decrease might be related to the finding that both G. muris and Giardia lamblia trophozoites can bind significant amounts of cholera toxin. Evidence is presented which suggests that the gut mucosal antibody response, mainly immunoglobulin A but also immunoglobulin G, to an immunization course with perorally administered cholera toxin was depressed in mice infected with G. muris. The reduction in antibody levels was particularly evident when the primary immunization was made very early after infection. The serum antitoxin antibodies to the oral immunization with cholera toxin were, however, not affected. Likewise, the delayed-type hypersensitivity response against sheep erythrocytes in animals primed subcutaneously with sheep erythrocytes was not modified during the course of G. muris infection.


[The immunological reactivity indices of patients with chronic nonspecific lung diseases].
At height of the disease patients with chronic bronchitis showed a reduction of immunological indices of reactivity of the body. A direct dependence was established between the severity of the course of the disease and degree of reactivity reduction. Absence of complete normalization of indices of immunological reactivity at discharge from the clinic indicates incomplete control of the inflammatory process and short-term character of the remission. The reaction of lymphocyte blast transformation may be used for detection of both latent and clinically manifest staphylococcal infection. Increased sensitivity to staphylococcal allergen results in a reduction of the phagocytic activity of neutrophils in patients with chronic bronchitis.


Interaction of Staphylococcus aureus and Host Cells upon Infection of Bronchial Epithelium during Different Stages of Regeneration.
The primary barrier that protects our lungs against infection by pathogens is a tightly sealed layer of epithelial cells. When the integrity of this barrier is disrupted as a consequence of chronic pulmonary diseases or viral insults, bacterial pathogens will gain access to underlying tissues. A major pathogen that can take advantage of such conditions is Staphylococcus aureus, thereby causing severe pneumonia. In this study, we investigated how S. aureus responds to different conditions of the human epithelium, especially nonpolarization and fibrogenesis during regeneration using an in vitro infection model. The infective process was monitored by quantification of the epithelial cell and bacterial populations, fluorescence microscopy, and mass spectrometry. The results uncover differences in bacterial internalization and population dynamics that correlate with the outcome of infection. Protein profiling reveals that, irrespective of the polarization state of the epithelial cells, the invading bacteria mount similar responses to adapt to the intracellular milieu. Remarkably, a bacterial adaptation that was associated with the regeneration state of the epithelial cells concerned the early upregulation of proteins controlled by the redox-responsive regulator Rex when bacteria were confronted with a polarized cell layer. This is indicative of the modulation of the bacterial cytoplasmic redox state to maintain homeostasis early during infection even before internalization. Our present observations provide a deeper insight into how S. aureus can take advantage of a breached epithelial barrier and show that infected epithelial cells have limited ability to respond adequately to staphylococcal insults.


Nonequilibrium molecular dynamics simulation of gas-mixtures transport in carbon-nanopore membranes.
The numerical simulation of nonequilibrium cotransport of H2 and alkane gas mixtures with very different molecular sizes through a porous carbon membrane structure was implemented. Simulated permeabilities and selectivities in binary diffusive systems (and in one ternary system), at pressure about tens of atmospheres and at operating condition of room temperature or higher, can be predicted from single-gas permeabilities. This suggests that the effect is geometrical and an approximate model of the transport is proposed. It can be used for an estimation of the separation factor of a membrane. Simulations are compared with experimental results of two- and three-component codiffusion and counterdiffusion in a carbon membrane. It is shown that diffusion in a porous molecular network and in a carbon nanotube are completely different. The uniqueness of this work lies in the comparison of simulated, approximate, and experimental results, which enables us to identify the important parameters.


[Medullary thyroid cancer, a tumour with many appearances].
Medullary thyroid cancer (MTC) has a variable clinical presentation. We present 3 patients with this endocrine tumour. The first patient, a 41-year-old woman complaining of diarrhoea, a painful abdomen, weight loss and sensibility disorders in both legs, had metastases of MTC in the spine, with little progression during 2 years of follow-up. The second patient, a 64-year-old woman suffering from a painful nodule in the neck and a painful shoulder, was diagnosed with MTC and liver, lung and bone metastases. She died after 14 months due to progressive disease. The third patient, an 81-year-old woman with hyperparathyroidism, was coincidentally diagnosed with MTC after goitre surgery at the age of 67. When she was evaluated for rising calcitonin levels, a pheochromocytoma was found. RET mutation analysis confirmed a MEN2A syndrome. Current diagnostic procedures of MTC may include positron emission tomography with 18F-deoxyglucose (FDG-PET) and 18F-diphenylalanine (DOPA-PET). MTC is usually treated surgically. Tyrosine kinase inhibitors appear to offer potential new therapeutic possibilities.


White matter microstructure correlates of mathematical giftedness and intelligence quotient.
Recent functional neuroimaging studies have shown differences in brain activation between mathematically gifted adolescents and controls. The aim of this study was to investigate the relationship between mathematical giftedness, intelligent quotient (IQ), and the microstructure of white matter tracts in a sample composed of math-gifted adolescents and aged-matched controls. Math-gifted subjects were selected through a national program based on detecting enhanced visuospatial abilities and creative thinking. We used diffusion tensor imaging to assess white matter microstructure in neuroanatomical connectivity. The processing included voxel-wise and region of interest-based analyses of the fractional anisotropy (FA), a parameter which is purportedly related to white matter microstructure. In a whole-sample analysis, IQ showed a significant positive correlation with FA, mainly in the corpus callosum, supporting the idea that efficient information transfer between hemispheres is crucial for higher intellectual capabilities. In addition, math-gifted adolescents showed increased FA (adjusted for IQ) in white matter tracts connecting frontal lobes with basal ganglia and parietal regions. The enhanced anatomical connectivity observed in the forceps minor and splenium may underlie the greater fluid reasoning, visuospatial working memory, and creative capabilities of these children.


[Efficient risk management].
Probably dentists will be sued more and more by patients because of errors. An adequate professionalism, good social abilities, some juridic knowledge and a comprehensive administration are the tools to prevent loss of money and psychological problems.


Association between variants of IL-8 and IL-10 genes, and efficacy of transcatheter arterial chemoembolization and subsequent prognosis in patients with liver cancer.
Our objective was to examine the association between single nucleotide polymorphisms of interleukin (IL)-8 (rs4073 and rs2227306) and IL-10 (rs1800871 and rs1800872) genes, and clinical effects of transcatheter arterial chemoembolization (TACE) and subsequent prognosis in patients with liver cancer. 115 patients with liver cancer underwent TACE. Venous blood specimens were collected for genomic DNA extraction. The restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) analysis was used to detect the above variants of IL-8 and IL-10 genes. In addition, blood levels of alpha fetal protein (AFP) were quantified by radioimmunoassay. Patients were followed up to uncover the association of the above genotypes with treatment efficacy and survival. Patients with the homozygous genotype AA or homozygous genotype TT (respectively, -251 and +781 sites) of IL-8 gene, and wild-type genotype TT or homozygous genotype AA (respectively, -819 and -592 sites) of IL-10 gene showed the best effectiveness of TACE. Furthermore, these patients also exhibited the lowest AFP levels and the longest survival after the treatment. Clinical efficacy of TACE and patient survival in liver cancer are associated with specific variants of IL-8 and IL-10 genes.


Postnatal development of calcium-binding proteins calbindin and parvalbumin in human visual cortex.
In adult primate visual cortex, the calcium-binding proteins calbindin (CB) and parvalbumin (PV) are localized in different subsets of GABAergic neurons with a characteristic laminar distribution. However, the emergence and development of CB and PV in relation to the periods of functional maturation of the human visual cortex are not known. Therefore, we examined (i) postnatal changes in the distribution of immunoreactivity (ir) for CB and PV in the visual cortex; (ii) the pattern of changes in immunoreactivity in relation to the synaptic maturation; and (iii) differences in the maturation of CB and PV immunoreactivity between areas 17 and 18. We found a consistently high expression of CB in neonatal visual cortex, particularly in layer IV and infragranular layers. However, despite an early appearance of PV, its peak in development occurred only after 2 months of age, characterized by a transient overexpression in the thalamo-recipient layer IV and a continuous inside-out maturation in supragranular layers. The neonatal pattern of high CB-ir in layers IV-VI was transformed during infancy and childhood into an adult pattern of high CB-ir in layer II, but low CB-ir in layer IV and infragranular layers. There was no difference in pattern and tempo of maturation of calcium-binding proteins between area 17 and 18, indicating simultaneous development of cortical inhibitory circuits among cytoarchitectonically and functionally distinct cortical areas. In addition, the reorganization of CB/PV expression temporally and spatially coincides with the course of cortical synaptogenesis, and delineates the major stages of maturation of the human visual cortex.


Double-Blind Prospective Randomized Controlled Trial of Dopamine Versus Epinephrine as First-Line Vasoactive Drugs in Pediatric Septic Shock.
The primary outcome was to compare the effects of dopamine or epinephrine in severe sepsis on 28-day mortality; secondary outcomes were the rate of healthcare-associated infection, the need for other vasoactive drugs, and the multiple organ dysfunction score. Double-blind, prospective, randomized controlled trial from February 1, 2009, to July 31, 2013. PICU, Hospital Universitário da Universidade de São Paulo, Brazil. Consecutive children who are 1 month to 15 years old and met the clinical criteria for fluid-refractory septic shock. Exclusions were receiving vasoactive drug(s) prior to hospital admission, having known cardiac disease, having already participated in the trial during the same hospital stay, refusing to participate, or having do-not-resuscitate orders. Patients were randomly assigned to receive either dopamine (5-10 μg/kg/min) or epinephrine (0.1-0.3 μg/kg/min) through a peripheral or intraosseous line. Patients not reaching predefined stabilization criteria after the maximum dose were classified as treatment failure, at which point the attending physician gradually stopped the study drug and started another catecholamine. Physiologic and laboratory data were recorded. Baseline characteristics were described as proportions and mean (± SD) and compared using appropriate statistical tests. Multiple regression analysis was performed, and statistical significance was defined as a p value of less than 0.05. Baseline characteristics and therapeutic interventions for the 120 children enrolled (63, dopamine; 57, epinephrine) were similar. There were 17 deaths (14.2%): 13 (20.6%) in the dopamine group and four (7%) in the epinephrine group (p=0.033). Dopamine was associated with death (odds ratio, 6.5; 95% CI, 1.1-37.8; p=0.037) and healthcare-associated infection (odds ratio, 67.7; 95% CI, 5.0-910.8; p=0.001). The use of epinephrine was associated with a survival odds ratio of 6.49. Dopamine was associated with an increased risk of death and healthcare-associated infection. Early administration of peripheral or intraosseous epinephrine was associated with increased survival in this population. Limitations should be observed while interpreting these results.


Methylene blue modulates transendothelial migration of peripheral blood cells.
Vasoplegia is a severe complication after cardiac surgery. Within the last years the administration of nitric oxide synthase inhibitor methylene blue (MB) became a new therapeutic strategy. Our aim was to investigate the role of MB on transendothelial migration of circulating blood cells, the potential role of cyclic cGMP, eNOS and iNOS in this process, and the influence of MB on endothelial cell apoptosis. Human vascular endothelial cells (HuMEC-1) were treated for 30 minutes or 2 hours with different concentrations of MB. Inflammation was mimicked by LPS stimulation prior and after MB. Transmigration of PBMCs and T-Lymphocytes through the treated endothelial cells was investigated. The influence of MB upon the different subsets of PBMCs (Granulocytes, T- and B-Lymphocytes, and Monocytes) was assessed after transmigration by means of flow-cytometry. The effect of MB on cell apoptosis was evaluated using Annexin-V and Propidium Iodide stainings. Analyses of the expression of cyclic cGMP, eNOS and iNOS were performed by means of RT-PCR and Western Blot. Results were analyzed using unpaired Students T-test. Analysis of endothelial cell apoptosis by MB indicated a dose-dependent increase of apoptotic cells. We observed time- and dose-dependent effects of MB on transendothelial migration of PBMCs. The prophylactic administration of MB led to an increase of transendothelial migration of PBMCs but not Jurkat cells. Furthermore, HuMEC-1 secretion of cGMP correlated with iNOS expression after MB administration but not with eNOS expression. Expression of these molecules was reduced after MB administration at protein level. This study clearly reveals that endothelial response to MB is dose- and especially time-dependent. MB shows different effects on circulating blood cell-subtypes, and modifies the release patterns of eNOS, iNOS, and cGMP. The transendothelial migration is modulated after treatment with MB. Furthermore, MB provokes apoptosis of endothelial cells in a dose/time-dependent manner.


Transcutaneous partial oxygen pressure changes following skew flap and Burgess-type below-knee amputations.
To evaluate the degree of flap hypoxia following different types of below-knee amputations. Prospective preoperative and postoperative measurements of transcutaneous partial oxygen pressure (TcPo2) at the site of amputation in 10 consecutive patients who underwent a Burgess-type below-knee amputation (group 1) and in 10 consecutive patients who underwent a skew flap amputation (group 2). An academic, tertiary care Veterans Affairs medical center. Individuals with severe arterial occlusive disease of the lower extremity, in many of whom vascular reconstruction has failed. Measurements of TcPo2 (in millimeters of mercury). The decrease in TcPo2 associated with the different "flaps" of a Burgess-type below-knee amputation. In all skin flaps, regardless of the type of amputation, an early postoperative reduction of the TcPo2 was noted. The greatest reduction (11 mm Hg) and persistence at 20 postoperative days were noted in posterior flaps. Strict conformity to the Burgess-type of below-knee flap design may not provide an optimal incisional blood supply. Consideration should be given to the skew flap technique in patients who require amputation for severe lower limb arterial insufficiency.


Oncogenic Osteomalacia Secondary to a Metastatic Phosphaturic Mesenchymal Tumor in the Talus: A Case Report and Review of the Literature.
We report the case of a 50-year-old woman with oncogenic osteomalacia secondary to a metastatic phosphaturic mesenchymal tumor (PMT) that presented, to our knowledge, with the first reported lesion in the talus. Oncogenic osteomalacia is a rare condition with a unique serum biochemical profile that requires a high index of suspicion for diagnosis. A PMT is a rare neoplasm that can lead to oncogenic osteomalacia through secretion of fibroblast growth factor 23. Symptoms can be debilitating, and diagnostic delays are extremely common. This case report emphasizes the importance of comprehensive anatomic assessment and the need for fastidious postoperative monitoring.


The earthworm Dendrobaena veneta (Annelida): A new experimental-organism for photobiomodulation and wound healing.
Photobiomodulation (PBM) is a manipulation of cellular behavior using non-ablative low intensity light sources. This manipulation triggers a cascade of metabolic effects and physiological changes resulting in improved tissue repair, of benefit in the treatment of tissue injury, degenerative or autoimmune diseases. PBM has witnessed an exponential increase in both clinical instrument technology and applications. It is therefore of benefit to find reliable experimental models to test the burgeoning laser technology for medical applications. In our work, we proposed the earthworm Dendrobaena veneta for the study of non-ablative laser-light effects on wound healing. In our preliminary work, D. veneta has been shown to be positively affected by PBM. New tests using D. veneta were set up to evaluate the effectiveness of a chosen 808 nm-64 J/cm2-1W-CW laser therapy using the AB2799 hand-piece with flat-top bean profile, on the wound healing process of the earthworm. Effective outcome was assimilated through examining the macroscopic, histological, and molecular changes on the irradiated posterior-segment of excised-earthworms with respect to controls. Three successive treatments, one every 24 hours, were concluded as sufficient to promote the wound healing, by effects on muscular and blood vessel contraction, decrement of bacteria load, reduction of inflammatory processes and tissue degeneration. D. veneta was demonstrated to be a reliable experimental organism that meets well the 3Rs principles and the National Science Foundation statement. Through their genetic and evolutionary peculiarity, comparable to those of scientifically accredited models, D. veneta allows the effect of laser therapies by multidisciplinary methods, at various degree of complexity and costs to be investigated.


A new approach to categorization of radiologic inflammation in chronic rhinosinusitis.
Chronic rhinosinusitis (CRS) is a prevalent condition. Clinical diagnosis requires subjective evidence (i.e. symptoms) and objective evidence of inflammation (e.g. sinus computed tomography [CT]). Few studies have assessed differences in common CT scoring approaches for CRS, the Lund-Mackay (LM) system and its modified version (mLM); none in a general population sample. The aims of this study were to answer the following: (1) Is mLM superior to LM? (2) Should nasal cavity opacification be included in scoring? (3) How should location-specific scores be utilized? (4) If location-specific scores are summed, what should be the cutoff? (5) Are associations of opacification with symptoms observed when using different measurement approaches? We scored sinus CTs using LM and mLM from 526 subjects selected from a larger CRS study. Exploratory factor analysis (EFA) assessed similarity of mLM and LM. Latent class analysis (LCA) identified subgroups of sinus opacification patterns. Factors associated with group membership and relations with nasal and sinus symptoms (NSS) guided clinical relevance. EFA suggested no differences between LM and mLM, or after addition of nasal cavity opacification. LCA identified three opacification groups: no/mild, localized, and diffuse. Males were 2.7x more likely to have diffuse opacification than females, as were those with asthma or hay fever. A LM cutoff of 3 had similar performance to the currently used 4. Diffuse opacification was associated with nasal blockage and smell loss. Differing patterns of opacification may be clinically relevant, improving measurement of objective evidence in studies of CRS and sinus diseases.


Reduced HDL particle size as an additional feature of the atherogenic dyslipidemia of abdominal obesity.
Reduced plasma HDL cholesterol concentration has been associated with an increased risk of coronary heart disease. However, a low HDL cholesterol concentration is usually not observed as an isolated disorder because this condition is often accompanied by additional metabolic alterations. The objective of this study was to document the relevance of assessing HDL particle size as another feature of the atherogenic dyslipidemia found among subjects with visceral obesity and insulin resistance. For that purpose, an average HDL particle size was computed by calculating an integrated HDL particle size using nondenaturing 4-30% gradient gel electrophoresis. Potential associations between this average HDL particle size versus morphometric and metabolic features of visceral obesity were examined in a sample of 238 men. Results of this study indicated that HDL particle size was a significant correlate of several features of an atherogenic dyslipidemic profile such as increased plasma TG, decreased HDL cholesterol, high apolipoprotein B, elevated cholesterol/HDL cholesterol ratio, and small LDL particles as well as increased levels of visceral adipose tissue (AT) (0.33 < or = absolute value of r < or = 0.61, P < 0.0001). Thus, men with large HDL particles had a more favorable plasma lipoprotein-lipid profile compared with those with smaller HDL particles. Furthermore, men with large HDL particles were also characterized by reduced overall adiposity and lower levels of visceral AT as well as reduced insulinemic-glycemic responses to an oral glucose load. In conclusion, small HDL particle size appears to represent another feature of the high TG- low HDL cholesterol dyslipidemia found in viscerally obese subjects characterized by hyperinsulinemia.


Protein engineering and preclinical development of a GM-CSF receptor antibody for the treatment of rheumatoid arthritis.
For antibody therapies against receptor targets, in vivo outcomes can be difficult to predict because of target-mediated clearance or antigen 'sink' effects. The purpose of this work was to engineer an antibody to the GM-CSF receptor α (GM-CSFRα) with pharmacological properties optimized for chronic, s.c. treatment of rheumatoid arthritis (RA) patients. We used an in silico model of receptor occupancy to guide the target affinity and a combinatorial phage display approach for affinity maturation. Mechanism of action and internalization assays were performed on the optimized antibody in vitro before refining the modelling predictions of the eventual dosing in man. Finally, in vivo pharmacology studies in cynomolgus monkeys were carried out to inform the predictions and support future clinical development. Antibody potency was improved 8600-fold, and the target affinity was reached. The refined model predicted pharmacodynamic effects at doses as low as 1 mg kg(-1) and a study in cynomolgus monkeys confirmed in vivo efficacy at 1 mg kg(-1) dosing. This rational approach to antibody drug discovery enabled the isolation of a potent molecule compatible with chronic, s.c. self-administration by RA patients. We believe this general approach enables the development of optimal biopharmaceuticals.


CEP3 encodes a centromere protein of Saccharomyces cerevisiae.
We have designed a screen to identify mutants specifically affecting kinetochore function in the yeast Saccharomyces cerevisiae. The selection procedure was based on the generation of "synthetic acentric" minichromosomes. "Synthetic acentric" minichromosomes contain a centromere locus, but lack centromere activity due to combination of mutations in centromere DNA and in a chromosomal gene (CEP) encoding a putative centromere protein. Ten conditional lethal cep mutants were isolated, seven were found to be alleles of NDC10 (CEP2) encoding the 110-kD protein of yeast kinetochore. Three mutants defined a novel essential gene CEP3. The CEP3 product (Cep3p) is a 71-kD protein with a potential DNA-binding domain (binuclear Zn-cluster). At nonpermissive temperature the cep3 cells arrest with an undivided nucleus and a short mitotic spindle. At permissive temperature the cep3 cells are unable to support segregation of minichromosomes with mutations in the central part of element III of yeast centromere DNA. These minichromosomes, when isolated from cep3 cultures, fail to bind bovine microtubules in vitro. The sum of genetic, cytological and biochemical data lead us to suggest that the Cep3 protein is a DNA-binding component of yeast centromere. Molecular mass and sequence comparison confirm that Cep3p is the p64 component of centromere DNA binding complex Cbf3 (Lechner, 1994).


Shared Decision Making for Urolithiasis: The Use of a Patient Decision Making Aid.
Patients desire an active role in health care decisions. We evaluated whether a patient decision making aid is useful when considering surgical treatment for urolithiasis. Patients with a history of urolithiasis were recruited for study. They were asked to consider a hypothetical case of an asymptomatic 10 mm proximal ureteral stone for which elective surgical intervention was recommended. Shock wave lithotripsy and ureteroscopy were presented as potential options. A patient decision making aid was developed to explain and compare the options. A urologist presented the information to the patients, once using the patient decision making aid and then without the aid. We assessed participant satisfaction with each format, and invited comments about the aid and its content, design and clarity. Mean ± SD age of the 4 male and 10 female participants was 61 ± 9 years. Of the participants 86% found the patient decision making aid helpful but identified areas for improvement. Specifically, patients wanted more information on stent placement, stent discomfort, long-term effects and cost. Of the participants 79% reported that the aid improved their understanding of the treatment options compared to the session without the aid. While 8 of 14 participants preferred hearing surgeon recommendations, most still reported value in the patient decision making aid. Patient decision making aids are increasingly used in the management of several diseases and they require patient input into development. In our study the aid improved patient self-reported understanding of surgical options for ureteral stone removal. Notably, most participants still preferred to make decisions based on the surgeon recommendation. Modification of the patient decision making aid based on patient suggestions will enhance its usefulness and applicability in the clinical setting.


Genetic variability of environmental sensitivity revealed by phenotypic variation in body weight and (its) correlations to physiological and behavioral traits.
Adaptive phenotypic plasticity is a key component of the ability of organisms to cope with changing environmental conditions. Fish have been shown to exhibit a substantial level of phenotypic plasticity in response to abiotic and biotic factors. In the present study, we investigate the link between environmental sensitivity assessed globally (revealed by phenotypic variation in body weight) and more targeted physiological and behavioral indicators that are generally used to assess the sensitivity of a fish to environmental stressors. We took advantage of original biological material, the rainbow trout isogenic lines, which allowed the disentangling of the genetic and environmental parts of the phenotypic variance. Ten lines were characterized for the changes of body weight variability (weight measurements taken every month during 18 months), the plasma cortisol response to confinement stress (3 challenges) and a set of selected behavioral indicators. This study unambiguously demonstrated the existence of genetic determinism of environmental sensitivity, with some lines being particularly sensitive to environmental fluctuations and others rather insensitive. Correlations between coefficient of variation (CV) for body weight and behavioral and physiological traits were observed. This confirmed that CV for body weight could be used as an indicator of environmental sensitivity. As the relationship between indicators (CV weight, risk-taking, exploration and cortisol) was shown to be likely depending on the nature and intensity of the stressor, the joint use of several indicators should help to investigate the biological complexity of environmental sensitivity.


Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with an overall 5-year survival rate of 10%. Disease lethality is due to late diagnosis, early metastasis and resistance to therapy, including immunotherapy. PDA creates a robust fibroinflammatory tumor microenvironment that contributes to immunotherapy resistance. While previously considered an immune privileged site, evidence demonstrates that in some cases tumor antigen-specific T cells infiltrate and preferentially accumulate in PDA and are central to tumor cell clearance and long-term remission. Nonetheless, PDA can rapidly evade an adaptive immune response using a myriad of mechanisms. Mounting evidence indicates PDA interferes with T cell differentiation into potent cytolytic effector T cells via deficiencies in naive T cell priming, inducing T cell suppression or promoting T cell exhaustion. Mechanistic research indicates that immunotherapy combinations that change the suppressive tumor microenvironment while engaging antigen-specific T cells is required for treatment of advanced disease. This review focuses on recent advances in understanding mechanisms limiting T cell function and current strategies to overcome immunotherapy resistance in PDA.


Clinical use of subjective visual horizontal and vertical in patients of unilateral vestibular neuritis.
Subjective visual horizontal (SVH) and subjective visual vertical (SVV) used to assess otolith dysfunction and ipsilesional deviation of SVV and SVH in unilateral vestibular dysfunction is well known. The goal of this study was to investigate the clinical use of SVH/SVV and a dizziness scale in the clinical setting of acute unilateral vestibular neuritis. Thirty-five patients with unilateral vestibular neuritis were investigated. Every patient was diagnosed by physical examination and electronystagmography. Subjective visual horizontal and SVV were assessed during the acute or subacute period; the Dizziness Handicap Inventory (DHI) and Vestibular Disorder Activities of Daily Living Scale (VADL) were used for a self-dizziness scale at the same time. All patients underwent rehabilitation therapy. Subjective visual horizontal/SVV and DHI/VADL were assessed again approximately 4 weeks later. Postrehabilitation SVH/SVV and DHI/VADL data were compared with initial data. Dizziness Handicap Inventory and VADL were improved after 4 weeks of rehabilitation, and the deviation toward ipsilesional side SVH and SVV was also improved. These results demonstrate that SVH and SVV correlated with clinical dizziness symptoms in patients with acute unilateral vestibular neuritis. Therefore, SVH and SVV would be useful tools for the evaluation of clinical manifestations of unilateral vestibular neuritis.


The neddylation inhibitor MLN4924 inhibits proliferation and triggers apoptosis of oral cancer cells but not for normal cells.
Increased neddylation benefits the survival of several types of cancer cells. The inhibition of neddylation has the potential to exert anticancer effects but is rarely assessed in oral cancer cells. This study aimed to investigate the antiproliferation potential of a neddylation inhibitor MLN4924 (pevonedistat) for oral cancer cells. MLN4924 inhibited the cell viability of oral cancer cells more than that of normal oral cells (HGF-1) with 100% viability, that is, IC50 values of oral cancer cells (CAL 27, OC-2, and Ca9-22) are 1.8, 1.4, and 1.9 μM. MLN4924 caused apoptotic changes such as the subG1 accumulation, activation of annexin V, pancaspase, and caspases 3/8/9 of oral cancer cells at a greater rate than in normal oral cells. MLN4924 induced greater oxidative stress in oral cancer cells compared to normal cells by upregulating reactive oxygen species and mitochondrial superoxide and depleting the mitochondrial membrane potential and glutathione. In oral cancer cells, preferential inductions also occurred for DNA damage (γH2AX and 8-oxo-2'-deoxyguanosine). Therefore, this investigation demonstrates that MLN4924 is a potential anti-oral-cancer agent showing preferential inhibition of apoptosis and promotion of DNA damage with fewer cytotoxic effects on normal cells.


RAD51 and XRCC3 gene polymorphisms and the risk of developing acute myeloid leukemia.
RAD51 (Rec A homolog of E. coli) is a polymorphic gene and one of the central proteins in homologous recombination-DNA-double-stand breaks (HR-DNA-DSB) repair pathway, which is vital in maintaining genetic stability within a cell. The x-ray repair cross complementing (XRCC3) protein also functions in HR-DNA-DSB repair pathway and directly interacts with and stabilizes RAD51 and the closely related RAD51C. The aim of this study was to determine the prevalence of the RAD51 and XRCC3 repair gene polymorphisms among acute myeloid leukemia (AML) patients and to define their role in development of AML and its correlation with the clinical presentation, laboratory data as well as treatment outcome using polymerase chain reaction-restriction fragment length polymorphism assay in 50 de novo AML patients as well as 30 healthy subjects as a control group. Our study revealed that RAD51 G135C and XRCC3 Thr241Met alleles were associated with increased risk of AML with odds ratio (OR) of 2.833 and 2.909 and 95% confidence interval (CI) of 1.527 to 8.983 and 1.761 to 9.788, respectively. Moreover, when combining the 2 genes polymorphisms, a significant elevation of the risk of AML was found with OR of 3.124 and 95% CI of 1.872 to 11.243. As regards treatment outcome, a highly statistical significant difference was found between XRCC3 genotypes with P value of 0.001, whereas no significant difference was present between RAD51 genotypes with P value of 0.29. This clarifies that XRCC3 gene polymorphisms was found to have a significant impact on the risk of treatment failure with OR of 3.560 and 95% CI of 1.167 to 10.875; however, RAD51 gene polymorphism was not found to have an equivalent effect with OR of 2.813 and 95% CI of 0.933 to 10.828. So XRCC3 gene polymorphism might be considered as a prognostic marker in AML. In conclusion, RAD51 and XRCC3 genes polymorphisms may play an important role in the development of AML.


The variability of blood pressure due to small changes of hematocrit.
The hematocrit (Hct) of awake hamsters was lowered to 90% of baseline by isovolemic hemodilution using hamster plasma to determine the acute effect of small changes in Hct and blood viscosity on systemic hemodynamics. Mean arterial blood pressure increased, reaching a maximum of about 10% above baseline (8.6 +/- 5.5 mmHg) when Hct decreased 8.4 +/- 1.9% (P < 0.005). Cardiac output increased continuously with hemodilution. These conditions were reached at approximately 60 min after exchange transfusion and remained stationary for 1 h. Peripheral vascular resistance was approximately constant up to a decrease of Hct of about 10% and then fell continuously with lowering Hct. Vascular hindrance or vascular resistance independent of blood viscosity increased by about 20% and remained at this level up to an Hct decrease of 20%, indicating that the vasculature constricted with the lowered Hct. The results for the initial 2-h period are opposite but continuous with previous findings with small increases in Hct. In conclusion, limited acute anemic conditions increase mean arterial blood pressure during the initial period of 2 h, an effect that is quantitatively similar but opposite to the acute increase of Hct during the same period.