Gene duplication and speciation in Drosophila: evidence from the Odysseus locus.
The importance of gene duplication in evolution has long been recognized. Because duplicated genes are prone to diverge in function, gene duplication could plausibly play a role in species differentiation. However, experimental evidence linking gene duplication with speciation is scarce. Here, we show that a hybrid-male sterility gene, Odysseus (OdsH), arose by gene duplication in the Drosophila genome. OdsH has evolved at a very high rate, whereas its most immediate paralog, unc-4, is nearly identical among species in the Drosophila melanogaster subgroup. The disparity in their sequence evolution is echoed by the divergence in their expression patterns in both soma and reproductive tissues. We suggest that duplicated genes that have yet to evolve a stable function at the time of speciation may be candidates for "speciation genes," which is broadly defined as genes that contribute to differential adaptation between species.


Cardioprotection during cardiac surgery.
Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide. For a large number of patients with CHD, coronary artery bypass graft (CABG) surgery remains the preferred strategy for coronary revascularization. Over the last 10 years, the number of high-risk patients undergoing CABG surgery has increased significantly, resulting in worse clinical outcomes in this patient group. This appears to be related to the ageing population, increased co-morbidities (such as diabetes, obesity, hypertension, stroke), concomitant valve disease, and advances in percutaneous coronary intervention which have resulted in patients with more complex coronary artery disease undergoing surgery. These high-risk patients are more susceptible to peri-operative myocardial injury and infarction (PMI), a major cause of which is acute global ischaemia/reperfusion injury arising from inadequate myocardial protection during CABG surgery. Therefore, novel therapeutic strategies are required to protect the heart in this high-risk patient group. In this article, we review the aetiology of PMI during CABG surgery, its diagnosis and clinical significance, and the endogenous and pharmacological therapeutic strategies available for preventing it. By improving cardioprotection during CABG surgery, we may be able to reduce PMI, preserve left ventricular systolic function, and reduce morbidity and mortality in these high-risk patients with CHD.


Regio- and Stereospecific Synthesis of Oridonin D-Ring Aziridinated Analogues for the Treatment of Triple-Negative Breast Cancer via Mediated Irreversible Covalent Warheads.
Covalent drug discovery has undergone a resurgence in recent years due to comprehensive optimization of the structure-activity relationship (SAR) and the structure-reactivity relationship (SRR) for covalent drug candidates. The natural product oridonin maintains an impressive pharmacological profile through its covalent enone warhead on the D-ring and has attracted substantial SAR studies to characterize its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time, we report the excessive reactivity of this covalent warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Importantly, aziridonin 44 (YD0514), with a more-druglike irreversible covalent warhead, has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with enhanced antitumor effects in vitro and in vivo while displaying lower toxicity to normal human mammary epithelial cells in comparison to oridonin.


Apoptotic function of tumor-associated antigen RCAS1 in oral squamous cell carcinoma.
Receptor-binding cancer antigen expressed on SiSo cell (RCAS1) is derived from uterine adenocarcinoma and can induce apoptosis in lymphocytes, allowing tumor cells to escape from immune surveillance. RCAS1 is reportedly expressed in a membranous pattern on tumor cell or soluble one in serum of patients. The aim of this study was to investigate expression patterns of RCAS1 and the effect on apoptosis in oral squamous cell carcinoma (OSCC) cell lines. In four kinds of OSCC cell lines (HSC-2, HSC-3, SQUU-A, and SQUU-B), RCAS1 mRNAs and proteins were determined by RT-PCR and immunocytochemistry. Membranous RCAS1 was determined by flow cytometry. Culture supernatants were analyzed for detection of soluble RCAS1 by dot blotting and enzyme-linked immunosorbent assay. Apoptotic ability of RCAS1 on the erythroid leukemia cell line K562 with the putative receptor was evaluated by flow cytometry in co-culture with highly metastatic SQUU-B, with knocked-down RCAS1 cells or in a no-cell contact condition. RCAS1 mRNA and proteins were expressed in all of OSCC cell lines. Membranous pattern were expressed in all cell lines, while soluble pattern was detected in all supernatants. RCAS1 mRNA, membranous and soluble RCAS1 were significantly seen in SQUU-B more than the other 3 cell lines (P < 0.05). K562 apoptosis was induced in co-culture with each of all cell lines, particularly with SQUU-B. Apoptosis was markedly reduced in co-culture with RCAS1 knockdown cells, but was induced in co-culture without cell contract of SQUU-B. Our study suggests that RCAS1 has an apoptotic function via membranous/soluble expression pattern in OSCC cells. RCAS1 may thus affect tumor escape from immune surveillance in OSCC by inducing apoptosis.


Unsupervised binning of environmental genomic fragments based on an error robust selection of l-mers.
With the rapid development of genome sequencing techniques, traditional research methods based on the isolation and cultivation of microorganisms are being gradually replaced by metagenomics, which is also known as environmental genomics. The first step, which is still a major bottleneck, of metagenomics is the taxonomic characterization of DNA fragments (reads) resulting from sequencing a sample of mixed species. This step is usually referred as "binning". Existing binning methods are based on supervised or semi-supervised approaches which rely heavily on reference genomes of known microorganisms and phylogenetic marker genes. Due to the limited availability of reference genomes and the bias and instability of marker genes, existing binning methods may not be applicable in many cases. In this paper, we present an unsupervised binning method based on the distribution of a carefully selected set of l-mers (substrings of length l in DNA fragments). From our experiments, we show that our method can accurately bin DNA fragments with various lengths and relative species abundance ratios without using any reference and training datasets. Another feature of our method is its error robustness. The binning accuracy decreases by less than 1% when the sequencing error rate increases from 0% to 5%. Note that the typical sequencing error rate of existing commercial sequencing platforms is less than 2%. We provide a new and effective tool to solve the metagenome binning problem without using any reference datasets or markers information of any known reference genomes (species). The source code of our software tool, the reference genomes of the species for generating the test datasets and the corresponding test datasets are available at http://i.cs.hku.hk/~alse/MetaCluster/.


Shunt nephritis: efficacy of an antibiotic trial for clinical diagnosis.
Coagulase negative staphylococcus, a normal skin flora, is especially nosopoietic under shunt management, because coagulase negative staphylococcus sometimes forms a biofilm around itself at catheter tips in vivo, which shields the organism from the effects of antibiotics. But it is difficult to distinguish this pathogen from a possible confounding contamination of a blood culture. In this article, we report a case, and discuss how a patient with suspected shunt nephritis should be examined and treated. In addition, to further histological and prognostic interpretation, we review the previously reported cases of shunt nephritis in Japanese adults.


Assessment of recovery from burn-related neuropathy by electrodiagnostic testing.
The purpose of this study was to investigate the recovery of burn-related neuropathies by electrodiagnostic testing. Burn patients who presented to an American Burn Association verified burn center were interviewed and examined for clinical evidence of peripheral neuropathies by a physiatrist. Patients whom consented to participate were tested for electrodiagnostic evidence of peripheral neuropathy. Repeated studies were performed to assess for evidence of recovery. A total of 370 patients were screened. Thirty-six (9.73%) patients had clinical evidence of neuropathy. Eighteen male patients with a mean TBSA burn of 42% had nerve conduction studies performed. Etiologies of the injuries included eight flame, eight electrical, and three others. Seventy-three nerve conduction studies were performed and 58 of the tests were abnormal. The most commonly affected nerve was the median sensory (10). For patients with repeated tests, the mean time between tests was 169 days (SD, 140 days). There was a significant difference between the initial and follow-up test (McNemar's change test P=.009). In subset analysis of motor and sensory abnormalities, there was no significant difference (P=.07). The most common neuropathy identified in this cohort was the median sensory. Overall, there was improvement in the nerve conduction abnormalities examined. This study suggests that the prognosis for recovery after burn-related neuropathy is good.


Impact of early oseltamivir treatment on outcome in critically ill patients with 2009 pandemic influenza A.
The impact of oseltamivir on mortality in critically ill patients with 2009 pandemic influenza A (2009 H1N1) is not clear. The main objective of this study was to investigate the relationship between the timing of antiviral administration and intensive care unit (ICU) outcomes. Prospective, observational study of a cohort of ICU patients with confirmed 2009 H1N1 infection. Clinical data, treatment and outcome were compared between patients receiving early treatment (ET) with oseltamivir, initiated within 2 days, and patients administered late treatment (LT), initiated after this timepoint. Multivariate analysis and propensity score were used to determine the effect of oseltamivir on ICU mortality. Six hundred and fifty-seven patients were enrolled. Four hundred and four (61.5%) patients required mechanical ventilation (MV; mortality 32.6%). Among them, 385 received effective antiviral therapy and were included in the study group. All patients received oseltamivir for a median duration of 10 days (interquartile range 8-14 days). Seventy-nine (20.5%) ET patients were compared with 306 LT patients. The two groups were comparable in terms of main clinical variables. ICU length of stay (22.7 ± 16.7 versus 18.4 ± 14.2 days; P = 0.03), hospital length of stay (34.0 ± 20.3 versus 27.2 ± 18.2 days; P = 0.001) and MV days (17.4 ± 15.2 versus 14.0 ± 12.4; P = 0.04) were higher in the LT group. ICU mortality was also higher in LT (34.3%) than in ET (21.5%; OR = 1.9; 95% CI 1.06-3.41). A multivariate model identified ET (OR = 0.44; 95% CI 0.21-0.87) as an independent variable associated with reduced ICU mortality. These results were confirmed by propensity score analysis (OR = 0.44; 95% CI 0.22-0.90; P < 0.001). Our findings suggest that early oseltamivir administration was associated with favourable outcomes among critically ill ventilated patients with 2009 H1N1 virus infection.


Discovery of Anti-Coronavirus Cinnamoyl Triterpenoids Isolated from Hippophae rhamnoides during a Screening of Halophytes from the North Sea and Channel Coasts in Northern France.
The limited availability of antiviral therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spurred the search for novel antiviral drugs. Here, we investigated the potential antiviral properties of plants adapted to high-salt environments collected in the north of France. Twenty-five crude methanolic extracts obtained from twenty-two plant species were evaluated for their cytotoxicity and antiviral effectiveness against coronaviruses HCoV-229E and SARS-CoV-2. Then, a bioguided fractionation approach was employed. The most active crude methanolic extracts were partitioned into three different sub-extracts. Notably, the dichloromethane sub-extract of the whole plant Hippophae rhamnoides L. demonstrated the highest antiviral activity against both viruses. Its chemical composition was evaluated by ultra-high performance liquid chromatography (UHPLC) coupled with mass spectrometry (MS) and then it was fractionated by centrifugal partition chromatography (CPC). Six cinnamoyl triterpenoid compounds were isolated from the three most active fractions by preparative high-performance liquid chromatography (HPLC) and identified by high resolution MS (HR-MS) and mono- and bi-dimensional nuclear magnetic resonance (NMR). Specifically, these compounds were identified as 2-O-trans-p-coumaroyl-maslinic acid, 3β-hydroxy-2α-trans-p-coumaryloxy-urs-12-en-28-oic acid, 3β-hydroxy-2α-cis-p-coumaryloxy-urs-12-en-28-oic acid, 3-O-trans-caffeoyl oleanolic acid, a mixture of 3-O-trans-caffeoyl oleanolic acid/3-O-cis-caffeoyl oleanolic acid (70/30), and 3-O-trans-p-coumaroyl oleanolic acid. Infection tests demonstrated a dose-dependent inhibition of these triterpenes against HCoV-229E and SARS-CoV-2. Notably, cinnamoyl oleanolic acids displayed activity against both SARS-CoV-2 and HCoV-229E. Our findings suggest that Hippophae rhamnoides could represent a source of potential antiviral agents against coronaviruses.


Outcomes of pregnancy termination by misoprostol at 14-32 weeks of gestation: a 10-year-experience.
To review outcomes of pregnancy termination between 14-32 weeks of gestation based on a 10-year-experience of misoprostol use at Maharaj Nakorn Chiang Mai Hospital. A retrospective, descriptive study Based on the authors' prospective database, all pregnancy terminations by misoprostol between 14-32 weeks of gestation between 1998 and 2008 were reviewed. The main outcomes included success rate of termination, mean induction-to-abortion time, and complication rate. In addition, regimens and routes of drug administration as well as indications for termination of pregnancy were also analyzed. Seven hundred forty one pregnancy terminations were performed using misoprostol with dosage varied from 50 mcg to 800 mcg, mostly 400 mcg intravagina every three hours. The most common indication for pregnancy termination was severe fetal thalassemia (35.8%). The majority of cases were pregnancies with live fetuses and only 18.2% were associated with a dead fetus in utero. Success rate of termination within 48 hours was 85.9%. Pregnancies with previous cesarean section accounted for 8.6% of cases. The mean gestational age was 20.94 weeks. The mean abortion time was 25.35 hours, ranging from 1.25 to 247.88 hours. The two most common adverse effects were chill and fever (43.7% and 34.3%). The rate of analgesia needed was 39.3%. No serious adverse complications such as uterine rupture were found This experience suggests that misoprostol has a high efficacy for pregnancy termination with acceptable minor side effects and it is relatively safe when used with precaution.


Screw Migration into Colon after Anterior Cervical Plating - An Unusual Complication: A Case Report.
Complications in the form of esophageal injury, tracheal injury, injury to carotids, implant failure, loosening of screws, etc do occur after anterior cervical surgeries. Although intra-operative esophageal injuries are as such rare, there have been few reports of delayed esophageal perforation as well after anterior cervical surgeries. We report a very rare case of migration of missing screw from anterior cervical plate after anterior cervical corpectomy and plating, which had ultimately migrated down to colon and had to be removed via colonoscopy. Along with removal of migrated screw from colon, revision of failed anterior cervical surgery was done wherein plate and screws were removed with mesh cage left in-situ as it was snug-fit while pharyngeophageal perforation was explored and was found to be spontaneously healing, with addition of posterior Bohlman's interspinous wiring for added stability. Migration of screw from the anterior cervical plate into the colon although very rare, should be always kept in mind and its potentially serious complications. We also conclude that particular attention should be given to elderly people with poor bony quality who have high chances of implant failure, along with attention to proper cage size, screw position and proper locking of the screw to further lessen the chances of implant failure.


OCT for the identification of vulnerable plaque in acute coronary syndrome.
After 2 decades of development and use in interventional cardiology research, optical coherence tomography (OCT) has now become a core intravascular imaging modality in clinical practice. Its unprecedented spatial resolution allows visualization of the key components of the atherosclerotic plaque that appear to confer "vulnerability" to rupture-namely the thickness of the fibrous cap, size of the necrotic core, and the presence of macrophages. The utility of OCT in the evaluation of plaque composition can provide insights into the pathophysiology of acute coronary syndrome and the healing that occurs thereafter. A brief summary of the principles of OCT technology and a comparison with other intravascular imaging modalities is presented. The review focuses on the current evidence for the use of OCT in identifying vulnerable plaques in acute coronary syndrome and its limitations.


Supramolecular polymerisation in water; elucidating the role of hydrophobic and hydrogen-bond interactions.
Understanding the self-assembly of small molecules in water is crucial for the development of responsive, biocompatible soft materials. Here, a family of benzene-1,3,5-tricarboxamide (BTA) derivatives that comprise a BTA moiety connected to an amphiphilic chain is synthesised with the aim to elucidate the role of hydrophobic and hydrogen-bonding interactions in the self-assembly of these BTAs. The amphiphilic chain consists of an alkyl chain with a length of 10, 11, or 12 methylene units, connected to a tetraethylene glycol (at the periphery). The results show that an undecyl spacer is the minimum length required for these BTAs to self-assemble into supramolecular polymers. Interestingly, exchange studies reveal only minor differences in exchange rates between BTAs containing undecyl or dodecyl spacers. Additionally, IR spectroscopy provides the first experimental evidence that hydrogen-bonding is operative and contributes to the stabilisation of the supramolecular polymers in water.


Allele specificity of gamma interferon responses to the carboxyl-terminal region of Plasmodium falciparum merozoite surface protein 1 by Kenyan adults with naturally acquired immunity to malaria.
Cross-sectional seroepidemiological studies of populations naturally exposed to Plasmodium falciparum suggest an association between protection from malaria and circulating antibodies to the carboxyl terminus of merozoite surface protein 1 (MSP1). Questions remain regarding the significance of cell-mediated immunity to MSP1 in conferring protection and inducing immunologic memory. Vaccine constructs have been based on the 42-kDa recombinant MSP1 protein (MSP1(42)), which includes the 19-kDa (MSP1(19)) and 33-kDa (MSP1(33)) fragments containing the major B- and T-cell epitopes, respectively. To evaluate T-cell responses to the MSP1(33) fragment, two libraries of overlapping 18-mer peptides from the 3D7 and FVO MSP1(33) regions were used to screen a cohort of asymptomatic Kenyan adults. Gamma interferon (IFN-γ) measured by enzyme-linked immunospot assay (ELISPOT) at multiple time points assessed the magnitude and stability of these responses. The percentage of individuals with IFN-γ responses to single MSP1(33) peptides ranged from nil to 24%, were clustered among a subset of peptides, and were not consistently recalled over time. In comparison to peptide responses, IFN-γ ELISPOT responses to recombinant MSP1(42) were more prevalent, more frequently elicited by the 3D7 as opposed to the FVO allele, and more stable over time. The prevailing MSP1(33) genotype infection was 3D7, with few mixed infections and no sole FVO infections. This study demonstrates that immunity against MSP1(33) after cumulative natural infections consists of low-magnitude and difficult-to-detect IFN-γ responses. Although immunity against MSP1 alone will not confer protection against malaria, demonstrating a relative and sustained increase in T-cell immunity to MSP1 after vaccination would be a reasonable measurement of vaccine responsiveness.


Management of gunshot wounds to the mandible.
The gunshot wound to the mandible is a unique traumatic injury. The resultant injury from the gunshot wound is diverse because of the variability of the projectile, motion, velocity, and tissue characteristics. When a high-velocity projectile strikes the mandible, often times the wound will consist of a severely comminuted mandible surrounded by nonvital soft tissues and the implantation of multiple foreign bodies. This represents a challenge for the treating surgeon. The anatomy and function of the mandible make it such that the care of the gunshot wound requires a combination of trauma and reconstructive surgeries. There are varying techniques advocated for the management of gunshot wound to the face. However, for the comminuted mandible fracture sustained from a gunshot wound, an approach involving the fabrication of an occlusal splint, intermaxillary fixation, aggressive debridement of hard and soft tissues, and immediate reconstruction with a titanium plate is a comprehensive approach that can restore the appropriate function and contour of the patient. At the Division of Oral and Maxillofacial Surgery, University of Miami, this approach to the comminuted mandible fracture secondary to the gunshot wound has led to the effective management of this specific subset of injury. The complication rate is comparable with the current literature and provides an advantage as a 1-stage management to restore appropriate function and cosmesis to the patient.


Preservation of Domesticated Honey Bee (Hymenoptera: Apidae) Drone Semen.
Preservation of honey bee (Apis mellifera L., Hymenoptera: Apidae) sperm, coupled with instrumental insemination, is an effective strategy to protect the species and their genetic diversity. Our overall objective is to develop a method of drone semen preservation; therefore, two experiments were conducted. Hypothesis 1 was that cryopreservation (-196 °C) of drone semen is more effective for long-term storage than at 16 °C. Our results show that after 1 yr of storage, frozen sperm viability was higher than at 16 °C, showing that cryopreservation is necessary to conserve semen. However, the cryoprotectant used for drone sperm freezing, dimethyl sulfoxide (DMSO), can harm the queen and reduce fertility after instrumental insemination. Hypothesis 2 was that centrifugation of cryopreserved semen to reduce DMSO prior to insemination optimize sperm quality. Our results indicate that centrifuging cryopreserved sperm to remove cryoprotectant does not affect queen survival, spermathecal sperm count, or sperm viability. Although these data do not indicate that centrifugation of frozen-thawed sperm improves queen health and fertility after instrumental insemination, we demonstrate that cryopreservation is achievable, and it is better for long-term sperm storage than above-freezing temperatures for duration of close to a year.


Enzyme-assisted asymmetric total synthesis of (-)-podophyllotoxin and (-)-picropodophyllin.
Described is the first catalytic, asymmetric synthesis of (-)-podophyllotoxin and its C(2)-epimer, (-)-picropodophyllin. Asymmetry is achieved via the enzymatic desymmetrization of advanced meso diacetate 20, through PPL-mediated ester hydrolysis. A second key feature of the synthesis is the strategically late introduction of the highly oxygenated natural ring E through an arylcopper species. The successful implementation of this approach augers well for the introduction of other functionalized rings E for future SAR work. The synthesis begins from piperonal, which is fashioned into isobenzofuran (IBF) precursor 14 in three steps (bromination, acetalization, and halogen-metal exchange/hydroxymethylation). Interestingly, treatment of 14 with HOAc in commerical dimethyl maleate (contains 5% dimethyl fumarate) leads to a nearly equimolar mixture of fumarate- (15) and maleate-IBF Diels-Alder adducts (16 and 17), indicating that IBF 11 reacts about 15 times faster with dimethyl fumarate than with dimethyl maleate. With scrupulously pure dimethyl maleate a 2.8:1 endo:exo mixture of maleate DA adducts is still obtained. On the other hand, the desired meso diester 16 is obtained pure and in nearly quantitative yield by employing neat dimethyl acetylene dicarboxylate as the dienophile, followed by catalytic hydrogenation. Reduction (LiAlH(4)) of 16 provides meso diol 19, which is then treated with Ac(2)O, BzCl, and PhCH(2)COCl to provide the corresponding meso diesters, 20-22. Screening of these meso benzoxabicyclo[2.2.1]heptyl substrate candidates across a battery of acyl transfer enzymes leads to an optimized match of diacetate 20 with PPL. Even on 10-20 g scales, asymmetry is efficiently introduced here, yielding the key chiral intermediate, monoacetate 25 (66% isolated yield, 83% corrected yield, 95% ee). Protecting group manipulation and oxidation (Swern) provide aldehyde 27b, which undergoes efficient retro-Michael ring opening to produce dihydronaphthalene 30, in which the C(3) and C(4) stereocenters are properly set. Following several unsuccessful approaches to the intramolecular delivery of ring E (via Claisen rearrangement, Heck-type cyclization, or radical cyclization), a highly diastereoselective, intermolecular conjugate addition of the arylcopper reagent derived from (3,4,5-trimethoxy)phenylmagnesium bromide and CuCN to acyl oxazolidinone 50 was developed (85% yield, only the required alpha-stereochemistry at C(1) is observed). The conjugate addition product is converted to (-)-picropodophyllin in two steps (lactonization, SEM deprotection) or to (-)-podophyllotoxin, in three steps, through the introduction of a C(2)-epimerization step, under Kende conditions, prior to the final conjugate addition.


Antitumor activity of ZD6474, a vascular endothelial growth factor-2 and epidermal growth factor receptor small molecule tyrosine kinase inhibitor, in combination with SC-236, a cyclooxygenase-2 inhibitor.
The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor (VEGF) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. Enhanced cyclooxygenase-2 (COX-2) expression has been linked to cancer cell proliferation, EGFR activation, VEGF secretion, and tumor-induced angiogenesis. ZD6474 is an orally available, small molecule, dual VEGF receptor-2 (VEGFR-2) and EGFR tyrosine kinase inhibitor. We investigated the activity of ZD6474 in combination with SC-236, a selective COX-2 inhibitor, to determine the antitumor activity of the simultaneous blockade of EGFR, COX-2, and VEGF functions. The antitumor activity in vitro and in vivo of ZD6474 and/or SC-236 was tested in human cancer cell lines with a functional EGFR autocrine pathway. The combination of ZD6474 and SC-236 determined supra-additive growth inhibition in all cancer cell lines tested. In nude mice bearing established human colon (GEO) or lung adenocarcinoma (A549) cancer xenografts and treated with ZD6474 and/or SC-236 for 3 weeks, a reversible tumor growth inhibition was seen with each agent, whereas a more prolonged growth inhibition that lasted for 3 to 5 weeks following the end of treatment resulted from the combination of the two agents. A long-term, 10-week treatment with ZD6474 plus SC-236 resulted in sustained tumor growth inhibition in all mice with tumor eradication in 3 of 10 GEO tumor-bearing mice and in 4 of 10 A549 tumor-bearing mice. This study provides a rationale for evaluating the simultaneous blockade of EGFR, COX-2, and VEGF signaling as cancer therapy in a clinical setting.


Anti-gay prejudice and all-cause mortality among heterosexuals in the United States.
We determined whether individuals who harbor antigay prejudice experience elevated mortality risk. Data on heterosexual sexual orientation (n = 20,226, aged 18-89 years), antigay attitudes, and mortality risk factors came from the General Social Survey, which was linked to mortality data from the National Death Index (1988-2008). We used Cox proportional hazard models to examine whether antigay prejudice was associated with mortality risk among heterosexuals. Heterosexuals who reported higher levels of antigay prejudice had higher mortality risk than those who reported lower levels (hazard ratio [HR] = 1.25; 95% confidence interval [CI] = 1.09, 1.42), with control for multiple risk factors for mortality, including demographics, socioeconomic status, and fair or poor self-rated health. This result translates into a life expectancy difference of approximately 2.5 years (95% CI = 1.0, 4.0 years) between individuals with high versus low levels of antigay prejudice. Furthermore, in sensitivity analyses, antigay prejudice was specifically associated with increased risk of cardiovascular-related causes of death in fully adjusted models (HR = 1.29; 95% CI = 1.04, 1.60). The findings contribute to a growing body of research suggesting that reducing prejudice may improve the health of both minority and majority populations.


Biomechanics of the anterior cruciate ligament.
The principal role of the anterior cruciate ligament (ACL) is to resist anterior displacement of the tibia on the femur. The ACL also has a major role in resisting internal rotation. The posterior fibers are longest, or most tense, in extension, and are therefore the major resistance to hyperextension and are more susceptible to injury in extension. The anterior fibers are longest, or most tense, in flexion and therefore are not susceptible to injuries with the knee flexed. The ACL is strong and stiff, yet because of its unique structure, it is precariously susceptible to injury.


Repeated Paradoxical Aggravation of Preexisting Psoriasis during Infliximab Treatment for Crohn's Disease.
As more rheumatologists and dermatologists have begun to use biological agents such as TNF-alpha blocker, they have confronted an unexpected complication: psoriasis was paradoxically aggravated or induced by the TNF-alpha blocker. Although it is not a common complication of TNF-alpha blocker, this aggravation may be more common than previously thought. To our knowledge, most reports about TNF-alpha blocker-induced psoriasis have been limited to western countries while only a few cases have been reported in Korea and Japan. In addition, new onset of pustular psoriasis by TNF-alpha blocker has been reported more commonly than worsening of preexisting psoriasis. Now we report a patient whose preexisting psoriasis vulgaris was aggravated repeatedly after using the TNF-alpha blocker, infliximab, to control Crohn's disease, which is a rare rheumatologic disease in Korea.


Noncatalytic Oxidative Coupling of Methane (OCM): Gas-Phase Reactions in a Jet Stirred Reactor (JSR).
Oxidative coupling of methane (OCM) is a promising technique for converting methane to higher hydrocarbons in a single reactor. Catalytic OCM is known to proceed via both gas-phase and surface chemical reactions. It is essential to first implement an accurate gas-phase model and then to further develop comprehensive homogeneous-heterogeneous OCM reaction networks. In this work, OCM gas-phase kinetics using a jet-stirred reactor are studied in the absence of a catalyst and simulated using a 0-D reactor model. Experiments were conducted in OCM-relevant operating conditions under various temperatures, residence times, and inlet CH4/O2 ratios. Simulations of different gas-phase models related to methane oxidation were implemented and compared against the experimental data. Quantities of interest (QoI) and rate of production analyses on hydrocarbon products were also performed to evaluate the models. The gas-phase models taken from catalytic reaction networks could not adequately describe the experimental gas-phase performances. NUIGMech1.1 was selected as the most comprehensive model to describe the OCM gas-phase kinetics; it is recommended for further use as the gas-phase model for constructing homogeneous-heterogeneous reaction networks.


Three-Hour Bundle Compliance and Outcomes in Patients With Undiagnosed Severe Sepsis.
The aim of this study was to compare completion of the Surviving Sepsis Campaign 3-hour treatment recommendations and patient-centered outcomes between patients with severe sepsis who received a sepsis-specific diagnosis code with those who did not. This was a retrospective cohort analysis of adult patients admitted through an academic medical center ED who received an antibiotic and met criteria for severe sepsis. We measured and compared the Surviving Sepsis Campaign 3-hour treatment recommendations along with patient-centered outcomes in patients who were diagnosed with severe sepsis and those who were not. A total of 5,631 patients were identified (60.6 ± 17.2 years of age; 48.9% women). Less than half (32.8%) received an International Classification of Diseases, ninth revision, diagnosis code of 995.92. Completion of all four bundle components in < 3 hours was low for all patients (8.72%). Therapeutic components (a broad-spectrum antibiotic and IV fluids) were completed more often (31.3%). Those with a diagnosis code received all four bundle components (10.2% vs 7.9%; P < .005), as well as therapeutic components at a higher frequency (36.0% vs 29.0%; P < .001). Patients with a diagnosis code had higher mortality (6.3% vs 2.3%), more frequent ICU admissions (44.7% vs 22.5%), and longer hospitalizations (9.2 ± 6.9 days vs 6.9 ± 6.7 days) than did patients with severe sepsis with no diagnosis code (all P < .001). Severe sepsis continues to be an underdiagnosed and undertreated condition. Patients who were diagnosed had higher treatment rates yet experienced worse outcomes. Continued investigation is needed to identify factors contributing to diagnosis, treatment, and outcomes in patients with severe sepsis.


Sudden Unexpected Death in Epilepsy Among Patients With Benign Childhood Epilepsy With Centrotemporal Spikes.
Children with benign epilepsy with centrotemporal spikes (BECTS) have traditionally been considered to have a uniformly good prognosis. However, benign may be a misnomer because BECTS is linked to cognitive deficits, a more severe phenotype with intractable seizures, and the potential for sudden unexpected death in epilepsy (SUDEP). To determine if cases of BECTS are present in the North American SUDEP Registry (NASR). The NASR is a clinical and biospecimen repository established in 2011 to promote SUDEP research. The NASR database, which includes medical records, results of electroencephalographic tests, and interviews with family members of patients with epilepsy who died suddenly without other identifiable causes of death, was queried from June 3, 2011, to June 3, 2016, for cases of BECTS. The patients with epilepsy had died suddenly without other identifiable causes of death (eg, drowning, trauma, exposure to toxic substances, or suicide); SUDEP classification was determined by the consensus of 2 epileptologists. Cases of SUDEP among children who received a diagnosis of BECTS among patients reported in the NASR. Three boys (median age at death, 12 years; range, 9-13 years) who received a diagnosis of BECTS by their pediatric epileptologist or neurologists were identified among 189 cases reported in the NASR. The median age of epilepsy onset was 5 years (range, 3-11 years), and the median duration of epilepsy was 4 years (range, 1-10 years). Two deaths were definite SUDEP, and 1 was probable SUDEP. Independent review of clinical and electroencephalographic data supported the diagnosis of BECTS in all 3 patients. None of the patients was prescribed antiseizure drugs, either owing to physician recommendation or mutual decision by the physician and parents. All 3 patients were found dead in circumstances typical of SUDEP. The 3 patients spanned the spectrum of BECTS severity: 1 had only a few seizures, 1 had more than 30 focal motor seizures, and 1 had 4 witnessed generalized tonic-clonic seizures and approximately 30 suspected generalized tonic-clonic seizures. Sudden unexpected death in epilepsy is a very rare outcome in BECTS that clinicians should consider discussing in appropriate circumstances and possibly factoring into treatment decisions.


Concise Total Synthesis of Peyssonnoside A.
Peyssonnoside A is a marine-derived sulfated diterpenoid glucoside with a unique 5/6/3/6 tetracyclic skeleton with a highly substituted cyclopropane ring deeply embedded into the structure. Herein, we report the first total synthesis of this natural product in a concise, efficient, scalable, and highly diastereoselective fashion. The aglucone peyssonnosol was synthesized in 21% overall yield after 15 steps, featuring a Simmons-Smith cyclopropanation and Mukaiyama hydration, fully controlled by the spatial structure of the substrates.


Chondroitin sulfate and chitosan-coated liposomes as a novel delivery system for betanin: Preparation, characterization and in vitro digestion behavior.
Betanin, a water-soluble pigment known for its high bioactivity, is hindered by pH and temperature sensitivity, weak ionic strength, and low bioavailability. In this study, nanoliposome (NPS), chitosan-coated NPS (CNPS), and chondroitin sulfate-chitosan bilayer-modified nanoliposomes (SCNPS) were prepared based on a layer-by-layer electrostatic interaction method for betanin encapsulation. The increase of polymer layers from NPS to SCNPS led to a monotonic increment from 223.57 to 522.33 nm in size, from -27.73 to 16.70 mV in negative charge and from 0.22 to 0.35 in polydispersity index. The chemical stability against pH (ranging from 2 to 10), ionic type (KCl, CaCl2, ALCl3) and ionic strength (100, 500 mM) significantly impacted the appearance and particle size of the double-layered nanoliposome. In vitro digestion experiment showed that SCNPS displayed higher stability and slower betanin release compared to NPS and CNPS. This study demonstrates that betanin can be efficiently encapsulated by SCNPS with improved stability and bioavailability.


Can infectious biofilm be controlled by blocking bacterial communication?
Many bacteria grow on surfaces forming biofilms but often high dosages of antibiotics can not clear infectious biofilms. Biofilms are controlled by a process called quorum-sensing triggered by species-specific, small, diffusible autoinducers (N-acyl homoserine lactones (AHL), small peptides or a furanosyl borate diester). Several herbal, animal and microbial extracts possess quorum-quenching activity but only few active compounds and synthetic analogues are known. However, quorum-sensing seems not to be the only way to control biofilms. Bacteria have mechanisms to dissolve their biofilms and return to planktonic lifestyle. Only few compounds responsible for the signalling of these processes are known but may open a completely novel line of biofilm control. Furthermore, controlling the attachment of bacterial by inhibiting the formation of pili is another option and some inhibitors have already been characterized. In this article different approaches to control bacterial biofilms are discussed together with the balance between biofilm formation and virulence.


Quantitative outcome of registration methods for correcting cardiac drift in cardiac PET/CT imaging.
Myocardial perfusion studies suffer from artifacts caused by misalignment of the transmission and emission data due to the influences of voluntary and involuntary patient motion. Regardless of 68Ge or respiratory-averaged CT based attenuation correction and good patient cooperation, approximately 21% of perfusion studies exhibit artifacts arising from misalignment that cannot be corrected by manipulating the attenuation acquisition protocol. This misalignment, termed cardiac drift, is caused by slow-moving abdominal cavity contents that reposition the heart in the thorax and appear as myocardial uptake overlying the left CT lung in fused PET/CT images. This study evaluates three postimaging registration techniques to correct PET/CT misalignment by altering the transmission map to match myo-cardial uptake. Simulated misalignment studies were performed with a cardiac torso phantom filled with [18F]FDG at 10:1 myocardium/background. An air-filled saline bag affixed to the medial left lung surface served as a distensible lung. An initial CT acquisition was followed by successive PET acquisitions consisting of small displacements of the cardiac insert into the left lung. Phantom transmission scans were aligned to the myocardial uptake in the emission scans by applying 1) full rigid-body translations and rotations, 2) rigid-body restricted to medial / lateral and superior / inferior translation, or 3) an emission-driven method that adds myocardial tissue to the transmission scan. These methods were also applied to 10 low-likelihood coronary artery disease (CAD) patients showing signs of cardiac drift. Full rigid-body registration showed significant over-correction (p < 0.004) of activity concentrations in the artifact areas of the phantom data due the relocation of highly attenuating structures (i.e., spine). Inaccurate regional activity distributions were also observed as streaks extending from the spine and these results were replicated in the patient population. There was no significant difference between the true phantom activity concentration after correction with the emission-driven method. Misalignment corrected with the rigid-body registration results in an increase in activity concentration but fails to accurately recover the true concentration. These data suggest that a nonlinear image registration approach such as an emission-driven method results in a more uniform activity distribution throughout the myocardium, and is more appropriate for addressing the cardiac drift misalignment problem.


Determination of amlodipine using terbium-sensitized luminescence in the presence of europium(III) as a co-luminescence reagent.
A sensitive time-resolved luminescence method for the determination of amlodipine (AM) in methanol and in aqueous solution is described. The method is based on the luminescence sensitization of terbium (Tb(3+) ) by formation of a ternary complex with AM in the presence of tri-n-octylphosphine oxide (TOPO) as co-ligand, dodecylbenzenesulfate as surfactant and europium ion as a co-luminescence reagent. The signal for Tb-AM-TOPO is monitored at λex = 242 nm and λem = 550 nm. Optimum conditions for the formation of the complex in aqueous system were 0.015 m Tris (hydroxylmethyl) amino methane buffer, pH 9.0, TOPO (1.0 × 10(-4) m), Eu(3+) (2.0 × 10(-7) m), dodecylbenzenesulfate (0.14%) and 6.0 × 10(-5) m of Tb(3+) , which allows the determination of 10-50 ppb of AM with a limit of detection of 1.2 ppb. The relative standard deviations of the method range between 0.1 and 0.2% indicated excellent reproducibility of the method. The proposed method was successfully applied for the assay of AM in pharmaceutical formulations and in plasma samples. Average recoveries of 98.5 ± 0.2% and 95.2 ± 0.2% were obtained for AM in tablet and plasma samples respectively.


Structure of tracheal cytotoxin in complex with a heterodimeric pattern-recognition receptor.
Tracheal cytotoxin (TCT), a naturally occurring fragment of Gram-negative peptidoglycan, is a potent elicitor of innate immune responses in Drosophila. It induces the heterodimerization of its recognition receptors, the peptidoglycan recognition proteins (PGRPs) LCa and LCx, which activates the immune deficiency pathway. The crystal structure at 2.1 angstrom resolution of TCT in complex with the ectodomains of PGRP-LCa and PGRP-LCx shows that TCT is bound to and presented by the LCx ectodomain for recognition by the LCa ectodomain; the latter lacks a canonical peptidoglycan-docking groove conserved in other PGRPs. The interface, revealed in atomic detail, between TCT and the receptor complex highlights the importance of the anhydro-containing disaccharide in bridging the two ectodomains together and the critical role of diaminopimelic acid as the specificity determinant for PGRP interaction.


Desvenlafaxine succinate ameliorates visceral hypersensitivity but delays solid gastric emptying in rats.
Desvenlafaxine succinate (DVS) is a novel serotonin and norepinephrine reuptake inhibitor. The aim of this study was to investigate the effects of DVS on visceral hypersensitivity and solid gastric emptying in a rodent model of gastric hyperalgesia. Twenty-eight gastric hyperalgesia rats and 20 control rats were used. Visceral sensitivity during gastric distention (GD) was assessed by recording of electromyogram (EMG) at pressures of 20, 40, 60, and 80 mmHg. DVS with doses of 1, 10, and 30 mg/kg were administrated by gavage, 5-HT1A antagonist (WAY-100635, 0.3 mg/kg) was given subcutaneously, and 5-HT2A antagonist (ketanserin, 1 mg/kg) was given intraperitoneally. The level of norepinephrine in plasma was measured by enzyme-linked immunosorbent assay. We found that 1) visceral hypersensitivity induced by acetic acid was validated. 2) DVS dose-dependently reduced visceral hypersensitivity in the gastric hypersensitivity rats. The EMG (% of baseline value without GD) during GD at 60 and 80 mmHg with DVS at a dose of 30 mg/kg were 119.4 ± 2.3% (vs. saline 150.9 ± 2.7%, P < 0.001) and 128.2 ± 3.2% (vs. saline 171.1 ± 2.4%, P < 0.001). Similar findings were observed at a dose of 10 mg/kg. DVS at a dose of 1 mg/kg reduced visceral hypersensitivity only during GD at 60 mmHg. 3) Neither WAY-100635 nor ketanserin blocked the effect of DVS on visceral sensitivity. 4) DVS at 30 mg/kg significantly increased plasma NE level (P = 0.012 vs. saline). 5) DVS at 30 mg/kg significantly delayed solid gastric emptying (P < 0.05 vs. saline). We conclude that DVS reduces visceral sensitivity in a rodent model of visceral hypersensitivity and delays solid gastric emptying. Caution should be made when DVS is used for treating patients.


An evaluation of inkjet printed amino acid fingerprint test targets for ninhydrin process monitoring - and some observations.
Ninhydrin was implemented as the primary police method of developing latent fingermarks on paper, cardboard and some other porous surfaces from the late 1960s. Some researchers have used individual amino acids, or mixtures of amino acids, as a method of testing the effectiveness of reagent formulations. It was not however known whether simple mixtures of amino acids could effectively emulate latent fingermarks in reactions with reagents such as ninhydrin. The first part of this study compared the effects of ninhydrin fingermark treatments used internationally in various police laboratories on test targets created by inkjet printing graduated concentrations of a representative mixture of amino acids in a series of blocks on paper. Variations in intensity of development were observed between laboratories which used various formulations and heat and humidity post treatment protocols. In a further trial in 2015 several participants in the International Fingerprint Research Group (IFRG) meeting processed test targets in their own laboratories and submitted them for measurement. Again, variation in developed intensity was observed. The depletion of the activity of ninhydrin solutions during use was also investigated in early evaluations of the test targets. An established fingerprint laboratory then processed a number of samples from a batch of targets to examine batch consistency. This was followed by designing a new test target which enabled comparisons between the developed intensity of printed test target blocks alongside depletion series of split, natural donor fingermarks. A panel of 20 donors provided depletion fingermarks and four ninhydrin formulations and treatment protocols were used. The developed test target blocks were scanned, intensity of development measured, and the results compared with the fingermark development which was evaluated by three assessors using two types of scale. Good correlation between the intensity of the developed test targets and latent fingermark quality and intensity scores was observed with the four ninhydrin treatment protocols, including some which used deliberately downgraded ninhydrin concentrations. This type of evaluation was carried out a second time to investigate modified heat and humidity protocols. The use of such test targets for routine reagent quality control and process verification would appear to be far more accurate and reliable than the use of small numbers of donor fingermarks. It is not clear why the different ninhydrin formulations investigated in the latter part of the work have very different optimum post treatment heating regimes.


Eczema, Atopic Dermatitis, or Atopic Eczema: Analysis of Global Search Engine Trends.
The lack of standardized nomenclature for atopic dermatitis (AD) creates challenges for scientific communication, patient education, and advocacy. We sought to determine the relative popularity of the terms eczema, AD, and atopic eczema (AE) using global search engine volumes. A retrospective analysis of average monthly search volumes from 2014 to 2016 of Google, Bing/Yahoo, and Baidu was performed for eczema, AD, and AE in English and 37 other languages. Google Trends was used to determine the relative search popularity of each term from 2006 to 2016 in English and the top foreign languages, German, Turkish, Russian, and Japanese. Overall, eczema accounted for 1.5 million monthly searches (84%) compared with 247 000 searches for AD (14%) and 44 000 searches for AE (2%). For English language, eczema accounted for 93% of searches compared with 6% for AD and 1% for AE. Search popularity for eczema increased from 2006 to 2016 but remained stable for AD and AE. Given the ambiguity of the term eczema, we recommend the universal use of the next most popular term, AD.


Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA.
Innate immune defences are essential for the control of virus infection and are triggered through host recognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs). Hepatitis C virus (HCV) is an RNA virus that replicates in the liver, and infects 200 million people worldwide. Infection is regulated by hepatic immune defences triggered by the cellular RIG-I helicase. RIG-I binds PAMP RNA and signals interferon regulatory factor 3 activation to induce the expression of interferon-alpha/beta and antiviral/interferon-stimulated genes (ISGs) that limit infection. Here we identify the polyuridine motif of the HCV genome 3' non-translated region and its replication intermediate as the PAMP substrate of RIG-I, and show that this and similar homopolyuridine or homopolyriboadenine motifs present in the genomes of RNA viruses are the chief feature of RIG-I recognition and immune triggering in human and murine cells. 5' terminal triphosphate on the PAMP RNA was necessary but not sufficient for RIG-I binding, which was primarily dependent on homopolymeric ribonucleotide composition, linear structure and length. The HCV PAMP RNA stimulated RIG-I-dependent signalling to induce a hepatic innate immune response in vivo, and triggered interferon and ISG expression to suppress HCV infection in vitro. These results provide a conceptual advance by defining specific homopolymeric RNA motifs within the genome of HCV and other RNA viruses as the PAMP substrate of RIG-I, and demonstrate immunogenic features of the PAMP-RIG-I interaction that could be used as an immune adjuvant for vaccine and immunotherapy approaches.


A perspective on Chiropractic Councils on Education accreditation standards and processes from the inside: a narrative description of expert opinion: Part 1: Themes.
The aim of this study was to report on key informant opinions of Councils on Chiropractic Education (CCE) regarding recent research findings reporting on improving accreditation standards and processes for chiropractic programs (CPs). This qualitative study employed in-depth semi-structured interviews with key experienced personnel from the five CCEs in June and July of 2018. The interviews consisted of open-ended questions on a range of issues surrounding accreditation, graduate competency standards and processes. All interviews were audio-recorded, and transcribed verbatim. The transcripts were analysed to develop codes and themes using thematic analysis techniques assisted by NVivo coding software. The study followed the COREQ guidelines for qualitative studies. Six themes were isolated from the interview transcripts; they were: professional differences; keep it in the family; to focus on outcomes or be prescriptive?; more resources please; inter-profession integration; and CPs making ends meet. Most respondents saw a need for CCEs standards and processes to improve interdisciplinarity while at the same time preserving the 'uniqueness' of chiropractic. Additionally, informants viewed CCEs as carrying out their functions with limited resources while simultaneously dealing with vocal disparate interest groups. Diverse views were observed on how CCEs should go about their business of assessing chiropractic programs for accreditation and re-accreditation. An overarching confounder for positive changes in CCE accreditation standards and processes is the inability to clearly define basic and fundamental terms such as 'chiropractic' and its resultant scope of practice. This is said to be because of vocal, diverse and disparate interest groups within the chiropractic profession. Silence or nebulous definitions negotiated in order to allow a diversity of chiropractic practice to co-exist, appears to have complicated and hindered the activities of CCEs. Recommendations are made including an adoption of an evidence-based approach to accreditation standards and processes and the use of expertise from other health professions. Further, the focus of attention should be moved away from professional interests and toward that of protection of the public and the patient.


Indoor Visual Positioning Aided by CNN-Based Image Retrieval: Training-Free, 3D Modeling-Free.
Indoor localization is one of the fundamentals of location-based services (LBS) such as seamless indoor and outdoor navigation, location-based precision marketing, spatial cognition of robotics, etc. Visual features take up a dominant part of the information that helps human and robotics understand the environment, and many visual localization systems have been proposed. However, the problem of indoor visual localization has not been well settled due to the tough trade-off of accuracy and cost. To better address this problem, a localization method based on image retrieval is proposed in this paper, which mainly consists of two parts. The first one is CNN-based image retrieval phase, CNN features extracted by pre-trained deep convolutional neural networks (DCNNs) from images are utilized to compare the similarity, and the output of this part are the matched images of the target image. The second one is pose estimation phase that computes accurate localization result. Owing to the robust CNN feature extractor, our scheme is applicable to complex indoor environments and easily transplanted to outdoor environments. The pose estimation scheme was inspired by monocular visual odometer, therefore, only RGB images and poses of reference images are needed for accurate image geo-localization. Furthermore, our method attempts to use lightweight datum to present the scene. To evaluate the performance, experiments are conducted, and the result demonstrates that our scheme can efficiently result in high location accuracy as well as orientation estimation. Currently the positioning accuracy and usability enhanced compared with similar solutions. Furthermore, our idea has a good application foreground, because the algorithms of data acquisition and pose estimation are compatible with the current state of data expansion.


Maugeri Centre for Telehealth and Telecare: A real-life integrated experience in chronic patients.
Management of chronic diseases in a progressively aging population is a major issue in western industrialized countries and telehealth is one way to ensure the continuity of care in chronic illness. We describe here our personal experience in a telehealth and telecare centre in Italy. Between January 2000 and December 2015, 1635 elderly patients (71% male) with one or more comorbidities have undergone a telehealth program tailored to their specific disease: chronic obstructive pulmonary disease (COPD)/chronic respiratory insufficiency; amyotrophic lateral sclerosis/neuromuscular diseases; chronic heart failure (CHF); post-stroke; and post-cardiac surgery patients discharged from hospital after an acute event. COPD and CHF represent the majority of patients treated (accounting for 80%). Interventions performed by the nurse tutor account for 39-82% of all activities in the five different programs. Specialist second opinion represents 12-27% of the health staff activities. Previously reported results show a reduction of the re-hospitalization rate and costs, and increase in quality of life and patient satisfaction with the service. A multidisciplinary telehealth and telecare integrated approach can provide efficient management for the growing number of complex patients.


The potential for crizotinib in non-small cell lung cancer: a perspective review.
Tyrosine kinases have a crucial role as key regulators of signaling pathways that influence cell differentiation and growth. Dysregulation of tyrosine kinase-mediated signaling is understood to be an important oncogenic driver. Genetic rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) gene occur in non-small cell lung cancer (NSCLC), anaplastic large cell lymphomoas, inflammatory myofibroblastic tumors, and other cancers. Cells with abnormal ALK signaling are sensitive to ALK inhibitors such as crizotinib. This review will highlight the discovery of the fusion between echinoderm microtubule-associated protein-like 4 (EML4) and ALK as an oncogenic driver, recognition of other ALK gene rearrangements in NSCLC, and the confirmation that crizotinib is an effective treatment for patients with ALK-positive NSCLC. Work is underway to further define the role for crizotinib in the treatment of ALK-positive lung cancer and other cancers and to investigate the molecular mechanisms for resistance to ALK inhibition with crizotinib.


Novel plant virus-based vaccine induces protective cytotoxic T-lymphocyte-mediated antiviral immunity through dendritic cell maturation.
Currently used vaccines protect mainly through the production of neutralizing antibodies. However, antibodies confer little or no protection for a majority of chronic viral infections that require active involvement of cytotoxic T lymphocytes (CTLs). Virus-like particles (VLPs) have been shown to be efficient inducers of cell-mediated immune responses, but administration of an adjuvant is generally required. We recently reported the generation of a novel VLP system exploiting the self-assembly property of the papaya mosaic virus (PapMV) coat protein. We show here that uptake of PapMV-like particles by murine splenic dendritic cells (DCs) in vivo leads to their maturation, suggesting that they possess intrinsic adjuvant-like properties. DCs pulsed with PapMV-like particles displaying the lymphocytic choriomeningitis virus (LCMV) p33 immunodominant CTL epitope (PapMV-p33) efficiently process and cross-present the viral epitope to p33-specific transgenic T cells. Importantly, the CTL epitope is also properly processed and presented in vivo, since immunization of p33-specific T-cell receptor transgenic mice with PapMV-p33 induces the activation of large numbers of specific CTLs. C57BL/6 mice immunized with PapMV-p33 VLPs in the absence of adjuvant develop p33-specific effector CTLs that rapidly expand following LCMV challenge and protect vaccinated mice against LCMV infection in a dose-dependent manner. These results demonstrate the efficiency of this novel plant virus-based vaccination platform in inducing DC maturation leading to protective CTL responses.


Additive effectiveness of mindfulness meditation to a school-based brief cognitive-behavioral alcohol intervention for adolescents.
This randomized controlled trial is the 1st study to evaluate the additive efficacy of mindfulness meditation to brief school-based universal cognitive behavior therapy (CBT + MM) for adolescent alcohol consumption. Previous studies have lacked strong controls for nonspecific effects, and treatment mechanisms remain unclear. The present study compared a CBT + MM condition to an active control CBT intervention with progressive muscle relaxation (CBT + PMR) for nonspecific effects and an assessment-only control (AoC). Cluster sampling was used to recruit Australian adolescents (N = 404; 62% female) ages 13-17 years (M = 14.99, SD = .66) of mostly Australian-New Zealand or European descent. School classes were randomized to 3 intervention conditions (CBT + PMR = 8 classes, CBT + MM = 7 classes, AoC = 7 classes), and adolescents completed preintervention, postintervention, and 3- and 6-month follow-up assessments, including measures of alcohol consumption, mindfulness, impulsivity, and the alcohol-related cognitions of alcohol expectancies and drinking refusal self-efficacy. Multilevel modeling analyses revealed that both intervention conditions reduced the growth of alcohol consumption compared to the AoC (b = -.18, p = .014), although CBT + MM was no more effective than was CBT + PMR (b = -.06, p = .484). Negative alcohol expectancies increased for adolescents in the intervention conditions compared to the AoC (b = 1.09, p = .012), as did positive alcohol expectancies (b = 1.30, p = .008). There was no effect of interventions on mindfulness, drinking refusal self-efficacy, or impulsivity. There was no evidence of mindfulness-specific effects beyond existing effects of CBT within a brief universal school-based CBT intervention. Hypothesized mechanisms of change were largely unsupported. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Comparison of dexmedetomidine-propofol and ketamine-propofol administration during sedation-guided upper gastrointestinal system endoscopy.
Dexmedetomidine and ketamine popular sedative agents that result in minimal respiratory depression and the presence of analgesic activity. We aimed to compare the effectiveness and safety of a dexmedetomidine-propofol combination and a ketamine-propofol combination during upper gastrointestinal system endoscopy. The study commenced after receiving approval from the local ethics committee. Patients between 18 and 60 years in the American Society of Anesthesiologists (ASA) I and II groups were included. Patients who had severe organ disease, who had allergies to the study drugs, and who refused to participate were excluded. Cases were randomized into a dexmedetomidine-propofol group (Group D, n = 30) and a ketamine-propofol group (Group K, n = 30). Cardiac monitoring, peripheral oxygen saturation, and bispectral index (BIS) monitoring were performed. Group D received 1 mg/kg dexmedetomidine + 0.5 mg/kg propofol intravenous (IV) bolus, 0.5 μg/kg/h dexmedetomidine + 0.5 mg/kg/h propfol infusion. Group K received 1 mg/kg ketamine + 0.125 mL/kg propofol iv bolus, 0.25 mg/kg/h ketamine + 0.125 mL/kg/h propfol infusion. Patients were followed up with a Ramsay Sedation Scale (RSS) of ≥4. Means, standard deviations, lowest and highest frequency values, and ratio values were used for descriptive statistics, and the SPSS 22.0 program was used for statistical analyses. In Group K, recovery time and mean blood pressure (MBP) values were significantly shorter. Furthermore, coughing rate, pulse, and BIS values were higher than in Group D (P < .05). Although there were no significant differences between the groups in terms of endoscopic tolerance and endoscopist satisfaction, we observed that the dexmedetomidine group experienced more comfortable levels of sedation. Dexmedetomidine-propofol and ketamine-propofol combinations may be suitable and safe for endoscopy sedation due to their different properties. It was observed that the dexmedetomidine-propfol combination was superior in terms of sedation depth and that the ketamine-propofol combination was superior in terms of early recovery. As a result, we suggest the dexmedetomidine-propofol combination for upper gastrointestinal system endoscopy sedation due to hemodynamic stability and minimal adverse effects.


Calculating State-Level Estimates of Upcoming Older Adult Health Needs.
Census demographers have provided projections of the increased numbers of older adults in upcoming decades, but it is less clear whether they will also be any more or less healthy than current seniors. This is critical information for state planners, as the majority of older adults will need assistance with activities of daily living to remain in their homes. Previous longitudinal and cohort studies have yielded national estimates, but those more costly sources are generally beyond the resources of state public health agencies. We provide a more practicable model for assessing state-level changes in health-related quality of life (HRQOL) among middle-aged versus older adults as a guide to probable upcoming home- and community-based service needs. We used 2 sets of state Behavioral Risk Factor Surveillance System data 15 years apart to calculate and compare adjusted odds ratios of 8 poor HRQOL measures for middle-aged and older adults. Compared with their peers only 15 years earlier, recent middle-aged adults had higher odds of poor outcomes across all HRQOL measures, whereas adults 65-74 years had higher odds of poor outcomes for far fewer of the measures. Among adults 75 years and older, odds were higher compared with 15 years ago for only 1 measure (multiple days of poor mental health). Compared with older adults, the health profile of middle-aged adults in this state appears to have worsened much more rapidly in the past 15 years, indicating that these adults will have many more health-related needs when they become seniors. While this model is less sophisticated than others using longitudinal data, it provides the state-level data that are often more compelling to state policy makers.


Lymphocytic Esophagitis: Current Understanding and Controversy.
This review summarizes our current understanding of lymphocytic esophagitis (LE), a novel form of chronic esophagitis that incorporates distinctive histologic, clinical, and endoscopic features. First described as a histologic entity, a diagnosis of LE requires intraepithelial lymphocytosis without significant granulocytic inflammation and some evidence of epithelial damage; the rationale for and studies supportive of these histologic criteria are discussed within. Clinically, the majority of patients who present with histologically confirmed LE are older women or patients with underlying immunologic abnormalities, such as Crohn disease, rheumatologic disorders, or common variable immunodeficiency. The most common presenting symptom of LE is dysphagia, and the endoscopic findings can vary from normal mucosa to mucosal changes that resemble eosinophilic esophagitis: edema, rings, furrows, and plaques. The incidence of luminal strictures and the persistent dysphagia and/or lymphocytosis present in some patients provide evidence that LE is a chronic inflammatory disorder, at least within a subset of individuals. Several histologic mimics of LE are examined, as are disagreements surrounding the LE diagnosis.


[Lipid peroxidation in the cyst fluid of craniopharyngiomas].
Comparing of the craniopharyngiomas cyst fluid, collected during the surgery, with blood plasma revealed significantly enhanced lipid peroxidation and lactate accumulation in tumour cysts contents. These processes were usually more prominent in endosuprasellar than in suprasellar craniopharyngiomas. The maximum of free radical formation in conjunction with the lowest level of malondialdehyde (MDA) was observed in primary tumours with relatively high proliferation rate. Controversial parameters ratio characterised the recurrent craniopharyngiomas, and in cyst fluids of the primary tumours with low proliferation rate the medium parameter's values were observed. Thus, the estimation of free radical formation level and MDA concentration in cyst fluid of craniopharyngioma seems to be prognostic for the tumour recurrence.


[Perforated jejunal diverticulum. A case report].
The Authors report on a case of a 69 years old woman with an acute peritonitis secondary to a perforated jejunal diverticulum, treated by laparotomy and intestinal resection with end-to-end anastomosis in one layer. The patient was dismissed after seven days, in good general conditions. Jejunal diverticula occur in around 1% of general population. They are usually asymptomatic; sometimes they give origin to dyspepsia or acute manifestations. These are due to complications at the site of the diverticulum like bleeding, occlusion and acute infection with perforation and peritonitis, as occurred in our patient. The main risk in diverticular complications is to prolong the interval between admission of the patient and surgical treatment, favouring the initiation of hypovolemic or septic shock. For these reasons, in most recent years, C.T. and, in case of bleeding, capsule endoscopy, were used in the diagnostic pre-operative work-up. The surgical technique is jejunal resection with direct anastomosis, leaving percutaneous drainage only for patients with an abscess, in poor general conditions for a narcosis.


An Evidence-Based Algorithm for Determining Venous Thromboembolism Prophylaxis After Degenerative Spinal Surgery.
Although venous thromboembolism (VTE) is a potentially serious and life-threatening complication, there is no widely accepted protocol to guide VTE prophylaxis in adult degenerative spinal surgery, and pharmacologic overtreatment may result in hemorrhagic complications. Previously, we published the VTE Prophylaxis Risk/Benefit Score, an evidence-based algorithm that balances the risk and consequences of thrombotic versus hemorrhagic complications by taking consideration of patient-related risks, procedure-related risks, and the risk of neurological compromise to guide VTE prophylaxis. To objective of this study was to validate the VTE Prophylaxis Risk/Benefit Score. From January 1, 2016, to December 31, 2017, VTE Prophylaxis Risk/Benefit Scores and corresponding prophylaxes were prospectively assigned. When indicated, chemoprophylaxis was dosed 24 to 36 hours postoperatively to allow for adequate surgical hemostasis. Patients were retrospectively evaluated for immediate and short-term complications. The Fisher exact test compared incidence of complications by VTE prophylaxis. Multinomial logistic regression modeled the probability of complication by prophylaxis type, demographics, and comorbidities. Significance was set at P < .05. Of the 266 patients who met inclusion criteria, 79.3% were given mechanical prophylaxis alone and 20.7% were given combined mechanical and chemical prophylaxis. Complications including VTE (0.38%), delayed wound healing or infection (2.26%), and hematoma (0.75%) were observed at rates similar to or lower than previously published studies with increased utilization of chemoprophylaxis. Use of chemoprophylaxis and continuation of perioperative aspirin were significantly associated with the development of a hemorrhagic complication. No patient developed persistent neurologic deficit from hematoma or pulmonary embolism. The VTE Prophylaxis Risk/Benefit Score comprehensively considers the risk of thrombotic, wound, and bleeding complications and is an effective tool for determining appropriate thromboprophylaxis in adult degenerative spinal surgery. 3.


Acute resetting of baroreceptor reflex in rabbits: a central component.
Electrical stimulation of the aortic nerve of the anesthetized rabbit was used to determine whether there is a central nervous system component to acute resetting of the baroreceptor reflex. After stimulation of the aortic nerve for 5 min at 10 Hz, a ramp test stimulus to the nerve produced a reflex arterial pressure response that was attenuated as compared with that produced by the same ramp prior to the five-min stimulation period. Renal sympathetic nerve activity was recorded simultaneously to determine whether a reduction in the magnitude of the reflex inhibition of sympathetic activity produced by the depressor nerve stimulation could account for the attenuated arterial pressure response. Renal activity during the test ramp was reduced to the same value both before and after the constant stimulus period and thus did not correlate with the attenuated pressure response. There was, however, prolonged inhibition of tonic sympathetic activity after the 5-min stimulus period such that during the test stimulus there was less sympathetic activity to inhibit. The results were similar when sympathetic activity was recorded from branches of the sciatic nerve and from thoracic postganglionic nerves. In these nerves the period of prolonged inhibition after aortic nerve stimulation was up to 5 min. The attenuated pressure response to baroreceptor nerve stimulation after a constant stimulus appears to reflect the reduced change in sympathetic activity rather than the value to which the sympathetic activity falls.


Hypertension and cardiovascular diseases intervention in the capital steel and iron company and Beijing Fangshan community.
Two intervention studies are described involving >110,000 subjects in each. The first was in a steel factory where one intervention site had health promotion, aimed at altering diet, and particularly reducing salt and fat intake, modest alcohol drinking and smoking cessation, together with a high-risk strategy of hypertension control. The second study involved similar population and high-risk strategies in three of five rural communities. Significant reductions occurred in both intervention and control factory sites in blood pressure, with greater falls in the intervention site, together with a marked additional reduction in salt intake and better control of hypertension. In the rural communities, blood pressure fell in all communities to a more modest degree than in the factory, but with greater blood pressure falls, together with greater smoking cessation and more modest alcohol drinking in the intervention compared with the control communities. Stroke mortality fell by 74.3% and all strokes morbidity by 54.7% in the steel factory as a whole. In the rural communities, the intervention sites showed significantly greater falls in stroke rates than in the control communities. These data show the value and effectiveness of combining a population and high-risk strategy for controlling blood pressure and cardiovascular diseases in both a rural setting and in the work place in China.


Detection of heterogeneous drug-protein binding by frontal analysis and high-performance affinity chromatography.
This study examined the use of frontal analysis and high-performance affinity chromatography for detecting heterogeneous binding in biomolecular interactions, using the binding of acetohexamide with human serum albumin (HSA) as a model. It was found through the use of this model system and chromatographic theory that double-reciprocal plots could be used more easily than traditional isotherms for the initial detection of binding site heterogeneity. The deviations from linearity that were seen in double-reciprocal plots as a result of heterogeneity were a function of the analyte concentration, the relative affinities of the binding sites in the system and the amount of each type of site that was present. The size of these deviations was determined and compared under various conditions. Plots were also generated to show what experimental conditions would be needed to observe these deviations for general heterogeneous systems or for cases in which some preliminary information was available on the extent of binding heterogeneity. The methods developed in this work for the detection of binding heterogeneity are not limited to drug interactions with HSA but could be applied to other types of drug-protein binding or to additional biological systems with heterogeneous binding.


Modulation of CRMP2 via (S)-Lacosamide shows therapeutic promise but is ultimately ineffective in a mouse model of CLN6-Batten disease.
CLN6-Batten disease is a rare neurodegenerative disorder with no cure, characterized by accumulation of lipofuscin in the lysosome, glial activation, and neuronal death. Here we test the therapeutic efficacy of modulating collapsin response mediator protein 2 (CRMP2) activity via S-N-benzy-2-acetamido-3-methoxypropionamide ((S)-Lacosamide) in a mouse model of CLN6-Batten disease. Promisingly, mouse neuronal cultures as well as Cln6 patient fibroblasts treated with varying concentrations of (S)-Lacosamide showed positive restoration of lysosomal associated deficits. However, while acute in vivo treatment enhanced glial activation in 3-month-old Cln6 mutant mice, chronic treatment over several months did not improve behavioral or long-term survival outcomes. Therefore, modulation of CRMP2 activity via (S)-Lacosamide alone is unlikely to be a viable therapeutic target for CLN6-Batten disease.


Computerized provider documentation: findings and implications of a multisite study of clinicians and administrators.
Clinical documentation is central to the medical record and so to a range of healthcare and business processes. As electronic health record adoption expands, computerized provider documentation (CPD) is increasingly the primary means of capturing clinical documentation. Previous CPD studies have focused on particular stakeholder groups and sites, often limiting their scope and conclusions. To address this, we studied multiple stakeholder groups from multiple sites across the USA. We conducted 14 focus groups at five Department of Veterans Affairs facilities with 129 participants (54 physicians or practitioners, 34 nurses, and 37 administrators). Investigators qualitatively analyzed resultant transcripts, developed categories linked to the data, and identified emergent themes. Five major themes related to CPD emerged: communication and coordination; control and limitations in expressivity; information availability and reasoning support; workflow alteration and disruption; and trust and confidence concerns. The results highlight that documentation intertwines tightly with clinical and administrative workflow. Perceptions differed between the three stakeholder groups but remained consistent within groups across facilities. CPD has dramatically changed documentation processes, impacting clinical understanding, decision-making, and communication across multiple groups. The need for easy and rapid, yet structured and constrained, documentation often conflicts with the need for highly reliable and retrievable information to support clinical reasoning and workflows. Current CPD systems, while better than paper overall, often do not meet the needs of users, partly because they are based on an outdated 'paper-chart' paradigm. These findings should inform those implementing CPD systems now and future plans for more effective CPD systems.


Optimization of imprintable nanostructured a-Si solar cells: FDTD study.
We present a finite-difference time-domain (FDTD) study of an amorphous silicon (a-Si) thin film solar cell, with nano scale patterns on the substrate surface. The patterns, based on the geometry of anisotropically etched silicon gratings, are optimized with respect to the period and anti-reflection (AR) coating thickness for maximal absorption in the range of the solar spectrum. The structure is shown to increase the cell efficiency by 10.2% compared to a similar flat solar cell with an optimized AR coating thickness. An increased back reflection can be obtained with a 50 nm zinc oxide layer on the back reflector, which gives an additional efficiency increase, leading to a total of 14.9%. In addition, the patterned cells are shown to be up to 3.8% more efficient than an optimized textured reference cell based on the Asahi U-type glass surface. The effects of variations of the optimized solar cell structure due to the manufacturing process are investigated, and shown to be negligible for variations below ±10%.


Physical growth of children and adolescents living at a moderate altitude: proposed percentiles based on age and sex.
Introduction: physical growth patterns and nutritional status of children and adolescents living at a moderate altitude are not applicable for clinical assessment of growth for diverse populations around the world. Objective: a) to compare weight, height and body mass index (BMI) variables with CDC-2012 references; b) to verify if BMI and/or ponderal index (PI) are applicable to children living at a moderate altitude; and c) to propose percentiles to assess physical growth by age and sex. Methods: a total of 5,377 students, ranging in age from 6.0 to 17.9 years, were evaluated. The students were from two geographic regions of moderate altitude in Peru (2,320 meters) and Colombia (2,640 meters). Weight and height were measured. BMI and PI were calculated. Weight, height and BMI were compared with CDC-2012 references. Results: males showed lower weight and height from age 11 to 17.9 years compared to CDC-2012. Females weighed less than the reference from 9.0 to 17.9 years. Female height was lower from 6.0 to 14.9 years; however, from 15.0 to 17.9 years, values were similar to the reference. As for BMI, there were differences in both sexes (in males, from 15.0 to 17.9 years, and in females, from 12.0 to 17.9 years). Age, weight and height explained BMI: between R2 = 17 and 83 % in males, and in females between R2 = 24 and 85 %. These same variables influenced PI in a lower percentage in both sexes: for males (R2 = 0.01 to 49 %) and for females (R2 = 0.01 to 18 %). Conclusions: children and adolescents living at a moderate altitude in Peru and Colombia diverge from the CDC-2012 physical growth patterns. In addition, PI is a new alternative for estimating weight in relation to BMI. The proposed curves for weight, height, and PI by age and sex could have greater implications in the control of child health programs and in clinical and epidemiological practices.


Body weight and the medial longitudinal foot arch: high-arched foot, a hidden problem?
This study had two objectives. First, to determine the prevalence of hollow (high-arched) and flat foot among primary school children in Cracow (Poland). Second, to evaluate the relationship between the type of medial longitudinal arch (MLA; determined by the Clarke's angle) and degree of fatness. The prevalence of underweight, overweight, and obesity was determined by means of IOTF cut-offs with respect to age and gender. A sample of 1,115 children (564 boys and 551 girls) aged between 3 and 13 years was analyzed. In all age groups, regardless of gender, high-arched foot was diagnosed in the majority of children. A distinct increase in the number of children with high-arched foot was observed between 7- and 8-year olds. Regardless of the gender, high-arched foot was more common among underweight children. In the group of obese children, the biggest differences were attributed to gender. High-arched foot was the most frequently observed among boys. In all gender and obesity level groups, the flat foot was more common among boys than among girls. High-arched foot is the most common foot defect among children 3-13 years old regardless of gender. Flat foot is least frequently observed in children 3-13 years old. A statistic correlation between MLA and adiposity is observed. Stronger correlation is observed among girls.


Contact transscleral laser cyclocoagulation in glaucoma.
A new way to treat glaucoma by laser coagulation of the ciliary body was developed. The laser beam is channeled to the eye through the fiberoptic system. The tip of the fiberoptic probe is placed in direct contact with the surface of the eye to be treated. The technical equipment developed for contact transscleral laser cyclocoagulation is simple, practical, and easy to use. The method was investigated experimentally (on animals and on human eyes to be enucleated) and tried in clinical practice. Only patients facing glaucoma surgery (on whom all other methods of conservative therapy failed) were selected for this kind of treatment. The immediate hypotensive effect was approximately 13 mmHg during the first 24 hours; then there was a gradual elevation of the tension, reducing the initial effect on average by 30%. This method has definite advantages over surgical cyclocoagulation as far as safety and simplicity are concerned. The use of contact fiberoptic systems may open up new possibilities in other fields of laser treatment of glaucoma, including techniques to channel the laser beam to the structures of the anterior chamber angle.


Functional sites of the Ada regulatory protein of Escherichia coli. Analysis by amino acid substitutions.
Specific cysteine residues at possible methyl acceptor sites of the Ada protein of Escherichia coli were converted to other amino acids by site-directed mutagenesis of the cloned ada gene of E. coli. Ada protein with the cysteine residue at 321 replaced by alanine was capable of accepting the methyl group from the methylphosphotriester but not from O6-methylguanine or O4-methylthymine of alkylated DNA, whereas the protein with alanine at position 69 accepted the methyl group from the methylated bases but not from the methylphosphotriester. These two mutants were used to elucidate the biological significance of repair of the two types of alkylation lesions. Introduction of the ada gene with the Ala69 mutation into an ada- cell rendered the cell more resistant to alkylating agents with respect to both killing and induction of mutations, but the gene with the Ala321 mutation exhibited no such activity. Replacement of the cysteine residue at position 69, but not at position 321, abolished the ability of Ada protein to promote transcription of both ada and alkA genes in vitro. These results are compatible with the idea that methylation of the cysteine residue at position 69 renders Ada protein active as a transcriptional regulator, whilst the cysteine residue at position 321 is responsible for repair of pre-mutagenic and lethal lesions in DNA. The actions of mutant Ada proteins on the ada and alkA promoters in vivo were investigated using an artificially composed gene expression system. When the ada gene with the Ala69 mutation was introduced into the cell, there was little induction of expression of either the ada or the alkA genes, even after treatment with an alkylating agent, in agreement with the data obtained from studies in vitro. With the Ala321 mutation, however, a considerable degree of ada gene expression occurred without adaptive treatment. The latter finding suggests that the cysteine residue at position 321, which is located near the C terminus of the Ada protein, is involved in regulating activity, as the transcriptional activator.


Copper-catalyzed intermolecular amidation and imidation of unactivated alkanes.
We report a set of rare copper-catalyzed reactions of alkanes with simple amides, sulfonamides, and imides (i.e., benzamides, tosylamides, carbamates, and phthalimide) to form the corresponding N-alkyl products. The reactions lead to functionalization at secondary C-H bonds over tertiary C-H bonds and even occur at primary C-H bonds. [(phen)Cu(phth)] (1-phth) and [(phen)Cu(phth)2] (1-phth2), which are potential intermediates in the reaction, have been isolated and fully characterized. The stoichiometric reactions of 1-phth and 1-phth2 with alkanes, alkyl radicals, and radical probes were investigated to elucidate the mechanism of the amidation. The catalytic and stoichiometric reactions require both copper and tBuOOtBu for the generation of N-alkyl product. Neither 1-phth nor 1-phth2 reacted with excess cyclohexane at 100 °C without tBuOOtBu. However, the reactions of 1-phth and 1-phth2 with tBuOOtBu afforded N-cyclohexylphthalimide (Cy-phth), N-methylphthalimide, and tert-butoxycyclohexane (Cy-OtBu) in approximate ratios of 70:20:30, respectively. Reactions with radical traps support the intermediacy of a tert-butoxy radical, which forms an alkyl radical intermediate. The intermediacy of an alkyl radical was evidenced by the catalytic reaction of cyclohexane with benzamide in the presence of CBr4, which formed exclusively bromocyclohexane. Furthermore, stoichiometric reactions of [(phen)Cu(phth)2] with tBuOOtBu and (Ph(Me)2CO)2 at 100 °C without cyclohexane afforded N-methylphthalimide (Me-phth) from β-Me scission of the alkoxy radicals to form a methyl radical. Separate reactions of cyclohexane and d12-cyclohexane with benzamide showed that the turnover-limiting step in the catalytic reaction is the C-H cleavage of cyclohexane by a tert-butoxy radical. These mechanistic data imply that the tert-butoxy radical reacts with the C-H bonds of alkanes, and the subsequent alkyl radical combines with 1-phth2 to form the corresponding N-alkyl imide product.


Liver transplantation of Budd-Chiari syndrome.
Orthotopic liver transplantation was accomplished in a 22-year-old woman dying of the Budd-Chiari syndrome. She is well and has normal liver function 16 months postoperatively. In view of the good early result, it will be appropriate to consider liver replacement for this disease in further well-selected cases.


Spatial seed and pollen games: dispersal, sex allocation, and the evolution of dioecy.
The evolutionary forces shaping within- and across-species variation in the investment in male and female sex function are still incompletely understood. Despite earlier suggestions that in plants the evolution or cosexuality vs. dioecy, as well as sex allocation among cosexuals, is affected by seed and pollen dispersal, no formal model has explicitly used dispersal distances to address this problem. Here, we present a game-theory model as well as a simulation study that fills in this gap. Our model predicts that dioecy should evolve if seeds and pollen disperse widely and that sex allocation among cosexuals should be biased towards whichever sex function produces more widely dispersing units. Dispersal limitations stabilize cosexuality by reinforcing competition between spatially clumped dispersal units from the same source, leading to saturating fitness returns that render sexual specialization unprofitable. However, limited pollen dispersal can also increase the risk of selfing, thus potentially selecting for dioecy as an outbreeding mechanism. Finally, we refute a recent claim that cosexuals should always invest equally in both sex functions.


Time-resolved dissection of early phosphoproteome and ensuing proteome changes in response to TGF-β.
Transforming growth factor-β (TGF-β) signaling promotes cell motility by inducing epithelial-to-mesenchymal transitions (EMTs) in normal physiology and development, as well as in pathological conditions, such as cancer. We performed a time-resolved analysis of the proteomic and phosphoproteomic changes of cultured human keratinocytes undergoing EMT and cell cycle arrest in response to stimulation with TGF-β. We quantified significant changes in 2079 proteins and 2892 phosphorylation sites regulated by TGF-β. We identified several proteins known to be involved in TGF-β-induced cellular processes, such as the cytostatic response, extracellular matrix remodeling, and epithelial dedifferentiation. In addition, we identified proteins involved in other cellular functions, such as vesicle trafficking, that were not previously associated with TGF-β signaling. Although many TGF-β responses are mediated by phosphorylation of the transcriptional regulators of the SMAD family by the TGF-β receptor complex, we observed rapid kinetics of changes in protein phosphorylation, indicating that many responses were mediated through SMAD-independent TGF-β signaling. Combined analysis of changes in protein abundance and phosphorylation and knowledge of protein interactions and transcriptional regulation provided a comprehensive representation of the dynamic signaling events underlying TGF-β-induced changes in cell behavior. Our data suggest that in epithelial cells stimulated with TGF-β, early signaling is a mixture of both pro- and antiproliferative signals, whereas later signaling primarily inhibits proliferation.


Piwi/PRG-1 Argonaute and TGF-β Mediate Transgenerational Learned Pathogenic Avoidance.
The ability to inherit learned information from parents could be evolutionarily beneficial, enabling progeny to better survive dangerous conditions. We discovered that, after C. elegans have learned to avoid the pathogenic bacteria Pseudomonas aeruginosa (PA14), they pass this learned behavior on to their progeny, through either the male or female germline, persisting through the fourth generation. Expression of the TGF-β ligand DAF-7 in the ASI sensory neurons correlates with and is required for this transgenerational avoidance behavior. Additionally, the Piwi Argonaute homolog PRG-1 and its downstream molecular components are required for transgenerational inheritance of both avoidance behavior and ASI daf-7 expression. Animals whose parents have learned to avoid PA14 display a PA14 avoidance-based survival advantage that is also prg-1 dependent, suggesting an adaptive response. Transgenerational epigenetic inheritance of pathogenic learning may optimize progeny decisions to increase survival in fluctuating environmental conditions.


Ion-specific and general ionic effects on contraction of skinned fast-twitch skeletal muscle from the rabbit.
We used single fibers from rabbit psoas muscle, chemically skinned with Triton X-100 nonionic detergent, to determine the salts best suited for adjusting ionic strength of bathing solutions for skinned fibers. As criteria we measured maximal calcium-activated force (Fmax), fiber swelling estimated optically, and protein extraction from single fibers determined by polyacrylamide gel electrophoresis with ultrasensitive silver staining. All things considered, the best uni-univalent salt was potassium methanesulfonate, while a number of uni-divalent potassium salts of phosphocreatine, hexamethylenediamine N,N,N',N'-tetraacetic acid, sulfate, and succinate were equally acceptable. Using these salts, we determined that changes in Fmax correlated best with variations of ionic strength (1/2 sigma ci z2i, where ci is the concentration of ion i, and zi is its valence) rather than ionic equivalents (1/2 sigma ci magnitude of zi). Our data indicate that increased ionic strength per sc decreases Fmax, probably by destabilizing the cross-bridge structure in addition to increasing electrostatic shielding of actomyosin interactions.


The metabolic profile of lemon juice by proton HR-MAS NMR: the case of the PGI Interdonato Lemon of Messina.
We have studied by means of High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HR-MAS NMR) the metabolic profile of the famous Sicilian lemon known as 'Interdonato Lemon of Messina PGI'. The PGI Interdonato Lemon of Messina possesses high organoleptic and healthy properties and is recognised as one of the most nutrient fruits. In particular, some of its constituents are actively studied for their chemo-preventive and therapeutic properties. In this paper, we have determined by means of HR-MAS NMR spectroscopy the molar concentration of the main metabolites constituent the juice of PGI Interdonato Lemon of Messina in comparison with that of the not-PGI Interdonato Lemon of Turkey. Our aim is to develop an analytical technique, in order to determine a metabolic fingerprint able to reveal commercial frauds in national and international markets.


Missed opportunities for HIV testing among newly diagnosed HIV-infected adults in Abidjan, Côte d'Ivoire.
HIV testing is crucial for starting ART earlier in HIV-infected people. We describe Missed Opportunities (MO) for HIV testing among adults newly diagnosed with HIV in Abidjan, Côte d'Ivoire. Between april,2nd 2013 and april 1st 2014, a cross-sectional study was conducted among all adults newly diagnosed (< 1year) for HIV at the Blood Donors Medical Center of Abidjan with face to face questionnaire. An MO for HIV testing was defined as a medical consultation for a clinical indicator (e.g. symptoms, hospitalization, and pregnancy) or a non-clinical indicator (e.g. high-risk sexual behavior, HIV-infected partner) potentially related to an HIV infection but did not lead to HIV test proposal by a health care professional. Of the 341 patients who attended the center suring this period, 273 (157 women and 116 men) were included in this analysis. 130 (47.6%) reported at least one medical consultation for an indicator relevant for a test proposal between 1 month and five years prior to their diagnosis. Among them, 92 (77.3%) experienced at least one MO for testing. The 273 included patients reported a total of 216 indicators; 146 (67.6%) were reported without test proposal and thus were MO. Hospitalization, extreme lose of weight, chronic or repeat fever and herpes zoster were the indicators with the largest number of MO. While 66 (24.2%) patients experienced non-clinical indicators relevant to risk of HIV infection, only 11 (4.0%) mentioned it to a health professional. MO for HIV testing are frequent, even in situations for which testing is clearly recommended. Better train healthcare professionals and creating new opportunities of testing inside and, outside of medical settings are crucial to improve HIV control.