Treating sarcopenia in older and oldest old.
The presence of sarcopenia is not only rapidly rising in geriatric clinical practice and research, but is also becoming a significant concept in numerous medical specialties. This rapidly rising concept has encouraged the need to identify methods for treating sarcopenia. Physical activity measures using resistance training exercise, combined with nutritional interventions (protein and amino acid supplementation) have shown to significantly improve muscle mass and strength in older persons. Moreover, resistance training may improve muscle strength and mass by improving protein synthesis in skeletal muscle cells. Aerobic exercise has also shown to hold beneficial impacts on sarcopenia by improving insulin sensitivity. At the moment, the literature indicates that most significant improvement in sarcopenia is based on exercise programs. Thus, this type of intervention should be implemented in a persistent manner over time in elders, with or at risk of muscle loss. At the same time, physical training exercise should include correcting nutritional deficits with supplementation methods. For example, in older sarcopenic patients with adequate renal function, daily protein intake should be increased to >1. 0 grams of protein per kilogram of body weight. In particular, leucine, - hydroxy β-methylbutyrate (HMB), creatine and some milk-based proteins have been shown to improve skeletal muscle protein balance. In addition, it is also recommended for adjustment of for vitamin D deficiency, if present, considering the crucial role of vitamin D in the skeletal muscle. In this review, we provide evidence regarding the effects of different physical exercise protocols, specific nutritional intervention, and some new metabolic agents (HMB, citrulline malate, ornithine, and others) on clinical outcomes related to sarcopenia in older adults.


How translocons select transmembrane helices.
Like all cellular proteins, membrane proteins are synthesized by ribosomes. But unlike their soluble counterparts, highly hydrophobic membrane proteins require auxiliary machineries to prevent aggregation in aqueous cellular compartments. The principal machine is the translocon, which works in concert with ribosomes to manage the orderly insertion of alpha-helical membrane proteins directly into the endoplasmic reticulum membrane of eukaryotes or into the plasma membrane of bacteria. In the course of insertion, membrane proteins come into thermodynamic equilibrium with the lipid membrane, where physicochemical interactions determine the final three-dimensional structure. Much progress has been made during the past several years toward understanding the physical chemistry of membrane protein stability, the structure of the translocon machine, and the mechanisms by which the translocon selects and inserts transmembrane helices. We review this progress and consider the connection between the physical principles of membrane protein stability and translocon selection of transmembrane helices.


Up-regulation of myometrial RHO effector proteins (PKN1 and DIAPH1) and CPI-17 (PPP1R14A) phosphorylation in human pregnancy is associated with increased GTP-RHOA in spontaneous preterm labor.
RHO GTP-binding proteins are important regulators of actin-myosin interactions in uterine smooth muscle cells. Active (GTP-bound) RHOA binds to RHO-associated protein kinase (ROCK1), which inhibits the myosin-binding subunit (PPP1R12A) of myosin light chain phosphatase, leading to calcium-independent increases in myosin light chain phosphorylation and tension, which are termed "calcium sensitization." The RHO effector protein kinase N (PKN1) also increases calcium sensitization by phosphorylating the protein kinase C (PRKCB)-dependent protein CPI-17 (PPP1R14A) to inhibit the PPP1c subunit of myosin phosphatase. Moreover, other RHO proteins, such as RHOB, RHOD, and their effectors (DIAPH1 and DIAPH2), may modulate PKN1/ ROCK1 signaling to effect changes in myosin phosphatase activity and myosin light chain phosphorylation. The increases in contractile activity observed in term and preterm labor may be due to an increase in RHO activity and/or changes in RHO-related proteins. We found that the RHOA and RHOB mRNA levels in the myometrium were increased in pregnancy, although the expression levels of the RHOA and RHOB proteins did not change with pregnancy or labor. GTP-bound RHOA was increased in pregnancy, and this increase was significant in spontaneous preterm labor myometrium. PKN1 expression and PPP1R14A phosphorylation were dramatically increased in the pregnant myometrium. We also observed increases in DIAPH1 expression in spontaneous term and preterm labor myometrial tissues. The present study shows that human pregnancy is characterized by increases in PKN1 expression and PPP1R14A phosphorylation in the myometrium. Moreover, increases in GTP-bound RHOA and DIAPH1 expression may contribute to the increase in uterine activity in idiopathic preterm labor.


A genetic screen for modifiers of E2F in Drosophila melanogaster.
The activity of the E2F transcription factor is regulated in part by pRB, the protein product of the retinoblastoma tumor suppressor gene. Studies of tumor cells show that the p16(ink4a)/cdk4/cyclin D/pRB pathway is mutated in most forms of cancer, suggesting that the deregulation of E2F, and hence the cell cycle, is a common event in tumorigenesis. Extragenic mutations that enhance or suppress E2F activity are likely to alter cell-cycle control and may play a role in tumorigenesis. We used an E2F overexpression phenotype in the Drosophila eye to screen for modifiers of E2F activity. Coexpression of dE2F and its heterodimeric partner dDP in the fly eye induces S phases and cell death. We isolated 33 enhancer mutations of this phenotype by EMS and X-ray mutagenesis and by screening a deficiency library collection. The majority of these mutations sorted into six complementation groups, five of which have been identified as alleles of brahma (brm), moira (mor) osa, pointed (pnt), and polycephalon (poc). osa, brm, and mor encode proteins with homology to SWI1, SWI2, and SWI3, respectively, suggesting that the activity of a SWI/SNF chromatin-remodeling complex has an important impact on E2F-dependent phenotypes. Mutations in poc also suppress phenotypes caused by p21(CIP1) expression, indicating an important role for polycephalon in cell-cycle control.


The Nociceptin Receptor (NOP) Agonist AT-312 Blocks Acquisition of Morphine- and Cocaine-Induced Conditioned Place Preference in Mice.
Treatment of drug addiction remains an unmet medical need due to the dearth of approved pharmacotherapies. There are no approved treatments for cocaine addiction, whereas the current opioid crisis has revealed the stark reality of the limited options to treat prescription and illicit opioid abuse. Preclinical studies in rodents and nonhuman primates have shown that orphanin FQ/nociceptin (N/OFQ), the endogenous ligand for the nociceptin opioid receptor (NOP) reduces the rewarding effects of several abused substances, including opioids, psychostimulants and alcohol. A few nonpeptide small-molecule NOP agonists have also shown efficacy in attenuating the rewarding effects of various abused drugs. We previously demonstrated that a high affinity small-molecule NOP agonist AT-312 selectively reduced the rewarding effects of ethanol in the conditioned place preference paradigm in mice. In the present study, we examined if AT-312 (3 mg/kg, i.p. or s.c. respectively), would alter the rewarding action of morphine (7.5 mg/kg, s.c.) or cocaine (15 mg/kg, i.p.). The effect of AT-312 on morphine- and cocaine-induced motor stimulation was also assessed on the conditioning days. The role of the NOP receptor in the effects of AT-312 was further confirmed by conducting the place conditioning experiments in NOP knockout mice and compared to their wild-type controls. Our results showed that AT-312 significantly reduced the acquisition of morphine and cocaine CPP in wild-type mice but not in mice lacking NOP receptors. AT-312 also suppressed morphine-induced and completely abolished cocaine-induced motor stimulation in NOP wild-type mice, but not in NOP knockout mice. These results show that small-molecule NOP receptor agonists have promising efficacy for attenuating the rewarding effects of morphine and cocaine, and may have potential as pharmacotherapy for opioid and psychostimulant addiction or for treating polydrug addiction.


Fibrinogen Hillsborough: a novel gammaGly309Asp dysfibrinogen with impaired clotting.
We present a novel gamma-chain dysfibrinogen that was discovered in a 32-year-old asymptomatic man admitted to the hospital after a car accident. He presented with a low fibrinogen concentration, 0.5 mg/mL, and a prolonged thrombin clotting time, 58 seconds. Analysis of purified fibrinogen by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a gamma-chain variant with an apparently higher molecular weight. Isoelectric focusing (IEF) demonstrated an anodal shift in the banding pattern of the chains and electrospray ionization mass spectrometry (ESIMS) showed a 27-Da increase in the average mass of the unresolved variant and normal gamma chains. DNA sequence analysis showed a heterozygous mutation of GGC (Gly)-->GAC (Asp) at codon 309 of the gamma chain gene. This Gly--> Asp substitution was consistent with the charge change shown by IEF as well as the mass change identified by ESIMS. Functional analysis revealed that thrombin-catalyzed polymerization occurred with a longer lag time, lower rate of lateral aggregation, and similar final turbidity compared to normal and that factor XIII cross-linking was normal. The polymerization results suggest that residue gamma309 is necessary for proper alignment of fibrinogen molecules, specifically in protofibril formation and D:D interactions. gammaGly309 is highly conserved and x-ray structures support the conclusion that the lack of a side chain at this position helps facilitate the close contact between abutting gammaD domains of condensing fibrin monomers during polymerization.


Timed Tissue P Systems with Channel States.
Tissue P systems with channel states are a variant of tissue P systems that can be employed as highly parallel computing devices, where the channel states can control the movements of objects. In a sense, the time-free approach can improve the robustness of P systems; hence, in this work, we introduce the time-free property into such P systems and explore their computational performances. Specifically, in a time-free manner, it is proved that this type of P systems have Turing universality by using two cells and four channel states with a maximum rule length of 2, or by using two cells and noncooper-ative symport rules with a maximum rule length of 1. Moreover, in terms of computational efficiency, it is proved that a uniform solution of the satisfiability (SAT ) problem can be obtained in a time-free manner by applying noncooperative symport rules with a maximum rule length of 1. The research results of this paper show that a highly robust dynamic membrane computing system is constructed. Theoretically, relative to the existing system, our constructed system can enhance robustness and expand its application scope.


Computed Tomography-Guided Kidney Transplant Biopsy Outcomes: A Single-Center Experience.
Percutaneous kidney transplant biopsy is typically performed using ultrasonographic guidance; computed tomography is an alternative modality used to obtain kidney allografttissuewhen ultrasonographyguided percutaneous kidney transplant biopsy is technically challenging. Studies examining postbiopsy outcomes in kidney transplant patients using a computed tomography-guided approach are scarce. Our goal was to reportthe incidence of nonsevere and severe complications in computed tomographyguided percutaneous kidney transplant biopsies and the potential risk factors. We retrospectively reviewed computed tomography-guided percutaneous kidney transplant biopsies in patients undergoing work-up for kidney allograft rejection between 2013 and 2017. Demographics, comorbidities, laboratory data, history of antiplatelet and/or anticoagulant use, and complications were assessed. : During the study period, 28 patients underwent computed tomography-guided percutaneous kidney transplant biopsies; mean age was 57.5 ± 15.5 years, and 12 (43%)werewomen.Twenty-three patients (82%) were obese, with a body mass index greater than 30 kg/m². Our cohort of kidney transplant recipients included 21 (75%) from deceased donors and 7 (25%) from living-related donors. At the time of biopsy, 6 patients (21%) had elevated blood pressure (defined as > 160/90 mm Hg). One patient had severe complications, which included a significant decrease in hemoglobin requiring transfusion and a perinephric hematoma with worsening renal function. This was a morbidly obese patient whose blood pressure was elevated at the time of biopsy with a platelet count of 93 × 10³/mm³ and international normalized ratio of 1.21. A computed tomography-guided percutaneous kidney transplant biopsy is a safe and effective alternative to obtain kidney tissue in the obese population and is associated with low rates of complications. In this study, we highlighted the need to achieve adequate blood pressure control and assess bleeding risk factors, such as platelet count and international normalized ratio, prior to biopsy.


Comparison of broad-spectrum antibiotics and narrow-spectrum antibiotics in the treatment of lower extremity cellulitis.
Cellulitis is a commonly encountered medical illness and is most frequently caused by Group A β-hemolytic Streptococcus species and Staphylococcus aureus. The purpose of this study was to compare clinical outcomes of patients with lower extremity cellulitis treated with broad-spectrum and narrow-spectrum antibiotics. This was a retrospective cohort study conducted in a community tertiary hospital between January 2016 and May 2016. Patients were included if they were diagnosed with uncomplicated non-purulent lower extremity cellulitis. Patients were divided into two groups: Individuals receiving narrow-spectrum antibiotics or receiving broad-spectrum antibiotics. Logistic regression analysis was used to estimate the odds ratio of repeat visit between the groups. A total of 599 patients with uncomplicated cellulitis were identified; of which 120 were included in the study (93 in narrow-spectrum arm and 27 in broad-spectrum arm). Repeat visit due to cellulitis was similar in both Groups 1 (4%) and 3 (3%) (P = 0.89) in the broad-spectrum arm and narrow-spectrum arm, respectively. Broad-spectrum antibiotic use in uncomplicated cellulitis was common and unjustified given the results of our study. Implementation of clinical practice guidelines is recommended in limiting broad-spectrum antibiotics use in such population.


Synthetic pheromones that promote inter-male aggression in mice.
Two volatile constituents of male mouse urine, dehydro-exo-brevicomin and 2-(sec-butyl)-dihydrothiazole, have been found active in bioassays of inter-male aggressive behavior. The two synthetic compounds act synergistically when added to castrated male urine but not when added to water, and they provoke fighting that is quantitatively and qualitatively comparable to that elicited by intact male urine.


Theoretical bases of non-ophthalmoscopically visible endpoint photocoagulation.
Laser photocoagulation is a photothermal process in which heat is produced by the absorption of laser energy by targeted tissues. The purpose of the treatment is to induce thermal therapeutic damage, which causes biological reactions and ultimately beneficial effects. The current endpoint of laser photocoagulation of the chorioretina is an ophthalmoscopically visible retinal whitening. Retinal blanching is the sign that the retina itself has been thermally damaged and results in a number of undesired adverse events. The mechanisms underpinning the efficacy of laser photocoagulation are still poorly understood. However, recent hypotheses postulate that full thickness retinal damage may not be needed to obtain beneficial therapeutic effectiveness. Preliminary studies with laser photocoagulation on animals demonstrated the ability to create therapeutic lesions confined around the Retinal Pigment Epithelium (RPE) cells without causing apparent damage to the overlying retina. The laser impacts were not visible by slit lamp biomicroscopy at the time of laser delivery. Recent experiments showed that the beneficial effect of retinal photocoagulation is mediated by factors derived from the RPE. Non Ophthalmoscopically Visible Endpoint Photocoagulation (NOVEP) protocols might allow treatments that confine minimal therapeutic damage around the cells of the RPE and minimize the damage to the neurosensory retina.


Borderline resectable pancreatic cancer: definitions and management.
Pancreatic cancer is the fourth leading cause of cancer death in the United States. While surgical resection remains the only curative option, more than 80% of patients present with unresectable disease. Unfortunately, even among those who undergo resection, the reported median survival is 15-23 mo, with a 5-year survival of approximately 20%. Disappointingly, over the past several decades, despite improvements in diagnostic imaging, surgical technique and chemotherapeutic options, only modest improvements in survival have been realized. Nevertheless, it remains clear that surgical resection is a prerequisite for achieving long-term survival and cure. There is now emerging consensus that a subgroup of patients, previously considered poor candidates for resection because of the relationship of their primary tumor to surrounding vasculature, may benefit from resection, particularly when preceded by neoadjuvant therapy. This stage of disease, termed borderline resectable pancreatic cancer, has become of increasing interest and is now the focus of a multi-institutional clinical trial. Here we outline the history, progress, current treatment recommendations, and future directions for research in borderline resectable pancreatic cancer.


Non-invasive monitoring of commonly used intraocular drugs against endophthalmitis by Raman spectroscopy.
To develop a non-contact and non-invasive method for quantification of the local concentration of certain antibiotic and antifungal drugs in the eye. An integrated CCD-based Raman spectroscopic system designed specifically for ophthalmic applications was used to non-invasively detect the presence of ceftazidime and amphotericin B in ocular media. Specific Raman signatures of the above named drugs were determined for various concentrations that were injected through a needle in the aqueous humor of rabbit eyes in vivo. Raman spectra were subsequently acquired by focusing an argon laser beam within the anterior chamber of the eye. Compared to ocular tissue, unique spectral features of ceftazidime appeared near 1,028, 1,506, 1,586, and 1,641 cm(-1). Amphotericin B exhibited its characteristic peaks at 1,156.5 and 1,556 cm(-1). The amplitude of the spectral peak corresponding to these drugs (acquired by 1 second exposure time and 25 mW of laser power) were determined to be linearly dependent on their local concentration in the anterior chamber of the eye. Raman spectroscopy may offer an effective tool to non-invasively assess the local concentration of the delivered drugs within the ocular media. This technique potentially could be used to investigate the pharmacokinetics of intraocular drugs in vivo either from a releasing implant or a direct injection.


Effect of red blood cells and hemoglobin on spontaneously hypertensive and normotensive rat aortas.
Experiments were designed to compare the contractile effect of red blood cells (RBC) on aortic rings with and without endothelium from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Red blood cells of 4 week old WKY and SHR rats induced a negligible increase in tension of aortic rings, either with or without endothelium, being slightly more effective in SHR rats. However, red blood cells of 16 week old rats increased tension of WKY and SHR aortic rings, with endothelium at this age being more pronounced then red blood cells in 4 week old animals. The contractions induced by WKY and SHR red blood cells both in WKY and SHR aortic rings without endothelium at this age are significantly greater compared to the effect on aortic rings with endothelium. Red blood cell ghosts of rats of both strains increased the tension of the rings without endothelium of SHR aorta to near 50% of those induced by red blood cells, whereas they were ineffective in aortic rings without endothelium of WKY rats. Oxyhemoglobin increased the tension of 16 week SHR aortic rings both with and without endothelium, whereas the effect on the rings of WKY rats was negligible. This increase in tension was inhibited by BM 13505, nordihydroguaiaretic acid, and indomethacin in SHR rings both with and without endothelium, demonstrating an eicosanoid involvement in oxyhemoglobin-induced contractions. Hemoglobin or its metabolites may be involved in development or in maintenance of spontaneous hypertension.


Computers in total quality management. Statistical process control to expedite stats.
We developed a system of computer programs to gather and then display data on turnaround time for stat tests. The data were those generated by the testing process itself so that no additional data entry was necessary. The system provided daily as well as longitudinal data for statistical process control implemented in the laboratory. The median and 90th percentile turnaround times were calculated for high-volume tests (complete blood cell count and Chem6 [six chemical serum component concentrations, ie, sodium, potassium, chloride, carbon dioxide, glucose, and urea nitrogen]), and a graphic display was automatically generated. These parameters and visual aids permitted evaluation of stat processing in the laboratory. The impact of management decisions on the stat process could be measured. Intralaboratory processing procedures were modified, and phlebotomy personnel were repositioned. Our various measurements showed which decisions improved stat turnaround time.


Tolerance of prefabricated skin flaps to ischaemia and reperfusion: experimental study.
Custom prefabrication of tissues allows the surgeon to build what is required for the reconstruction and has enabled the surgeon to reinforce new blood supply into selected blocks of tissue without vessel anastomosis. However, prefabricated flaps have several drawbacks and characteristics that differentiate them from conventional flaps. The objective of this study was to test the tolerance of prefabricated flaps to ischaemia/reperfusion injury in rats. In the first stage, the unilateral-inferior-epigastric pedicle was ligated and divided, and then a skin flap was fabricated by implantation of distally ligated femoral arteriovenous pedicle beneath the abdominal skin. The femoral vessels were implanted either in skeletonised or in muscle-cuffed fashion beneath the abdominal skin, a portion of which was raised as an island flap, based on these vessels. Prefabricated flaps (3×6 cm) were raised 6 weeks after, and were subjected to 10 h ischaemia and followed by 12 h reperfusion. Flap survival and histological changes at the pedicle-skin junction were evaluated at 7 days. Flap necrosis in the sham group was 0%, whereas the control group (conventional) had 47.27±13.50% necrosis. Flaps prefabricated with skeletonised femoral pedicle demonstrated an insignificant pattern with 63.74±10.62% necrosis when compared with prefabricated flaps with muscle-cuffed pedicle with the percentage of necrosis of 64.51±11.24. The area of necrosis was significantly increased when both the prefabricated flaps were compared with the control group or with the sham-prefabricated group (p<0.05). Skin flaps prefabricated with either pedicle-alone or pedicles with muscle cuff are more susceptible to ischaemia and following reperfusion in comparison with the normal flaps.


Gene expression profile of mesenchymal stromal cells after co-culturing with injured liver tissue.
Mesenchymal stromal cells (MSCs) are a potential cell source for the development of therapeutic products. Recent studies have shown that the transplantation of MSCs to damaged organs, including the heart, liver and kidneys, results in the restoration of the damaged tissues. However, the mechanisms underlying this regeneration process have yet to be clearly characterized. Consequently, in this study, we focused on the therapeutic potential of MSCs in injured liver tissue by evaluating the gene expression profiles of MSCs in the presence of injured liver and normal liver cells using a microarray chip containing 44,000 genes. In order to mimic the state of liver cell regeneration in vitro, we respectively co-cultured MSCs with CCl4-injured liver cells and normal liver cells from C57BL/6 female mice. After 48 h of co-culturing, MSCs were collected and the RNA was extracted for microarray analysis. Under conditions of co-culture with normal liver cells, upregulated expression of CXCR6, CCR3, IL-2, IL-11, CD34, CD74, procollagen, FMS-like tyrosine kinase, neuregulin 4, Wnt2 and catenins was noted. Under conditions of co-culture with the CCl4-injured liver cells, expression of CXCL2, cytoglobin, erythropoietin, v-Erb, hypoxia-inducible factor 3 (α subunit), retinoic acid receptor β and Vav2 was upregulated. Our research provides information regarding the differential molecular mechanisms that regulate the properties of MSCs in the regeneration of injured liver tissue.


Evaluation of an enzyme-linked immunoassay employing a covalently bound capture antibody for direct detection of herpes simplex virus.
The FDL enzyme-linked immunosorbent assay (ELISA; Fairleigh Dickinson Laboratories, Inc., Abilene, Tex.) for the detection of herpes simplex virus (HSV) makes use of a covalently attached antibody. This assay was compared with viral isolation and with the Ortho HSV Antigen Detection ELISA (Ortho Diagnostic Systems, Inc., Raritan, N.J.). One hundred forty-eight specimens were tested. The FDL ELISA identified 66 of 104 specimens from which HSV was isolated, yielding a sensitivity of 63% and a specificity of 95%. These results compared favorably with those obtained by using the Ortho ELISA. The total test time was shorter and the washing step was simpler than that with the Ortho assay, making the FDL assay an attractive alternative to similar methodologies.


Isolation and physiological characterization of mitomycin C-sensitive/UV-sensitive mutants in Bacteroides fragilis.
Mutants of Bacteroides fragilis sensitive to mitomycin C were isolated after mutagenesis with ethyl methane sulphonate. One mutant (MTC25) was markedly sensitive to mitomycin C but was unaffected as regards UV sensitivity; another mutant (UVS9) was sensitive to UV radiation but was only moderately sensitive to mitomycin C. Caffeine decreased the survival after UV-irradiation of the wild-type, MTC25 and UVS9 strains by the same relative amount. Aerobic liquid holding recovery occurred in each of the three strains. The MTC25 and UVS9 mutants showed reduced host cell phage reactivation. The wild-type, MTC25 and UVS9 strains all showed UV- and H2O2-induced phage reactivation. The physiological characterization of the MTC25 and UVS9 mutants indicates that it is possible to differentiate between mechanisms for the repair of mitomycin C- and UV-induced DNA damage in B. fragilis.


Caring for the informal cancer caregiver.
Informal cancer caregivers play a vital role in the physical, functional, and emotional well being of cancer patients. However, the majority of informal caregivers are not prepared for their caregiving role. We reviewed and synthesized the recent literature (last 18 months) and focused on research in the following understudied areas: technology-driven interventions for informal caregivers; informal caregivers of older adults with cancer; interrelationship between informal caregiver and dyadic outcomes; and research priorities and guidelines to improve informal caregiver support. Studies focused on technology-driven informal caregiver interventions, with evidence of good feasibility and acceptability with benefits for burden and quality of life (QOL). Studies also focused on QOL for caregivers of older adults with cancer. Finally, research priorities and clinical guidelines were established through Delphi survey studies. Despite the substantial evidence on informal cancer caregiving, more research is needed to further characterize caregivers at high risk for burden, explicate interrelationships between caregiver/patient outcomes, and test innovative and scalable interventions. Studies are also needed to understand the specific needs of informal caregivers in cancer surgery, an understudied treatment population.


Shaping the Structure and Properties of TiO2-ZnO Oxide Coatings Produced by Plasma Electrolytic Oxidation on Titanium Substrate.
The paper presents the results of preliminary research on the possibility of synthesizing ZnO-TiO2 mixed coatings by plasma electrochemical oxidation (PEO). The aim of the work was to synthesize TiO2-ZnO mixed coatings on a titanium substrate from an electrolyte containing ZnO nanoparticles (NPs) and to assess the parameters of PEO on the structure, chemical composition, and properties of the obtained oxide coatings. The PEO process was carried out under various current-voltage conditions using different signals: DC, DC pulse, and AC. In this work, optimal conditions for the PEO process were determined to obtain well-adhering oxide coatings with the highest possible content of ZnO. The structure and morphology of the resulting oxide coatings were investigated, and their chemical and phase composition was comprehensively examined (EDX, XRD, XPS, and GD-OES). In addition, their basic optical properties were assessed. It has been shown that in the PEO DC pulse process, it is possible to obtain oxide coatings characterized by a high degree of structure order, high ZnO content in the oxide coating (3.6 at.%, XPS), and prospective applications for photocatalytic purposes (3.12 eV).


The ins and outs of ring-cleaving dioxygenases.
Ring-cleaving dioxygenases catalyze the oxygenolytic fission of catecholic compounds, a critical step in the aerobic degradation of aromatic compounds by bacteria. Two classes of these enzymes have been identified, based on the mode of ring cleavage: intradiol dioxygenases utilize non-heme Fe(III) to cleave the aromatic nucleus ortho to the hydroxyl substituents; and extradiol dioxygenases utilize non-heme Fe(II) or other divalent metal ions to cleave the aromatic nucleus meta to the hydroxyl substituents. Recent genomic, structural, spectroscopic, and kinetic studies have increased our understanding of the distribution, evolution, and mechanisms of these enzymes. Overall, extradiol dioxygenases appear to be more versatile than their intradiol counterparts. Thus, the former cleave a wider variety of substrates, have evolved on a larger number of structural scaffolds, and occur in a wider variety of pathways, including biosynthetic pathways and pathways that degrade non-aromatic compounds. The catalytic mechanisms of the two enzymes proceed via similar iron-alkylperoxo intermediates. The ability of extradiol enzymes to act on a variety of non-catecholic compounds is consistent with proposed differences in the breakdown of this iron-alkylperoxo intermediate in the two enzymes, involving alkenyl migration in extradiol enzymes and acyl migration in intradiol enzymes. Nevertheless, despite recent advances in our understanding of these fascinating enzymes, the major determinant of the mode of ring cleavage remains unknown.


Clinical significance of neutropenia in patients with human immunodeficiency virus infection.
To determine the incidence of infection in human immunodeficiency virus (HIV)-infected patients during periods of neutropenia and non-neutropenia. To compare the infection rates in patients with HIV disease to those in a group hospitalized with neutropenia and hematologic malignancy. Prospective observational study conducted between December 1985 and December 1987 at a university teaching hospital. Thirty patients with documented acquired immunodeficiency syndrome (AIDS) and absolute T-helper cells less than 200 mm/mm3. All patients had a period of non-neutropenia following a neutropenic period (neutrophils less than 1000 cells/mm3). The rate of first infection during neutropenic and non-neutropenic periods for opportunistic infection and nonopportunistic infections were compared. There were no differences between infection rates for the two time periods for both types of infections. A subgroup of patient care days in which non-neutropenic days followed neutropenic days also was studied to eliminate selection bias. In this group, a comparison of infection rates also revealed no difference between neutropenic and non-neutropenic periods. An alternate analysis of the time until first infection during periods of neutropenia or non-neutropenia was done using the Kaplan-Meier product limit method. There was a longer infection-free period for the neutropenic group for opportunistic infections, but it was not statistically significant (p less than .1). In addition, we compared HIV-infected patients with a group of 37 patients with neutropenia from hematologic malignancy. There was a significantly higher rate of all infections, particularly bacteremias (p less than .001), in the group of patients with hematologic malignancies when compared with all subsets of patients with HIV disease. We conclude that patients with HIV disease and modest neutropenia do not have an increased risk of bacterial infection. The incidence of all infections is significantly greater in patients with neutropenia secondary to hematologic malignancy.


How morphometric analysis of metastatic load predicts the (un)usefulness of PET scanning: the case of lymph node staging in melanoma.
In primary cutaneous melanoma, the sentinel node (SN) biopsy is an accurate method for the staging of the lymph nodes. Positron emission tomography (PET) has been suggested as a useful alternative. However, the sensitivity of PET may be too low to detect SN metastases, which are often small. To predict the value of PET for initial lymph node staging in melanoma based on morphometric analysis of SN metastatic load, without exposing patients to PET. In 59 SN positive patients with melanoma, the sizes of tumour deposits in the SNs and subsequent dissection specimens were measured by morphometry and correlated with the detection limits of current and future PET scanners. The median tumour volume within the basin was 0.15 mm(3) (range, 0.0001-118.86). Seventy per cent of these deposits were smaller than 1 mm(3). State of the art PET scanners that have a resolution of about 5 mm would detect only 15-49% of positive basins. Logistic regression analysis revealed no pretest indicators identifying patients expected to have a positive PET. However, the SN tumour load was a significant and single predictor of the presence of PET detectable residual tumour. Morphometric analysis of metastatic load predicts that PET scanning is unable to detect most metastatic deposits in sentinel lymph nodes of patients with melanoma because the metastases are often small. Therefore, the SN biopsy remains the preferred method for initial regional staging.


General practitioners' detection and management of patients with a dual diagnosis: implications for education and training.
General practitioners (GPs) are in a unique position to detect and manage patients with co-morbid mental health and substance use disorders (dual diagnosis). It has been estimated that over 30% of patients presenting to general practice have a diagnosable mental disorder and 12% have dual diagnosis. Unfortunately, between 30 and 50% of these problems go undetected in general practice. Limited GP education and training in mental health may account for this deficit, with a little over 8% of GPs receiving any formal postgraduate training in mental health. Prior to developing an educational resource for GPs, the present study aimed to establish baseline estimates of GP treatment practices with patients who have dual diagnosis. Two GP division-wide surveys of screening, assessment and treatment for dual diagnosis were conducted one year apart. In addition, five GPs conducted a clinical audit of 508 patient consultations. Results indicate that without ongoing targeted interventions, patient management activities such as GP counselling, use of screening devices, referral to specialist services, coordination and use of EPC items are not likely to improve and are at risk of declining.


[A differentiated approach to the therapy of the Parsonage-Turner syndrome].
The authors have analyzed the anamnestic, clinical and laboratory data in 44 patients with Parsonage-Turner syndrome. Two forms of the disease were distinguished: radicular ischemia of vascular genesis, and the local form of infectious allergic polyradiculoneuritis associated with injury to the shoulder girdle of infectious genesis.


Cumulative inhibition of NK cells and T cells resulting from engagement of multiple inhibitory Ly49 receptors.
Inhibitory receptors specific for MHC class I molecules are expressed on partially overlapping subpopulations of NK cells and memory T cells. A central question pertinent to NK cell development and function is how the combinatorial expression of different receptors with distinct class I specificities affects functional recognition. We therefore studied the quantitative effects resulting from class I engagement of multiple inhibitory Ly49 receptors. We used a transgenic mouse model in which all NK cells and T cells express two different Ly49 receptors with shared class I specificity. Comparisons of cells from these mice with cells from single transgenic mice and wild-type mice revealed that Ly49 receptors cumulatively inhibit lymphocyte effector functions. Multiple Ly49 interactions also had a cumulative impact on NK cell development. The findings suggest that the interactions of inhibitory receptors with class I are interpreted quantitatively rather than as on/off switches. They have intriguing implications concerning NK cell tolerance and reactivity toward cells with extinguished expression of a limited number of class I molecules.


The role of synphilin-1 in synaptic function and protein degradation.
The name synphilin-1 comes from its identification as an alpha-synuclein-interacting protein (SNCAIP) in yeast two-hybrid screens. Since alpha-synuclein ( PARK1) was the first gene identified as causing inherited forms of Parkinson's disease (PD), synphilin-1 was quickly implicated in neurodegeneration in PD. Recently, the first genetic evidence for the direct contribution of synphilin-1 in the pathogenesis of PD has been defined with the identification of an R621C mutation as a susceptibility factor for PD in two German patients. Extensive in vitro studies have determined the physiological functions of synphilin-1, identified novel synphilin-1-interacting proteins, and linked synphilin-1 to ubiquitin-mediated protein degradation. The present article provides an overview of the current concepts of the role of synphilin-1 in synaptic function and protein degradation and in the molecular mechanisms leading to neurodegeneration in PD.


Brain Delivery of a Potent Opioid Receptor Agonist, Biphalin during Ischemic Stroke: Role of Organic Anion Transporting Polypeptide (OATP).
Transporters (expressed) at the blood-brain barrier (BBB) can play an essential role in the treatment of brain injury by transporting neuroprotective substance to the central nervous system. The goal of this study was to understand the role of organic anion transporting polypeptide (OATP1; OATP1A2 in humans and oatp1a4 in rodents) in the transport of a potent opioid receptor agonist, biphalin, across the BBB during ischemic stroke. Brain microvascular endothelial cells (BMECs) that were differentiated from human induced pluripotent stem cells (iPSCs) were used in the present study. The effect of oxygen-glucose deprivation (OGD) and reperfusion on the OATP1 expression, uptake, and transport of biphalin was measured in induced pluripotent stem cells differentiated brain microvascular endothelial cells (iPSC-BMECs) in the presence and absence of an OATP1 substrate, estrone-3-sulfate (E3S). Biphalin brain permeability was quantified while using a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. It was found that iPSC-BMECs expressed OATP1. In vitro studies showed that biphalin BBB uptake and transport decreased in the presence of an OATP1 specific substrate. It was also observed that OGD and reperfusion modulate the expression and function of OATP1 in BMECs. This study strongly demonstrates that OATP1 contributes to the transport of biphalin across the BBB and increased expression of OATP1 during OGD-reperfusion could provide a novel target for improving ischemic brain drug delivery of biphalin or other potential neurotherapeutics that have affinity to this BBB transporter.


Cardiac Resynchronization Therapy in Patients with Ebstein's Anomaly.
Ebstein's anomaly is a rare congenital heart disease characterized by apical displacement of the septal and posterior tricuspid valve leaflets. It is often complicated with left ventricular (LV) dysfunction as well as right-sided abnormalities. On the other hand, in the presence of LV dysfunction, right ventricular pacing is likely to aggravate the diseased LV function, which is termed pacemaker-induced cardiomyopathy. Thus, deteriorating effects of RV pacing on cardiac function might be enhanced and result in pacemaker-induced cardiomyopathy in patients with Ebstein's anomaly, even if they have preserved LVEF. Cardiac resynchronization therapy (CRT) is effective for the treatment of pacemaker-induced cardiomyopathy, and we present the first case of effect of CRT on pacemaker-induced cardiomyopathy associated with Ebstein's anomaly.


Label Information Guided Graph Construction for Semi-Supervised Learning.
In the literature, most existing graph-based semi-supervised learning methods only use the label information of observed samples in the label propagation stage, while ignoring such valuable information when learning the graph. In this paper, we argue that it is beneficial to consider the label information in the graph learning stage. Specifically, by enforcing the weight of edges between labeled samples of different classes to be zero, we explicitly incorporate the label information into the state-of-the-art graph learning methods, such as the low-rank representation (LRR), and propose a novel semi-supervised graph learning method called semi-supervised low-rank representation. This results in a convex optimization problem with linear constraints, which can be solved by the linearized alternating direction method. Though we take LRR as an example, our proposed method is in fact very general and can be applied to any self-representation graph learning methods. Experiment results on both synthetic and real data sets demonstrate that the proposed graph learning method can better capture the global geometric structure of the data, and therefore is more effective for semi-supervised learning tasks.


Gerrymandering and computational redistricting.
Partisan gerrymandering poses a threat to democracy. Moreover, the complexity of the districting task may exceed human capacities. One potential solution is using computational models to automate the districting process by optimizing objective and open criteria, such as how spatially compact districts are. We formulated one such model that minimised pairwise distance between voters within a district. Using US Census Bureau data, we confirmed our prediction that the difference in compactness between the computed and actual districts would be greatest for states that are large and, therefore, difficult for humans to properly district given their limited capacities. The computed solutions highlighted differences in how humans and machines solve this task with machine solutions more fully optimised and displaying emergent properties not evident in human solutions. These results suggest a division of labour in which humans debate and formulate districting criteria whereas machines optimise the criteria to draw the district boundaries. We discuss how criteria can be expanded beyond notions of compactness to include other factors, such as respecting municipal boundaries, historic communities, and relevant legislation.


Comparison of continuous thoracic epidural with paravertebral block on perioperative analgesia and hemodynamic stability in patients having open lung surgery.
Epidural analgesia can result in perioperative hypotension in patients having thoracotomy. This randomized prospective study assessed the effects of epidural and paravertebral analgesia on hemodynamics during thoracotomy. Thirty-two patients were randomized to receive either epidural analgesia (n = 16, 0.25% levobupivacaine and 30 μg/kg morphine) or paravertebral block (n = 16; 0.5% levobupivacaine and 30 μg/kg morphine). Oxygen delivery, stroke volume and systemic vascular resistance indices, heart rate, and mean arterial pressure measurements were performed before administration of local anesthetic, after induction of general anesthesia, institution of 1-lung ventilation, first skin incision, retractor placement, lung-inflation maneuver, and at last skin suture. The primary end point was the volume of the colloid infusion necessary to maintain oxygen delivery index of 500 mL/min per squared meter or higher. Postoperative analgesia was provided immediately after surgery by an infusion of 0.125% levobupivacaine and 20 μg/mL morphine in epidural/paravertebral infusion. Pain, rescue-analgesia consumption, arterial pressure, and heart rate were recorded at 6, 24, and 48 hrs after surgery. Administration of anesthesia and data collection were done by research staff blinded to the regional analgesia technique. The groups did not differ significantly in heart rate, mean arterial blood pressure, or systemic vascular resistance indices. However, to maintain the targeted oxygen delivery index, a greater volume of colloid infusion and phenylephrine were required, respectively, in the epidural than in the paravertebral group (554 ± 50 vs 196 ± 75 mL, P = 0.04; and 40 ± 10 vs 17 ± 4 μg, P = 0.04). Pain intensity before and after respiratory physiotherapy as well as 24 hr rescue piritramide consumption was similar in the epidural (4.1 ± 3.1 mg) and the paravertebral (2.5 ± 1.5 mg) groups (P = 0.14). Systolic blood pressure after 24 and 48 hrs was lower in the epidural group. Under the conditions of our study, continuous paravertebral block resulted in similar analgesia but greater hemodynamic stability than epidural analgesia in patients having thoracotomy. Paravertebral block also required smaller volume of colloids and vasopressors to maintain the target oxygen delivery index (DO2I).


Arteriographic demonstration of collateral arterial supply to the liver after hepatic artery ligation.
Eight patients were studied arteriographically after hepatic artery ligation (done to control bleeding in 6). Sources of arterial flow to the liver after ligation were (a) replaced or accessory hepatic artery; (b) interlobar collaterals in the liver; (c) right inferior phrenic artery; (d) through the gastroduodenal artery from arterial branches in the pancreas, duodenum, and omentum; (e) fine collateral branches of the gastroduodenal artery as they pass into the porta hepatis; and (f) recanalization of the ligated hepatic artery. Collateral vessels, seen as early as four hours after ligation, increase in size and number during the following six months.


Alpha-thrombin stimulates sis-inducing factor-A DNA binding activity in rat aortic smooth muscle cells.
Exposure of rat aortic vascular smooth muscle cells to alpha-thrombin resulted in the appearance of sis-inducing factor-A (SIF-A)-like DNA binding activity. This response to alpha-thrombin was delayed (detectable at 1 hour) compared with the rapid activation (15 to 30 minutes) by platelet-derived growth factor and the cytokine interleukin-6. alpha-Thrombin-induced SIF-A was sensitive to treatment with the tyrosine kinase inhibitor genistein. The thrombin inhibitor hirudin prevented the alpha-thrombin-mediated SIF-A induction. Cycloheximide had no effect on the ability of alpha-thrombin to induce SIF-A, suggesting that induction does not require new protein synthesis. alpha-Thrombin-induced SIF-A could be resolved into two additional subcomplexes termed SIF-A, and SIF-As. Antibodies against Stat3 reacted with alpha-thrombin-induced SIF-Af, suggesting that Stat3 or a related protein is present in this subcomplex. Induction of SIF-A DNA binding activity may contribute to alpha-thrombin-mediated cellular responses, including wound healing, cell proliferation, and inflammation in the vasculature.


Detection of expansin proteins and activity during tomato fruit ontogeny.
Expansins are plant proteins that have the capacity to induce extension in isolated cell walls and are thought to mediate pH-dependent cell expansion. J.K.C. Rose, H.H. Lee, and A.B. Bennett ([1997] Proc Natl Acad Sci USA 94: 5955-5960) reported the identification of an expansin gene (LeExp1) that is specifically expressed in ripening tomato (Lycopersicon esculentum) fruit where cell wall disassembly, but not cell expansion, is prominent. Expansin expression during fruit ontogeny was examined using antibodies raised to recombinant LeExp1 or a cell elongation-related expansin from cucumber (CsExp1). The LeExp1 antiserum detected expansins in extracts from ripe, but not preripe tomato fruit, in agreement with the pattern of LeExp1 mRNA accumulation. In contrast, antibodies to CsExp1 cross-reacted with expansins in early fruit development and the onset of ripening, but not at a later ripening stage. These data suggest that ripening-related and expansion-related expansin proteins have distinct antigenic epitopes despite overall high sequence identity. Expansin proteins were detected in a range of fruit species and showed considerable variation in abundance; however, appreciable levels of expansin were not present in fruit of the rin or Nr tomato mutants that exhibit delayed and reduced softening. LeExp1 protein accumulation was ethylene-regulated and matched the previously described expression of mRNA, suggesting that expression is not regulated at the level of translation. We report the first detection of expansin activity in several stages of fruit development and while characteristic creep activity was detected in young and developing tomato fruit and in ripe pear, avocado, and pepper, creep activity in ripe tomato showed qualitative differences, suggesting both hydrolytic and expansin activities.


Limitations to Participation in Family of Origin Among Same Sex Couples: A Couple-Level Minority Stressor.
Emerging studies focus on minority stressors emanating from society's stigmatization of particular relationship forms (i.e., couple-level minority stressors). The present study examines how same-sex couples experience one such couple-level minority stressor: limitations to participation in families of origin. Qualitative data are drawn from a sub-sample of same-sex couples (N = 18) who participated in a large-scale study of minority stress among 120 same-sex couples distributed equally across two study sites (Atlanta and San Francisco) in 2012 and 2013. Instances of limitations to participation in families of origin ranged in severity, falling into three distinct areas: 1) partial acceptance, where some family members were accepting and others were not, 2) mixed messages where some family members said they were accepting but behaved as though they were not and, 3) rejection, where some family members were blatantly unwelcoming or hostile. These types of exclusion were also evidenced in dyadic minority stress processes of stress proliferation (e.g., stress discrepancies and stress contagion) causing additional stress for both partners. These narratives portray struggles associated with experiences of couple-level minority stress faced by people in same-sex relationships.


The sealing ability of an epoxy resin root canal sealer used with five gutta-percha obturation techniques.
The purpose of the present study was to evaluate the apical sealing ability of an epoxy resin root canal sealer (AH-26) when used with different gutta-percha obturation techniques (i.e. cold lateral condensation, warm vertical condensation, hybrid condensation) and with Thermafil and Soft-Core obturators. Straight single-rooted teeth with mature apices were prepared according to the crown-down/step-back technique and divided in five groups of 45 teeth and one group of 12 control teeth. After root canal filling 15 teeth of each group were kept for 1 day, another 15 teeth for 1 week, and another 15 teeth for 4 months at 37 degrees C in vacutainers in 80% relative humidity. The 237 teeth were immersed in india ink for 90 hours, each root was split and sectioned longitudinally, and the maximum extent of leakage was measured using a stereomicroscope at x6 magnification. It became clear that leakage occurred whatever technique was combined with AH26 and that leakage increased with time. The amount of apical leakage and the number of leaking teeth in the Soft-Core obturator groups was significantly higher than all other 4 gutta-percha obturation techniques combined with AH26. In this respect, the hybrid gutta-percha condensation technique turned out to be superior to the four other condensation techniques.


Predictive Value of Middle Cerebral Artery to Umbilical Artery Pulsatility Index Ratio for Neonatal Outcomes in Hypertensive Disorders of Pregnancy.
Hypertension may lead to notifying adverse perinatal events that should be diagnosed and managed precisely. This study aims to investigate the values of cerebroplacental ration for the prediction of adverse perinatal events in hypertensive disorders of pregnancy. The current descriptive-comparative study has been conducted on 100 singleton pregnant women with the diagnosis of preeclampsia or pregnancy-induced hypertension. The Cerebroplacental ratio (CPR) was measured for the included population and divided into normal and abnormal ranges of >1 and ≤1. The adverse perinatal outcomes, including abnormal 5 min APGAR, low birth weight, perinatal death, neonatal intensive care unit (NICU) admission, academia, seizure, emergency cesarean delivery, and Tchirikov index as the general manifestation of adverse perinatal outcomes were compared between the groups. The specificity, sensitivity, positive predictive value, negative predictive value (NPV), and accuracy were measured for the adverse perinatal outcomes. The two groups were remarkably different in terms of 5 min APGAR, low birth weight, cesarean section delivery, and Tchirikov index (P < 0.05). The specificity of CPR for prediction of small-for-gestational age, poor APGAR, requirement of assisted respiration, academia, Tchirikov score and NICU admission was 93.1%, 93.1%, 67.1%, 91.8%, 71.2%, and 63%, and its sensitivity was 26%, 14.8%, 51.8%, 14.8%, 51.8%, and 37%, respectively. CPR seems to be an appropriate means for the prediction of adverse perinatal outcomes with diversity in the prediction values of different determinants of adverse perinatal outcomes; however, in general, it had sensitivity, specificity, PP, NPV, and accuracy of 51.8%, 71.2%, 40%, 80%, and 66%, respectively.


The contribution of distance education to health promotion in Chile.
The objective of this paper is to present the distance education's contribution to developing health promotion in Chile, through evaluation of a postgraduate certificate program for professionals, and a training course for nurse technicians working in primary healthcare, with an 8-month follow-up after program completion. The program methodology was participatory, interactive and reflective, with mentoring support, exercises, group work and discussions as well as content pertinent to the needs of practice. The evaluation was quali-quantitative with an analysis of the student profile, the implementation process, outcomes at the end of the training and impacts on workplace changes. The results showed a high rate of student approval (87 and 76%), good academic performance and a high level of satisfaction with the methodology and knowledge delivered. The participants' final projects were adapted to local work places realities and were implemented by 62.6% of technicians and 43% of professionals, in addition to changes in work practices that favor health promotion. The level of fulfillment of participants' expectations was very high and the most frequent barriers to implementing the final project were lack of time and personnel, along with minimal support from management and low prioritization of health promotion. This study shows the effectiveness of a distance training model for professionals and technicians that can reach the most remote parts of the country, where there is no access to presencial training, with an educational program centered on work activities and current health challenges.


Advice to stay active as a single treatment for low back pain and sciatica.
Low back pain is one of the most common conditions managed in primary care. Restricted activity, rest, and symptomatic analgesics are the most commonly prescribed treatment for low back pain and sciatica. To assess the effects of advice to stay active as single treatment for patients with low back pain. Computerised searches in MEDLINE, EMBASE, Sport, The Cochrane Controlled Trials Register, Musculoskeletal Group's Trials Register and Scisearch, and scanning of reference lists from relevant articles were undertaken. Relevant studies were also traced by contacting authors. Date of the most recent searches: December 1998. We included all randomised trials or quasi-randomised trials where the study population consisted of adult patients with low back pain or sciatica, in which one comparison group was advised to stay active. The main outcomes of interest were pain, functional status, recovery and return to work. Two reviewers independently selected trials for inclusion, assessed the validity of included trials and extracted data. Investigators were contacted to collect missing data or for clarification when needed. Four trials, with a total of 491 patients, were included. Advice to stay active was compared to advice to rest in bed in all trials. Two trials were assessed to have low risk of bias and two to have moderate to high risk of bias. The results were heterogeneous. Results from one high quality trial of patients with acute simple LBP found small differences in functional status [Weighted Mean Difference (on a 0-100 scale) 6.0 (95% CI: 1.5, 10.5)] and length of sick leave [WMD 3.4 days (95% CI: 1.6, 5.2)] in favour of staying active compared to advice to stay in bed for two days. The other high quality trial compared advice to stay active with advice to rest in bed for 14 days for patients with sciatic syndrome, and found no differences between the groups. One of the high quality trials also compared advice to stay active with exercises for patients with acute simple LBP, and found improvement in functional status and reduction in sick leave in favour of advice to stay active. The best available evidence suggests that advice to stay active alone has small beneficial effects for patients with acute simple low back pain, and little or no effect for patients with sciatica. There is no evidence that advice to stay active is harmful for either acute low back pain or sciatica. If there is no major difference between advice to stay active and advice to rest in bed, and there is potential harmful effects of prolonged bed rest, then it is reasonable to advise people with acute low back pain and sciatica to stay active. These conclusions are based on single trials.


The learning rate in three dimensional high definition video assisted microvascular anastomosis in a rat model.
Three-dimensional (3D) high definition (HD) video systems are changing microsurgical practice by providing stereoscopic imaging not only for the surgeon and first assistant using the binocular microscope, but also for others involved in the surgery. The purpose of this study was to evaluate the potential to replace the binocular microscope for microarterial anastomoses and assess the rate of learning based on surgeons' experience. Two experienced and two novice microsurgeons performed a total of 88 rat femoral arterial anastomoses: 44 using a 3D HD video device ('Trenion', Carl Zeiss Meditech) and 44, a binocular microscope. We evaluated anastomosis time and modified OSATS scores as well as the subjects' preference for comfort, image adequacy and technical ease. Experienced microsurgeons showed a steep learning curve for anastomosis times with equivalent OSATS scores for both systems. However, prolonged anastomosis times were required when using the novel 3D-HD system rather than direct binocular vision. Comparable learning rates for anastomosis time were demonstrated for novice microsurgeons and modified OSATS scores did not differ between the different viewing technologies. All microsurgeons reported improved comfort for the 3D HD video system but found the image quality of the conventional microscope superior, facilitating technical ease. The present study demonstrates the potential of 3D HD video systems to replace current binocular microscopes, offering qualitatively-equivalent microvascular anastomosis with improved comfort for experienced microsurgeons. However, image quality was rated inferior with the 3D HD system resulting in prolonged anastomosis times. Microsurgical skill acquisition in novice microsurgeons was not influenced by the viewing system used.


Reconstitution of functional membrane-bound acetylcholine receptor from isolated Torpedo californica receptor protein and electroplax lipids.
Purified acetylcholine receptor and total lipids, both extracted from Torpedo californica electroplax, were utilized to reconstitute chemically excitable membrane vesicles. Reconstitution was achieved by dialysis of the extraction detergent, octyl beta-D-glucoside from protein/lipid incubation mixtures. The reconstituted preparations could be fractionated by sucrose density gradient centrifugation and consisted of vesicular structures visible in electron micrographs. In addition, the reconstituted vesicles exhibited;the following properties characteristic of native receptor-enriched membranes: (i) an external distribution of alpha-bungarotoxin-binding sites, (ii) a time-dependent binding of alpha-bungarotoxin that is depressed by preincubation with the cholinergic agonist carbamoylcholine ("desensitization"), (iii) an ability to retain 22Na+ that is lost in the presence of detergents or gramicidin A, and (iv) a carbamoylcholine-induced acceleration of 22Na+ efflux that can be blocked by alpha-bungarotoxin. The purified acetylcholine receptor that was utilized in the reconstitution experiments apparently does not require other protein components for ligand recognition or ion translocation.


Daily rhythms, light exposure and social jetlag correlate with demographic characteristics and health in a nationally representative survey.
The timing of daily activity in humans have been associated with various demographic and health-related factors, but the possibly complex patterns of confounding and interaction between these has not been systematically explored. We use data from Hungarostudy 2021, a nationally representative survey of 7000 Hungarian adults to assess the relationship between self-reported chronotype, social jetlag (using the Munich Chronotype Questionnaire), demographic variables and self-reported health and demographic variables, including ethnic minority membership. Supporting the validity of self-reports, participants with later chronotypes reported the lowest daytime sleepiness at a later clock time. We found that older age, female sex, a more eastward and southward geographical position, residence in a smaller settlement, less education and income, religiousness and cohabiting with small children were associated with an earlier chronotype. Younger age, higher education and income, and cohabiting with small children were associated with increased social jetlag. Of the 48 health-related variables surveyed, the relationship with both chronotype and social jetlag were mostly accounted for by age, sex, and socioeconomic effects, but we identified alcohol consumption, smoking, and physical activity as predictors of both social jetlag and chronotype, while a number of disorders were either positively or negatively associated with chronotype and social jetlag. Our findings from a large, nationally representative sample indicate that both biological and social factors influence chronotype and identified both demographic and health-related variables as risk factors for social jetlag. Our results, however, do not support a causal relationship between light exposure and mental health.


Interaction of Bacillus subtilis CsaA with SecA and precursor proteins.
CsaA from the Gram-positive bacterium Bacillus subtilis has been identified previously as a suppressor of the growth and protein-export defect of Escherichia coli secA(Ts) mutants. CsaA has chaperone-like activities in vivo and in vitro. To examine the role of CsaA in protein export in B. subtilis, expression of the csaA gene was repressed. While export of most proteins remained unaffected, export of at least two proteins was significantly reduced upon CsaA depletion. CsaA co-immunoprecipitates and co-purifies with the SecA proteins of E. coli and B. subtilis, and binds the B. subtilis preprotein prePhoB. Purified CsaA stimulates the translocation of prePhoB into E. coli membrane vesicles bearing the B. subtilis translocase, whereas it interferes with the SecB-mediated translocation of proOmpA into membrane vesicles of E. coli. The specific interaction with the SecA translocation ATPase and preproteins suggests that CsaA acts as a chaperone that promotes the export of a subset of preproteins in B. subtilis.


Cytoreductive nephrectomy in metastatic renal cell carcinoma: the evolving role of surgery in the era of molecular targeted therapy.
Despite contemporary surgical and therapeutic innovation, renal cell carcinoma remains the most lethal of the urologic malignancies. Up to a third of patients with renal cell carcinoma have metastatic disease at presentation and 30% with localized disease will eventually progress to metastatic disease. In the past, cytoreductive nephrectomy was reserved for palliative circumstances. With the emergence and integration of targeted therapies into current treatment protocols, the role of cytoreductive nephrectomy should be reexamined. Three targeted therapy trials revolutionized the management of metastatic renal cell carcinoma by showing unprecedented efficacy and tolerable therapeutic options. The benefits of targeted therapy observed in clinical trials have been in the setting of prior cytoreductive nephrectomy. Therefore, any evidence for the potential benefit of cytoreductive nephrectomy in the era of targeted therapy is currently extrapolated and it is unclear where surgery integrates into the current treatment ladder. Other surgical approaches such as laparoscopy and nephron-sparing surgery have also been transferred to a carefully selected metastatic disease population. The concept of presurgical systemic therapy, though not new to oncology, is novel for metastatic renal cell carcinoma treated with targeted therapy. With the maturation of ongoing multicenter clinical trials, answers to these questions will hopefully be clarified.


Effects of naloxone on schizophrenia: reduction in hallucinations in a subpopulation of subjects.
Endogenous opiate-like peptides (endorphins) are putative neuroregulators located throughout the mammalian brainstem. There is some evidence for their role in pain, stress, and affect. We report that the opiate antagonist, naloxone, alters some schizophrenic symptoms. In a double-blind, cross-over study, naloxone produced decreases in auditory hallucinations in some schizophrenic patients. This finding supports the hypothesis that the endorphins may play a roll in modulating hallucinations in a highly selected subgroup of chronically hallucinating schizophrenic patients.


What Is the Role of Endodontic Predisposing Factors in Early Implant Failure?
We aimed to investigate a possible relationship between early implant failure (EIF) and an adjacent root canal-treated tooth and/or tooth with a periapical lesion (PL), considering the duration between implantation and root canal treatment (RCT). The importance of prior RCT and/or presence of a PL before implantation was also investigated. A total of 810 implants from 342 patients were included and scored according to the implant failure before abutment connection, adjacent root canal treated teeth, adjacent teeth without RCT, no adjacent teeth, adjacent teeth with PL, extraction of teeth with PL, and/or RCT before implantation. The durations between the extraction and implantation and between RCT and implantation adjacent to the root canal-treated teeth were recorded. The time from the RCT of adjacent teeth to implant placement was categorized into 5 groups: less than 4 weeks before implantation, 4-12 weeks before implantation, at least 12 weeks before implantation, within 4 weeks after implantation, and at least 4 weeks after implantation. Among the endodontic predictors, a prior PL on the tooth extracted was associated with an increased risk of EIF (P < .05, odds ratio: 4.37; 95% confidence interval: 1.604-11.891). Furthermore, EIF was more likely to occur when the RCT of an adjacent tooth was performed within 4 weeks of implantation (P < .05). Additional investigations with larger sample sizes are necessary to validate our findings.


Prevalence and characteristics of hospitalized adults on chronic opioid therapy.
As chronic opioid therapy (COT) becomes more common, complexity of pain management in the inpatient setting increases; little is known about medical inpatients on COT. To determine the prevalence of COT among hospitalized patients and to compare outcomes among these patients relative to those not receiving COT. Observational study of inpatient and outpatient administrative data. All veterans with acute medical admissions to 129 Veterans Administration hospitals during fiscal years 2009 to 2011, residing in the community, and with outpatient pharmacy use. We defined COT as 90 or more days of opioids prescribed in the 6 months prior to hospitalization. Patient characteristics included demographic variables and major comorbidities. Outcomes included 30-day readmission and death during hospitalization or within 30 days, with associations ascertained using multivariable logistic regression. Of 122,794 hospitalized veterans, 31,802 (25.9%) received COT. These patients differed from comparators in age, sex, race, residence, and presence of chronic noncancer pain, chronic obstructive pulmonary disease, complicated diabetes, cancer, and mental health diagnoses including post-traumatic stress disorder. After adjustment for demographic factors, comorbidities, and admission diagnosis, COT was associated with hospital readmission (odds ratio [OR]: 1.15, 95% confidence interval [CI]: 1.10-1.20) and death (OR: 1.19, 95% CI: 1.10-1.29). COT is common among medical inpatients. Patients on COT differ from patients without COT beyond dissimilarities in pain and cancer diagnoses. Occasional and chronic opioid use are associated with increased risk of hospital readmission, and COT is associated with increased risk of death. Additional research relating COT to hospitalization outcomes is warranted.


Pathology in the new medical curriculum: what has replaced the subject courses?
In line with the UK General Medical Council recommendations, the traditional, taught curriculum at Liverpool was replaced from 1996 by a new one using problem-based learning (PBL) as its principal method of information transfer. There is integration of clinical and preclinical studies, coupled with a reduction in the factual knowledge content and the disappearance of identifiable separate subject courses. Learning is now student-centred. This requires a new approach to the acquisition of pathology knowledge. 1. Pathology is included in all relevant PBL case scenarios by pathology representation on module planning and review committees. 2. Special study modules (SSMs) allow students to observe the practice of pathology including surgical and autopsy work, carry out a detailed study and write a dissertation. Career selectives are provided for individual students in the final year. 3. Clinicopathological (CPC) teaching meetings are held, with the discussion of case examples, clinicians and students contributing. 4. Assessments include the input of appropriate pathology content, integrated with other subjects. 5. A pathology teaching website is provided, containing images, notes, self-assessment questions, handouts, timetables and information. Although the 1996 intake have not yet completed their studies, the results of in-course assessments have been encouraging. The response to the pathology SSMs has been very positive, and the level of presentations and dissertations reached is of a high standard. With the disappearance of a separate subject course in pathology, the subject is being learned by other routes, and the students will complete their undergraduate course with a sound basis for proceeding with their further studies.


Correlation-based network analysis combined with machine learning techniques highlight the role of the GABA shunt in Brachypodium sylvaticum freezing tolerance.
Perennial grasses will account for approximately 16 billion gallons of renewable fuels by the year 2022, contributing significantly to carbon and nitrogen sequestration. However, perennial grasses productivity can be limited by severe freezing conditions in some geographical areas, although these risks could decrease with the advance of climate warming, the possibility of unpredictable early cold events cannot be discarded. We conducted a study on the model perennial grass Brachypodium sylvaticum to investigate the molecular mechanisms that contribute to cold and freezing adaption. The study was performed on two different B. sylvaticum accessions, Ain1 and Osl1, typical to warm and cold climates, respectively. Both accessions were grown under controlled conditions with subsequent cold acclimation followed by freezing stress. For each treatment a set of morphological parameters, transcription, metabolite, and lipid profiles were measured. State-of-the-art algorithms were employed to analyze cross-component relationships. Phenotypic analysis revealed higher adaption of Osl1 to freezing stress. Our analysis highlighted the differential regulation of the TCA cycle and the GABA shunt between Ain1 and Osl1. Osl1 adapted to freezing stress by repressing the GABA shunt activity, avoiding the detrimental reduction in fatty acid biosynthesis and the concomitant detrimental effects on membrane integrity.


Cancer patient management strategy in a Cancer Center of Zhejiang, China during the COVID-19 pandemic.
Due to the increased risk of viral infection and the severe shortage of medical resources during the pandemic of COVID-19, most hospitals in the epidemic areas significantly reduced non-emergency admissions and services, if not closed. As a result, it has been difficult to treat cancer patients on time, which adversely affects their prognosis. To address this problem, cancer centers must develop a strategic plan to manage both inpatients and outpatients during the pandemic, provide them with the necessary treatment, and at the same time prevent the spread of the virus among patients, visitors and medical staff. Based upon the epidemic situation in Zhejiang Province, China, the number of running non-emergency medical wards in the Zhejiang Cancer Hospital was gradually increased in a controlled manner. All staff of the hospital received COVID-19 preventive training and was provided with three different levels of protection according to the risks of their services. Only patients without a known history of SARS-CoV-2 contact were eligible to schedule an appointment. Body temperature was measured on all patients upon their arrival at the hospital. Chest CT image, blood cell counting and travel/contact history were investigated in patients with fever. Respiratory tract samples, such as sputum and throat swabs, from all patients, including those clinically suspected of SARS-CoV-2 infection, were collected for nucleic acid detection of SARS-CoV-2 before treatment. A total of 3697 inpatients and 416 outpatients seeking cancer treatment were enrolled from February 1 to April 3, 2020, in compliance with the hospital's infection-control interventions. The clinicopathological parameters of the patients were summarized herein. 4237 samples from 4101 patients produced negative RNA testing results. Four clinically suspected patients all presented negative RNA test results and were excluded from the SARS-CoV-2 infection through follow-up retesting and monitoring. Seven patients with only N-gene positive results were retested, followed by CT scan and SARS-CoV-2 contact history investigation. All of them were finally diagnosed as non-infected patients. There was one outpatient who was confirmed positive by virus RNA test and then followed up. She might be an asymptomatic laboratory-confirmed case. During the study period, there was no SARS-CoV-2 infection among staff, patients and escorts of patients in the Zhejiang Cancer Hospital. This study suggested our infection-control interventions, including viral nucleic acid test, could be used as a reliable method to screen cancer patients in the area with moderate COVID-19 prevalence. Cancer may not be a high-risk factor of SARS-CoV-2 infection.


Generic acquisition protocol for quantitative MRI of the spinal cord.
Quantitative spinal cord (SC) magnetic resonance imaging (MRI) presents many challenges, including a lack of standardized imaging protocols. Here we present a prospectively harmonized quantitative MRI protocol, which we refer to as the spine generic protocol, for users of 3T MRI systems from the three main manufacturers: GE, Philips and Siemens. The protocol provides guidance for assessing SC macrostructural and microstructural integrity: T1-weighted and T2-weighted imaging for SC cross-sectional area computation, multi-echo gradient echo for gray matter cross-sectional area, and magnetization transfer and diffusion weighted imaging for assessing white matter microstructure. In a companion paper from the same authors, the spine generic protocol was used to acquire data across 42 centers in 260 healthy subjects. The key details of the spine generic protocol are also available in an open-access document that can be found at https://github.com/spine-generic/protocols . The protocol will serve as a starting point for researchers and clinicians implementing new SC imaging initiatives so that, in the future, inclusion of the SC in neuroimaging protocols will be more common. The protocol could be implemented by any trained MR technician or by a researcher/clinician familiar with MRI acquisition.


[Immunotoxicity assessment in the preclinical study of biologically active compounds].
The immunotropic action of different drugs was considered on the basis of the modern theory of immunity (theory of network regulation). The immunosuppression and immunostimulation effects were analyzed retrospectively, as well as "disordered" immunity under the action of drugs. A systemic immunomodulated action of different drugs was postulated. Methodical recommendations for the preclinical estimation of immunotoxicity were generalized. A new protocol was proposed, concerning the examination of drug effects on the immune system.


[Outcome of haploidentical hematopoietic stem cell transplantation for refractory/relapsed acute leukemia].
To explore the outcome of human leukocyte antigen (HLA)-mismatched/haploidentical hematopoietic stem cell transplantation (HSCT) for refractory/relapsed acute leukemia (AL) patients and its related risk factors. 96 refractory/relapsed AL patients who received HLA-mismatched/haploidentical HSCT following conditioning regimen comprised of modified busulfan/cyclophosphamide (BU/CY) plus thymoglobulin (ATG) from Jan 2003 to Jun 2011 were analyzed retrospectively. Of the 96 patients, 61 suffered from acute myeloid leukemia (AML), and 35 acute lymphoid leukemia (ALL), all of them in non-remission (NR) or relapse before transplantation. With a median follow-up of 373 (34 - 3157) d, 33 cases (34%) survived, 31 survived without leukemia, and 35 relapsed. The estimated 3-year overall survival (OS) and disease-free survival (DFS) rate was 30.2% and 29.0%, respectively. The 3-year OS rate was significantly higher for AML patients (39.2%) than for ALL patients (15.4%) (P = 0.005). The estimated 3-year OS probabilities for patients with and without prophylactic donor lymphocyte infusion (DLI) were 38.0% and 11.8%, respectively (P = 0.001). Sex, age, conditioning regimen (BU/CY or not, dosage of ATG), the number of HLA mismatches between the donor and recipient, and the number of infused mononuclear cells were not independent factors affecting OS, DFS and relapse. Multivariate analysis showed that DFS rate was significantly higher in patients receiving prophylactic DLI (P = 0.003), in patients with AML (vs with ALL) (P = 0.037) and with chronic GVHD (P = 0.006). Haploidentical HSCT may prolong DFS in part refractory/relapsed AL patients and even cure them. Prophylactic DLI may reduce relapse and increase survival; for patients with refractory/relapsed ALL, other therapy for prevention and treatment of post-transplant relapse should be explored.


Tumor Retention of Enzyme-Responsive Pt(II) Drug-Loaded Nanoparticles Imaged by Nanoscale Secondary Ion Mass Spectrometry and Fluorescence Microscopy.
In nanomedicine, determining the spatial distribution of particles and drugs, together and apart, at high resolution within tissues, remains a major challenge because each must have a different label or detectable feature that can be observed with high sensitivity and resolution. We prepared nanoparticles capable of enzyme-directed assembly of particle therapeutics (EDAPT), containing an analogue of the Pt(II)-containing drug oxaliplatin, an 15N-labeled monomer in the hydrophobic block of the backbone of the polymer, the near-infrared dye Cy5.5, and a peptide that is a substrate for tumor metalloproteinases in the hydrophilic block. When these particles reach an environment rich in tumor associated proteases, the hydrophilic peptide substrate is cleaved, causing the particles to accumulate through a morphology transition, locking them in the tumor extracellular matrix. To evaluate the distribution of drug and EDAPT carrier in vivo, the localization of the isotopically labeled polymer backbone was compared to that of Pt by nanoscale secondary ion mass spectrometry (NanoSIMS). The correlation of NanoSIMS with super-resolution fluorescence microscopy revealed the release of the drug from the nanocarrier and colocalization with cellular DNA within tumor tissue. The results confirmed the dependence of particle accumulation and Pt(II) drug delivery on the presence of a Matrix Metalloproteinase (MMP) substrate and demonstrated antitumor activity. We conclude that these techniques are powerful for the elucidation of the localization of cargo and carrier, and enable a high-resolution assessment of their performance following in vivo delivery.


Electrowetting: A Consideration in Electroadhesion.
With the commercialization of haptic devices, understanding behavior under various environmental conditions is crucial for product optimization and cost reduction. Specifically, for surface haptic devices, the dependence of the friction force and the electroadhesion effect on the environmental relative humidity and the finger hydration level can directly impact their design and performance. This article presents the influence of relative humidity on the finger-surface friction force and the electroadhesion performance. Mechanisms including changes to Young's modulus of skin, contact angle change and capillary force were analyzed separately with experimental and numerical methods. Through comparison of the calculated capillary force in this paper and the electroadhesion force calculated in published papers, it was found that electrowetting at high voltage could contribute up to 60% of the total friction force increase in electroadhesion. Therefore, in future design of surface haptic devices, the effect of electrowetting should be considered carefully.


Medium-dose methrotrexate/folinic acid regimen in the chemotherapy of gestational trophoblastic disease.
Under the aegis of the Queensland Trophoblastic Tumour Registry, a screening and monitoring programme with the beta-subunit of chorionic gonadotrophin as a marker was adopted in the management of patients with gestational trophoblastic disease. Twenty-six patients had been treated with pulses of methotrexate, followed by folinic acid rescue, up to a total dose of 200 mg of methotrexate in each course; the side effects were minor and infrequent. This regimen was effective in producing biochemical and clinical remission in 18 of 19 patients both with non-metastatic and with metastatic persistent disease; the mean duration of treatment was nine weeks and 19.2 weeks respectively. However, it was effective in only three of seven patients with histologically confirmed choriocarcinoma, which suggests that a more aggressive multidrug regimen should be considered from the outset in this high risk group of patients. Our preliminary data have revealed no permanent effects on subsequent fertility or observable effects on the babies so far studied.


The sorting determinant guiding Hsp150 to the COPI-independent transport pathway in yeast.
The COPI coatomer is thought to be required in yeast directly for retrograde transport from the Golgi to the endoplasmic reticulum (ER), and directly or indirectly for ER-to-Golgi transport. Unexpectedly, the secretory glycoproteins Hsp150 and invertase have been found not to require COPI for ER exit. The features according to which cargo proteins are selected for the COPI-independent pathway are not known. The ER form of Hsp150 has three distinct domains: an N-terminal fragment of 54 amino acids (subunit I) is followed by 11 repeats of a 19 amino acid peptide plus a unique C-terminal fragment of 114 amino acids (subunit II). By fusing heterologous proteins to different Hsp150 domains and expressing them in sec21-1 and sec21-3 mutants with temperature-sensitive mutations in the gamma-COPI subunit, we show here that the repeats of subunit II function as sorting determinants for COPI-independent ER exit. The C-terminal fragment of Hsp150 could be replaced by E. coli beta-lactamase or rat nerve growth factor receptor ectodomain (NGFRe), and subunit I could be deleted, without inhibiting COPI-independent transport. However, when the repetitive region was omitted and beta-lactamase was fused directly to the C terminus of subunit I, COPI was required for efficient ER exit. Mass spectroscopic analysis demonstrated that both subunit I and II of Hsp150 were extensively O-glycosylated, suggesting that the O-glycosylation pattern was not decisive for cargo selection.


Vinyl bromide as a surrogate for determining vinyl chloride reductive dechlorination potential.
Site evaluation for bioremediation of chlorinated ethenes may need treatability studies to assess the reductive dechlorination potential of vinyl chloride (VC). Dehalogenation of vinyl bromide (VB) was investigated as a surrogate measurement for the dechlorination potential of VC. VB dehalogenation rates and kinetics were studied and compared with those of VC by a methanogenic reductive dechlorinating enrichment culture that was dominated by Dehalococcoides species and by microcosms from two chloroethene-contaminated sites. The enrichment culture dehalogenated VB to ethene at higher rates than VC at similar concentrations. VB was dehalogenated with a higher enzyme affinity than was VC, as indicated by their half-velocity constants, 240 +/- 150 and 21 +/- 8 microM, for VC and VB, respectively. Cross-inhibition study exhibited some evidence for competitive inhibition between VC and VB, suggesting that their degradation might be catalyzed by the same enzyme in the culture. Laboratory microcosm studies using subsurface soil and groundwater from two contaminated sites demonstrated that the production of the reductive dehalogenation product (ethene) could be detected faster with VB as a substrate than with VC. As a result, a substantially shorter (up to 5-10 times) incubation time would be required to detect the same level of reductive dehalogenation activity using VB as a surrogate for VC in treatability assessments.


Characterization of a mutagenic DNA adduct formed from 1,2-dibromoethane by O6-alkylguanine-DNA alkyltransferase.
It has been proposed that the DNA repair protein O6-alkylguanine-DNA alkyltransferase increases the mutagenicity of 1,2-dibromoethane by reacting with it at its cysteine acceptor site to form a highly reactive half-mustard, which can then react with DNA (Liu, L., Pegg, A. E., Williams, K. M., and Guengerich, F. P. (2002) J. Biol. Chem. 277, 37920-37928). Incubation of Escherichia coli-expressed human alkyltransferase with 1,2-dibromoethane and single-stranded oligodeoxyribonucleotides led to the formation of covalent transferaseoligo complexes. The order of reaction determined was Gua>Thy>Cyt>Ade. Mass spectrometry analysis of the tryptic digest of the reaction product indicated that some of the adducts led to depurination with the release of the Gly136-Arg147 peptide cross-linked to a Gua at the N7 position, with the site of reaction being the active site Cys145 as established by chromatographic retention time and the fragmentation pattern determined by tandem mass spectrometry of a synthetic peptide adduct. The alkyltransferase-mediated mutations produced by 1,2-dibromoethane were predominantly Gua to Ade transitions but, in the spectrum of such rifampicin-resistant mutations in the RpoB gene, 20% were Gua to Thy transversions. The latter are likely to have arisen from the apurinic site generated from the Gua-N7 adduct. Support exists for an additional adduct/mutagenic pathway because evidence was obtained for DNA adducts other than at the Gua N7 atom and for mutations other than those attributable to depurination. Thus, chemical and biological evidence supports the existence of at least two alkyltransferase-dependent pathways for 1,2-dibromoethane-induced mutagenicity, one involving Gua N7-alkylation by alkyltransferase-S-CH2CH2Br and depurination, plus another as yet uncharacterized system(s).


The effects of hypertension and body mass index on cognition in schizophrenia.
In recent years there has been a greater appreciation of the elevated prevalence of cardiovascular risk factors in the schizophrenia population and the liability some treatments have for their development. These vascular risk factors are in turn important risk factors in the development of dementia and more subtle cognitive impairments. However, their impact on the cognitive functions of patients with schizophrenia remains underexplored. The authors investigated whether vascular risk factors influence the cognitive impairments of schizophrenia and whether their effects on cognition in schizophrenia are different from those observed in nonpsychiatric comparison subjects. The authors compared 100 patients with schizophrenia and 53 comparison subjects on cognitive test performance in 2×2 matrices composed of individual vascular risk factors and group (schizophrenia patients and comparison subjects). Hypertension exerted a significant negative effect on immediate delayed and recognition memory in both groups. Patients with schizophrenia and hypertension were adversely affected in recognition memory, whereas comparison subjects were not. A body mass index above 25 was associated with negative effects on delayed memory in both groups, although the association fell short of statistical significance. Given that patients with schizophrenia have a higher prevalence of vascular risk factors than the general population and are undertreated for them, treatment of these risk factors may significantly improve cognitive outcome in schizophrenia.


Variations in HDL-carried miR-223 and miR-135a concentrations after consumption of dietary trans fat are associated with changes in blood lipid and inflammatory markers in healthy men - an exploratory study.
A high consumption of trans fatty acids (TFAs) is associated with an increased risk of cardiovascular diseases (CVDs). High-density lipoproteins (HDLs) have many cardioprotective properties and transport functional microRNAs (miRNAs) to recipient cells. We hypothesized that dietary TFAs modify the HDL-carried miRNA profile, therefore modulating its cardioprotective properties. We assessed whether consumption of dietary TFAs modifies HDL-carried miR-223-3p and miR-135a-3p concentration and the inter-relationship between diet-induced changes in HDL-carried miRNA concentration and CVD risk markers. In a double blind, randomized, crossover, controlled study, 9 men were fed each of 3 experimental isoenergetic diets: 1) High in industrial TFA (iTFA; 3.7% energy); 2) High in TFA from ruminants (rTFA; 3.7% energy); 3) Low in TFA (control; 0.8% energy) for 4 weeks each. HDLs were isolated by ultracentrifugation and miRNAs were quantified by RT-qPCR. Variations in HDL-miR-223-3p concentration were negatively correlated with variations in HDL-cholesterol after the iTFA diet (rs = 0.82; P = 0.007), and positively correlated with variations in C-reactive protein concentration after the rTFA diet (rs = 0.75; P = 0.020). Variations in HDL-miR-135a-3p concentration were positively correlated with variations in total triglyceride (TG) concentration following the iTFA diet (rs = -0.82; P = 0.007), and with variations in low-density lipoprotein (LDL)-TG concentration following the rTFA diet (rs = 0.83; P = 0.005), compared to the control diet. However, the consumption of dietary TFAs has no significant unidirectional impact on HDL-carried miR-223-3p and miR-135a-3p concentrations. Our results suggest that the variability in the HDL-carried miRNAs response to TFA intake, by being associated with variations in CVD risk factors, might reflect physiological changes in HDL functions.


The drugs or the disease? Causal attributions of symptoms held by HIV-positive adults on HAART.
Studies of HIV-related symptom and treatment side effect prevalence often fail to distinguish individual causal attributions between the two types of problems. However, an understanding of causal appraisals is critical to clarifying and intervening on coping in the context of HIV symptoms and treatment side effects. The objectives of this study are (1) to present causal attributions of symptoms reported by HIV+ adults taking combination therapy and (2) to describe the differential impact on health-related quality of life. In a cross-sectional interview study, a convenience sample of 109 HIV-positive adults taking highly active antiretroviral therapy (HAART) were interviewed using a combination of self- and interviewer-administered measures of quality of life, physical problem checklists, and side effect and HIV-related symptom attribution assessments. The most prevalent physical problems were fatigue, stiff/painful joints, aching muscles, diarrhea, feelings of depression, and neuropathy. Those most commonly labeled as side effects of HAART included upset stomach, nausea/vomiting, constipation, and changes in taste. Most commonly cited as symptoms related to HIV disease were tender lymph nodes, night sweats, weight loss, fever, and loss of strength. Impact of side effects, symptoms, and both were associated with impaired physical and social functioning. Disease-related symptoms, but not side effects, were related to perceptions of general health. Results suggest that HIV-positive persons taking HAART make distinctions between symptoms of disease and side effects of treatment. Perceived disease-related symptoms and side effects have significant and unique associations with quality of life. Findings have implications for symptom and side effects management, provider relations, and future research.


Cutaneous T-cell Lymphoma.
BACKGROUND: Cutaneous T-cell lymphoma (CTCL) represents a spectrum of diseases composed of malignant helper T lymphocytes. An accurate diagnosis of early CTCL is difficult because of the varied clinical and histologic expressions of the disease. METHODS: The authors review the epidemiology, possible risk factors, clinical manifestations, diagnostic techniques, staging, prognosis, and treatment options for CTCL. RESULTS: The varied and often nonspecific clinical and histologic presentations of CTCL may delay diagnosis and staging, thus necessitating further studies such as immunophenotyping, flow cytometry, and T-cell receptor gene rearrangement analysis. CONCLUSIONS: A multidisciplinary approach to the diagnosis, staging, and treatment of CTCL assists in optimizing outcomes from management of patients with this disease.


Free-Base Corrole Anion.
Free-base corroles have long been known to be acidic, readily undergoing deprotonation by mild bases and in polar solvents. The conjugate base, however, has not been structurally characterized until now. Presented here is a first crystal structure of a free-base corrole anion, derived from tris(p-cyanophenyl)corrole, as the tetrabuylammonium salt. The low-temperature (100 K) structure reveals localized hydrogens on a pair of opposite pyrrole nitrogens. DFT calculations identify such a structure as the global minimum but also point to two cis tautomers only 4-7 kcal/mol above the ground state. In terms of free energy, however, the cis tautomers are above or essentially flush with the trans-to-cis barrier so the cis tautomers are unlikely to exist or be observed as true intermediates. Thus, the hydrogen bond within each dipyrrin unit on either side of the molecular pseudo-C2 axis through C10 (i.e., between pyrrole rings A and B or between C and D) qualifies as or closely approaches a low-barrier hydrogen bond. Proton migration across the pseudo-C2 axis entails much higher activation energies >20 kcal/mol, reflecting the relative rigidity of the molecule along the C1-C19 pyrrole-pyrrole linkage.