Receiving support to quit smoking and quit attempts among smokers with and without smoking related diseases: Findings from the EUREST-PLUS ITC Europe Surveys.
Having a chronic disease either caused or worsened by tobacco smoking does not always translate into quitting smoking. Although smoking cessation is one of the most cost-effective medical interventions, it remains poorly implemented in healthcare settings. The aim was to examine whether smokers with chronic and respiratory diseases were more likely to receive support to quit smoking by a healthcare provider or make a quit attempt than smokers without these diseases. This population-based study included a sample of 6011 adult smokers in six European countries. The participants were interviewed face-to-face and asked questions on sociodemographic characteristics, current diagnoses for chronic diseases, healthcare visits in the last 12 months and, if so, whether they had received any support to quit smoking. Questions on smoking behavior included nicotine dependence, motivation to quit smoking and quit attempts in the last 12 months. The results are presented as weighted percentages with 95% confidence intervals (CI) and as adjusted odds ratios with 95% CI based on logistic regression analyses. Smokers with chronic respiratory disease, those aged 55 years and older, as well as those with one or more chronic diseases were more likely to receive smoking cessation advice from a healthcare professional. Making a quit attempt in the last year was related to younger age, high educational level, higher motivation to quit, lower nicotine dependence and having received advice to quit from a healthcare professional but not with having chronic diseases. There were significant differences between countries with smokers in Romania consistently reporting more support to quit as well as quit attempts. Although smokers with respiratory disease did indeed receive smoking cessation support more often than smokers without disease, many smokers did not receive any advice or support to quit during a healthcare visit.


Nutrient Intake and Physical Exercise Significantly Impact Physical Performance, Body Composition, Blood Lipids, Oxidative Stress, and Inflammation in Male Rats.
Humans consuming a purified vegan diet known as the "Daniel Fast" realize favorable changes in blood lipids, oxidative stress, and inflammatory biomarkers, with subjective reports of improved physical capacity. We sought to determine if this purified vegan diet was synergistic with exercise in male rats. Long⁻Evans rats (n = 56) were assigned to be exercise trained (+E) by running on a treadmill three days per week at a moderate intensity or to act as sedentary controls with normal activity. After the baseline physical performance was evaluated by recording run time to exhaustion, half of the animals in each group were fed ad libitum for three months a purified diet formulated to mimic the Daniel Fast (DF) or a Western Diet (WD). Physical performance was evaluated again at the end of month 3, and body composition was assessed using dual-energy x-ray absorptiometry. Blood was collected for measurements of lipids, oxidative stress, and inflammatory biomarkers. Physical performance at the end of month 3 was higher compared to baseline for both exercise groups (p < 0.05), with a greater percent increase in the DF + E group (99%) than in the WD + E group (51%). Body fat was lower in DF than in WD groups at the end of month 3 (p < 0.05). Blood triglycerides, cholesterol, malondialdehyde, and advanced oxidation protein products were significantly lower in the DF groups than in the WD groups (p < 0.05). No significant differences were noted in cytokines levels between the groups (p > 0.05), although IL-1β and IL-10 were elevated three-fold and two-fold in the rats fed the WD compared to the DF rats, respectively. Compared to a WD, a purified diet that mimics the vegan Daniel Fast provides significant anthropometric and metabolic benefits to rats, while possibly acting synergistically with exercise training to improve physical performance. These findings highlight the importance of macronutrient composition and quality in the presence of ad libitum food intake.


Digestion of rice straw and oil palm fronds by microflora from rumen and termite bacteria, in vitro.
The digestion and Volatile Fatty Acid (VFA) production from rice straw and oil palm fronds by cellulolytic bacteria isolated from the termite Coptotermes curvignathus were investigated. The bacteria were Acinetobacter strain Raminalimon, Enterobacter aerogenes strain Razmin C, Enterobacter cloacae strain Razmin B, Bacillus cereus strain Razmin A and Chryseobacterium kwangyangense strain Cb. Acinetobacter strain Raminalimon is an aerobic bacterium, while the other species are facultative anaerobes. There were significant differences (p<0.05) among the bacteria for Dry Matter (DM) lost and acetic acid production from rice straw and Acinetobacter strain Raminalimon showed the highest activity. The facultative bacteria C. kwangyangense strain Cb (cfu mL(-1) 231 x 10(-6), OD: 0.5), E. cloacae (cfu mL(-1) 68 x 10(-7), OD: 0.5) and E. aerogenes (cfu mL(-1) 33 x 10(-7), OD: 0.5) were used for digestion study with the rumen fluid microflora. The in vitro gas production technique was applied for the comparative study and the parameters measured were pH, gas (volume), dry matter lost, acetic acid, propionic acid and butyric acid concentrations. pH was not significantly (p<0.05) different among the five treatments. The bacterium C. kwangyangense strain Cb showed the highest activity (p<0.05) for DM lost, acetic acid, propionic acid and butyric acid production from rice straw when compared to the other bacterial activities. There was no significance (p<0.05) difference between the three bacteria for the dry matter lost of oil palm fronds but the production of Volatile Fatty Acids (VFA) was significantly (p<0.05) high in the treatment which was inoculated with C. kwangyangense strain Cb. The Gen Bank NCBI/EMBL accession numbers for the bacterial strains are EU332791, EU305608, EU305609, EU294508 and EU169201.


Toward a geriatric approach to patients with advanced age and cardiovascular diseases: position statement of the EuGMS Special Interest Group on Cardiovascular Medicine.
Cardiovascular diseases (CVD) are highly prevalent in older adults and represent a major geriatric health-care concern. Management of CVD in older patients may be challenging due to specific geriatric issues, such as frailty and multi-morbidity, which may influence patients' outcomes. In this clinical context, diagnostic and therapeutic strategies should target those outcomes that have higher priority in geriatric health care, including disability prevention and quality of life. Older adults with CVD should be offered a reasonably optimized treatment, customized to the individual's frailty level and functional status. Yet, most clinical trials excluded comorbid and frail patients and evidence to support CVD management in this vulnerable population is lacking. Therefore, a geriatric approach is needed in cardiovascular medicine, characterized by a holistic, patient-centered perspective focusing on functional status and quality of life. With a view to promote the geriatric approach in the management of older patients with CVD, the EuGMS Special Interest Group (SIG) on Cardiovascular Medicine was founded in 2018, consisting of a network of geriatricians with an extensive expertise in geriatric cardiovascular medicine. The present position paper aims to present the Cardiovascular SIG and illustrate its main purposes and action programs.


Income Inequality in Quality of Life among Rural Communities in Malaysia: A Case for Immediate Policy Consideration.
Quality of life (QOL) is a proxy of health and social well-being. Hence, it is vital to assess QOL as it informs the strategies of policymakers to enhance the living conditions in communities. Rural areas in emerging economies are underserved in terms of modern facilities and technologies, which impact QOL. To address this, this study investigated whether income played a role in the QOL of rural residents within emerging economies using a large survey of Malaysian adults above 18 years old. The study extracted data from a sample of 18,607 respondents of a health and demographic surveillance system survey. A generalized linear model was used to estimate the impact of three income groups, the bottom 40%, middle 40% and top 20%, on perceived QOL, controlling for sociodemographic, chronic disease co-morbidities and mental health status. Results of the study showed a statistically significant association between income and the physical, psychological, social and environmental QOL domains. Using the bottom 40% as a reference category, the middle 40% and top 20% income groups showed a significant and positive association across the four domains of QOL. Hence, intervention programs are necessary to escalate the income levels of rural communities, especially the bottom 40%, to uplift perceived QOL among rural residents.


Decolorization and detoxification of Direct Blue 2B by indigenous bacterial consortium.
Azo dyes are widely used in the textile industry despite being poorly biodegradable and highly toxic. Hence, azo dyes need to be removed from effluent prior to environmental discharge. Microbial communities are efficient for the degradation and mineralization of azo dyes. However, little is known about the functional microbial communities responsible for the degradation process. In this study, a novel indigenous bacteria consortium was developed for characterizing the functional microbial communities involved in the degradation of a sulfonated azo dye, Direct Blue 2B (DB2) in a simple batch reactor. The optimal temperature, pH, and salinity for the decolorization process were 38.70 °C, pH 7.57, and 20.10 g L-1 NaCl, respectively. The effect of the operating conditions on microbial community structure were determined using high-throughput Illumina HiSeq sequencing. Gammaproteobacteria, Betaproteobacteria, and Bacilli were dominant under most of the operating conditions. At pH above 8 and NaCl concentration above 30 g L-1, Firmicutes relative abundance did not significantly change suggesting tolerance towards alkaline and hypersaline environments. Tritium aestivum and Glycine max seed germination following exposure to YHK treated DB2 solution was above 80% compared to 50% in untreated DB2 solution. The YHK consortium decolorized dyes structurally different from DB2 such as trimethyl phenyl and direct dyes. The results of this study offer valuable data on improving optimization of dye biodegradation processes and the capability of YHK in in situ bioremediation.


Foodborne pathogen inactivation in fruit juices utilizing commercial scale high-pressure processing: Effects of acidulants and pH.
The effects of juice pH, type of acidulant, and post-treatment refrigeration on the high-pressure processing (HPP) inactivation of Escherichia coli O157:H7, Salmonella enterica, and Listeria monocytogenes in acid beverages were evaluated. Inoculated apple, orange, and grape juices (at their original pH and adjusted to pH 4.00, 4.50, and 5.00) were treated at 550 MPa for 1 min at 5 °C. In addition, inoculated model solutions acidified to a pH of 5.00 with acetic, citric, malic, and tartaric acids were treated at 400 MPa for 1 min at 5 °C. The effect of refrigerated storage for 24 h after treatment on pathogen inactivation in both experiments was also assessed. A greater than 5-log reduction of the three pathogens inoculated was achieved in all juices immediately after HPP at the juices' original pH, and of L. monocytogenes under all experimental conditions. Refrigerated storage for 24 h after HPP treatment improved the inactivation of E. coli O157:H7, to >5-log reduction, at pH 4.00 in apple juice and of Salmonella in the three juices at pH 4.00. The type of acidulant did not significantly (p > 0.01) affect E. coli or Salmonella inactivation in acidified model solutions but a greater than 5-log reduction after HPP was only achieved for L. monocytogenes when acetic acid was used. The effectiveness of HPP for pathogen inactivation depended largely on product pH and the target pathogen of concern.


Combining Molecular Dynamics Simulations and Biophysical Characterization to Investigate Protein-Specific Excipient Effects on Reteplase during Freeze Drying.
We performed molecular dynamics simulations of Reteplase in the presence of different excipients to study the stabilizing mechanisms and to identify the role of excipients during freeze drying. To simulate the freeze-drying process, we divided the process into five distinct steps: (i) protein-excipient formulations at room temperature, (ii) the ice-growth process, (iii)-(iv) the partially solvated and fully dried formulations, and (v) the reconstitution. Furthermore, coarse-grained (CG) simulations were employed to explore the protein-aggregation process in the presence of arginine. By using a coarse-grained representation, we could observe the collective behavior and interactions between protein molecules during the aggregation process. The CG simulations revealed that the presence of arginine prevented intermolecular interactions of the catalytic domain of Reteplase, thus reducing the aggregation propensity. This suggests that arginine played a stabilizing role by interacting with protein-specific regions. From the freeze-drying simulations, we could identify several protein-specific events: (i) collapse of the domain structure, (ii) recovery of the drying-induced damages during reconstitution, and (iii) stabilization of the local aggregation-prone region via direct interactions with excipients. Complementary to the simulations, we employed nanoDSF, size-exclusion chromatography, and CD spectroscopy to investigate the effect of the freeze-drying process on the protein structure and stability.


Membrane transporters as determinants of the pharmacology of platinum anticancer drugs.
Membrane transporters govern the movement of drugs and their metabolites across biological membranes, thereby determining their pharmacokinetics, efficacy and adverse drug reactions. Platinum-based anticancer drugs are a mainstay of chemotherapy for many human malignancies. However, their clinical utility is limited by tumor resistance and normal tissue toxicities, which are determined at least in part by the level of tissue accumulation of platinum. Recently, several members of the ATP-binding cassette (ABC), solute carrier (SLC) and ATPase membrane protein superfamilies have been found to contribute to the net accumulation of platinum drugs in malignant and normal tissues. Herein, a review has been carried out to critically evaluate current preclinical and clinical evidence implicating membrane transporters as determinants of the pharmacology of cisplatin, oxaliplatin, carboplatin and related investigational compounds. The evidence includes studies of recombinant cell systems with genetically modified expression of individual membrane transporters, platinum-resistant or -sensitive human cancer cells and in vivo xenografted tumors, animal models of platinum-induced nephro-, oto- or neurotoxicity, and clinical studies of associations between the membrane transporter tumor expression and patient outcomes from platinum-based chemotherapy. Understanding the role of membrane transporters as determinants of the pharmacology of platinum drugs will be a basis for targeting these drug transporters in individualized and optimized platinum-based cancer therapy, and new drug development.


Sliced Inverse Regression With Adaptive Spectral Sparsity for Dimension Reduction.
Dimension reduction is an important topic in pattern analysis and machine learning, and it has wide applications in feature representation and pattern classification. In the past two decades, sliced inverse regression (SIR) has attracted much research efforts due to its effectiveness and efficacy in dimension reduction. However, two drawbacks limit further applications of SIR. First, the computation complexity of SIR is usually high in the situation of high-dimensional data. Second, sparsity of projection subspace is not well mined for improving the feature selection and model interpretation abilities. This paper proposes to compute the SIR projection vectors in the spectral space, then an approximated regression solution can be obtained with a faster speed. Moreover, the adaptive lasso is used to attain a sparse and globally optimal solution, which is important in variable selection. To complete the robust pattern classification task with corruptions, a correntropy-based and class-wise regression model is designed in this paper. It takes a smooth penalty instead of sparsity constraint in the regression coefficients, and it can be conducted in class-wise, thus it is more flexible in practice. Extensive experiments are conducted by using some real and benchmark data sets, e.g., high-dimensional facial images and gene microarray data, to evaluate the new algorithms. The new proposals attain competitive results and are compared with other state-of-the-art methods.


Direct measurement of the tryptophan-mediated photocleavage kinetics of a protein disulfide bond.
Disulfide cleavage is one of the major causes underlying ultraviolet (UV) light-induced protein damage. While previous studies have provided strong evidence to support the notion that this process is mediated by photo-induced electron transfer from the excited state of an aromatic residue (e.g., tryptophan) to the disulfide bond, many mechanistic details are still lacking. For example, we do not know how quickly this process occurs in a protein environment. Herein, we design an experiment, which uses the unfolding kinetics of a protein as an observable, to directly assess the kinetics and mechanism of photo-induced disulfide cleavage. Our results show that this disulfide bond cleavage event takes place in ∼2 μs via a mechanism involving electron transfer from the triplet state of a tryptophan (Trp) residue to the disulfide bond. Furthermore, we find that one of the photoproducts of this reaction, a Trp-SR adduct, is formed locally, thus preventing the protein from re-cross-linking. Taken together, these findings suggest that a Trp-disulfide pair could be used as a photo-trigger to initiate protein folding dynamics and control the biological activities of disulfide-containing peptides.


A multicentre, randomized, double-blinded, placebo-controlled Phase III study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND).
Thrombolytic therapy with tissue plasminogen activator is effective for acute ischaemic stroke within 4·5 h of onset. Patients who wake up with stroke are generally ineligible for stroke thrombolysis. We hypothesized that ischaemic stroke patients with significant penumbral mismatch on either magnetic resonance imaging or computer tomography at three- (or 4·5 depending on local guidelines) to nine-hours from stroke onset, or patients with wake-up stroke within nine-hours from midpoint of sleep duration, would have improved clinical outcomes when given tissue plasminogen activator compared to placebo. EXtending the time for Thrombolysis in Emergency Neurological Deficits is an investigator-driven, Phase III, randomized, multicentre, double-blind, placebo-controlled study. Ischaemic stroke patients presenting after the three- or 4·5-h treatment window for tissue plasminogen activator and within nine-hours of stroke onset or with wake-up stroke within nine-hours from the midpoint of sleep duration, who fulfil clinical (National Institutes of Health Stroke Score ≥4-26 and prestroke modified Rankin Scale <2) will undergo magnetic resonance imaging or computer tomography. Patients who also meet imaging criteria (infarct core volume <70 ml, perfusion lesion : infarct core mismatch ratio >1·2, and absolute mismatch >10 ml) will be randomized to either tissue plasminogen activator or placebo. The primary outcome measure will be modified Rankin Scale 0-1 at day 90. Clinical secondary outcomes include categorical shift in modified Rankin Scale at 90 days, reduction in the National Institutes of Health Stroke Score by 8 or more points or reaching 0-1 at day 90, recurrent stroke, or death. Imaging secondary outcomes will include symptomatic intracranial haemorrhage, reperfusion and or recanalization at 24 h and infarct growth at day 90.


Human Melioidosis.
The causative agent of melioidosis, Burkholderia pseudomallei, a tier 1 select agent, is endemic in Southeast Asia and northern Australia, with increased incidence associated with high levels of rainfall. Increasing reports of this condition have occurred worldwide, with estimates of up to 165,000 cases and 89,000 deaths per year. The ecological niche of the organism has yet to be clearly defined, although the organism is associated with soil and water. The culture of appropriate clinical material remains the mainstay of laboratory diagnosis. Identification is best done by phenotypic methods, although mass spectrometric methods have been described. Serology has a limited diagnostic role. Direct molecular and antigen detection methods have limited availability and sensitivity. Clinical presentations of melioidosis range from acute bacteremic pneumonia to disseminated visceral abscesses and localized infections. Transmission is by direct inoculation, inhalation, or ingestion. Risk factors for melioidosis include male sex, diabetes mellitus, alcohol abuse, and immunosuppression. The organism is well adapted to intracellular survival, with numerous virulence mechanisms. Immunity likely requires innate and adaptive responses. The principles of management of this condition are drainage and debridement of infected material and appropriate antimicrobial therapy. Global mortality rates vary between 9% and 70%. Research into vaccine development is ongoing.


Large amplitude oscillatory shear of block copolymer spheres on a body-centered cubic lattice: are micelles like metals?
Small-angle X-ray diffraction experiments have uncovered a remarkable mechanism of grain alignment during plastic deformation of ordered sphere-forming diblock copolymer micelles when subjected to large amplitude dynamic shearing. A nearly monodisperse poly(styrene-b-ethylene-alt-propylene) (SEP) diblock copolymer with block molecular weights of 42,000 and 60,000 was mixed with squalane (C(30)H(62)), an EP selective solvent, at a concentration of 10 wt%. After high temperature annealing, the sample formed an ordered polydomain morphology containing glassy S cores at room temperature. SAXS powder patterns confirm body-centered cubic (BCC) symmetry and reveal the development of a complex array of two-dimensionally resolved Bragg reflections following the application, and cessation, of oscillatory shearing. These diffraction results are interpreted on the basis of the classic mechanism of crystalline slip, which accounts for plastic deformation of ductile materials such as metals. Four distinct slip systems are shown to be active in this work, suggesting a robust basis for deforming and mixing of soft ordered solids.


A Mixed-Methods Analysis of a Novel Mistreatment Program for the Surgery Core Clerkship.
To review mistreatment reports from before and after implementation of a mistreatment program, and student ratings of and qualitative responses to the program to evaluate the short-term impact on students. In January 2014, a video- and discussion-based mistreatment program was implemented for the surgery clerkship at the Stanford University School of Medicine. The program aims to help students establish expectations for the learning environment; create a shared and personal definition of mistreatment; and promote advocacy and empower ment to address mistreatment. Counts and types of mistreatment were compared from a year before (January-December 2013) and two years after (January 2014-December 2015) implementation. Students' end-of-clerkship ratings and responses to open-ended questions were analyzed. From March 2014-December 2015, 141/164 (86%) students completed ratings, and all 47 (100%) students enrolled from January-August 2014 provided qualitative program evaluations. Most students rated the initial (108/141 [77%]) and final (120/141 [85%]) sessions as excellent or outstanding. In the qualitative analysis, students valued that the program helped establish expectations; allowed for sharing experiences; provided formal resources; and provided a supportive environment. Students felt the learning environment and culture were improved and reported increased interest in surgery. There were 14 mistreatment reports the year before the program, 9 in the program's first year, and 4 in the second year. The authors found a rotation-specific mistreatment program, focused on creating shared understanding about mistreatment, was well received among surgery clerkship students, and the number of mistreatment reports decreased each year following implementation.


Maintenance of aseptic barriers in the conventional operating room: general principles.
Contamination of operative wounds during surgery occurs primarily through contact and secondarily through the airborne route. Inspection and maintenance of air-handling equipment is essential, with special reference to air intakes, filters, humidifiers, and exhaust systems. Doors should remain closed to maintain positive pressure. Surgical attire for all personnel must provide for complete coverage of hair and arms. Intensive interim cleaning of all horizontal sufaces between operations is essential. The infection rate is proportional to the duration of the operation and the number of personnel in the room, and inversely proportional to the air changes per hour.


Viewing time as a measure of sexual interest among child molesters and normal heterosexual men.
Although phallometric assessment is the best scientific method for measuring male sexual interest, it is intrusive and highly technical. We examined viewing time as an unobtrusive and technically simple measure of sexual preference and compared the discrimination obtained by viewing time measures with that obtained by phallometric measures. Slides of nude males and females of various ages were shown to child molesters and normal men while their viewing times were recorded. Subjects then rated the sexual attractiveness of the stimulus persons. Phallometric assessments using the same stimulus categories were also given to some of the Ss. Deviance scores calculated from the viewing time data significantly discriminated between the child molesters and the normals, although the discrimination achieved was less than that obtained using phallometric measures. Sexual attractiveness ratings did not differentiate the two groups. Among the normal men, viewing time and sexual attractiveness ratings were highly correlated; but the correlation was much lower for child molesters. Viewing time shows considerable promise as an unobtrusive measure of male sexual interest.


Long-term outcome of nephron sparing surgery and simple nephrectomy for unilateral localized Wilms tumor.
We retrospectively assessed survival and local recurrence rates in children with unilateral localized Wilms tumor (WT) treated with nephron sparing surgery (NSS) or simple nephrectomy with removal only of the perirenal fat adherent to the tumor surface. The records of 70 children with renal tumor, operated on by the same surgeon between January 1968 and December 2003, were reviewed. Of 64 children with WT 52 with localized nonanaplastic WT were enrolled. Treatment was administered according to International Society of Pediatric Oncology protocols 1 to 2001 in all patients but 7, who were operated on between 1968 and 1971. Patients were stratified as having stage I (27), stage II (23) or stage III (2) disease. Surgical treatment included 40 simple nephrectomies, 10 NSSs (only stage I cases ascertained by frozen section) and 2 radical nephrectomies. Mean patient age at operation was 39.5 months (range 1 to 126). Followup ranged from 27 to 431 months (mean 188.4). Event-free survival rate in all localized stages was 88.5% (stage I 92.6%, stage II 87%, stage III 50%). Two infants with stage I disease died after surgery for reasons not related to malignancy. Only 1 patient with stage II lymph node negative WT had local relapse. Our results are similar to those achieved by radical nephrectomy in previous studies. Leaving Gerota's fascia in situ does not seem to confer a higher risk of local recurrence in patients with low stage nonanaplastic WT. After NSS Gerota's fascia may be used to cover the defect and to maintain tissue plains, thus, facilitating reintervention if necessary.


Analgesic and cognitive effects of intravenous ketamine-alfentanil combinations versus either drug alone after intradermal capsaicin in normal subjects.
Combinations of opioids and N-methyl-D-aspartate (NMDA) antagonists enhance acute antinociception and reduce opioid tolerance in some animal experiments but have received little rigorous study in humans. To quantitatively assess the nature of the interaction of these two classes of drugs in producing analgesia and cognitive impairment, we compared i.v. infusions of ketamine, alfentanil, and ketamine-alfentanil combinations in 12 normal volunteers after an intradermal injection of capsaicin. Drug doses for a 70-kg subject in this six-session, randomized, double-blind, cross-over study were: ketamine 20 mg, ketamine 5 mg, alfentanil 2 mg, alfentanil 0.5 mg, ketamine 10 mg + alfentanil 1 mg, and ketamine 2.5 mg + alfentanil 0.25 mg, given over 35 min. Outcome measures were background pain, area and magnitude of hyperalgesia to pinprick, and cognitive performance on the Digit Symbol Substitution Test and the Perception Speed Test. The results demonstrated simple additivity for the effects of ketamine and alfentanil on pain, pinprick hyperalgesia, and cognitive impairment. We conclude that, at least in this experimental pain model, there is no clear advantage or disadvantage of a ketamine-alfentanil combination over equianalgesic doses of either component. In a double-blind, controlled trial, we administered doses of an opioid analgesic (alfentanil), an N-methyl-D-aspartate receptor antagonist (ketamine), or their combination to normal volunteers and found no advantage of the combination over a larger dose of either drug alone in relieving pain caused by painful chemical stimulation.


Stimulus-responsive self-assembly: reversible, redox-controlled micellization of polyferrocenylsilane diblock copolymers.
In depth studies of the use of electron transfer reactions as a means to control the self-assembly of diblock copolymers with an electroactive metalloblock are reported. Specifically, the redox-triggered self-assembly of a series of polystyrene-block-polyferrocenylsilane (PS-b-PFS) diblock copolymers in dichloromethane solution is described. In the case of the amorphous polystyrene(n)-b-poly(ferrocenylphenylmethylsilane)(m) diblock copolymers (PS(n)-b-PFMPS(m): n = 548, m = 73; n = 71, m = 165; where n and m are the number-averaged degrees of polymerization), spherical micelles with an oxidized PFS core and a PS corona were formed upon oxidation of more than 50% of the ferrocenyl units by [N(C(6)H(4)Br-4)(3)][SbX(6)] (X = Cl, F). Analogous block copolymers containing a poly(ferrocenylethylmethylsilane) (PFEMS) metalloblock, which has a lower glass transition temperature, behaved similarly. However, in contrast, on replacement of the amorphous metallopolymer blocks by semicrystalline poly(ferrocenyldimethylsilane) (PFDMS) segments, a change in the observed morphology was detected with the formation of ribbon-like micelles upon oxidation of PS(535)-b-PFDMS(103) above the same threshold value. Again the coronas consisted of fully solvated PS and the core consisted of partially to fully oxidized PFS associated with the counteranions. When oxidation was performed with [N(C(6)H(4)Br-4)(3)][SbF(6)], reduction of the cores of the spherical or ribbon-like micelles with [Co(η-C(5)Me(5))(2)] enabled full recovery of the neutral chains and no significant chain scission was detected.


Lateral femoral wall thickness. A reliable predictor of post-operative lateral wall fracture in intertrochanteric fractures.
Although the importance of lateral femoral wall integrity is increasingly being recognised in the treatment of intertrochanteric fracture, little attention has been put on the development of a secondary post-operative fracture of the lateral wall. Patients with post-operative fractures of the lateral wall were reported to have high rates of re-operation and complication. To date, no predictors of post-operative lateral wall fracture have been reported. In this study, we investigated the reliability of lateral wall thickness as a predictor of lateral wall fracture after dynamic hip screw (DHS) implantation. A total of 208 patients with AO/OTA 31-A1 and -A2 classified intertrochanteric fractures who received internal fixation with a DHS between January 2003 and May 2012 were reviewed. There were 103 men and 150 women with a mean age at operation of 78 years (33 to 94). The mean follow-up was 23 months (6 to 83). The right side was affected in 97 patients and the left side in 111. Clinical information including age, gender, side, fracture classification, tip-apex distance, follow-up time, lateral wall thickness and outcome were recorded and used in the statistical analysis. Fracture classification and lateral wall thickness significantly contributed to post-operative lateral wall fracture (both p < 0.001). The lateral wall thickness threshold value for risk of developing a secondary lateral wall fracture was found to be 20.5 mm. To our knowledge, this is the first study to investigate the risk factors of post-operative lateral wall fracture in intertrochanteric fracture. We found that lateral wall thickness was a reliable predictor of post-operative lateral wall fracture and conclude that intertrochanteric fractures with a lateral wall thickness < 20.5 mm should not be treated with DHS alone.


Aspects on the intensity and the relief of pain in the prehospital phase of acute coronary syndrome: experiences from a randomized clinical trial.
The primary aim of this study was to evaluate the pain relief and tolerability of two pain-relieving strategies in the prehospital phase of presumed acute coronary syndrome (ACS), and the secondary aim was to assess the relationship between the intensity and relief of pain and heart rate, blood pressure, and ST deviation. Patients with chest pain judged as caused by ACS were randomized (open) to either metoprolol 5 mg intravenously (i.v.) three times at 2-min intervals (n = 84; metoprolol group) or morphine 5 mg i.v. followed by metoprolol 5 mg three times i.v (n = 80; morphine group). Pain was assessed on a 10-grade scale before randomization and 10, 20, and 30 min thereafter. The mean pain score decreased from 6.5 at randomization to 2.8 30 min later, with no significant difference between groups. The percentages with complete pain relief (pain score < or = 1) after 10, 20, and 30 min were 11, 16, and 21%, respectively, with no difference between groups. Hypotension was less frequent in the metoprolol group compared with the morphine group (0 vs. 6.3%; P=0.03), as was nausea/vomiting (7.2 vs. 24.0%; P=0.004). At randomization intensity of pain was associated with degree of ST elevation (P=0.009). The degree of pain relief over 30 min was associated with decrease in heart rate (P=0.03) and decrease in ST elevation (P=0.01).In conclusion, in the prehospital phase of presumed ACS, neither a pain-relieving strategy including an anti-ischemic agent alone nor an analgesic plus anti-ischemic strategy in combination resulted in complete pain relief. Fewer side effects were found with the former strategy. Other pain-relieving strategies need to be evaluated.


Visual object recognition: do we know more now than we did 20 years ago?
We review the progress made in the field of object recognition over the past two decades. Structural-description models, making their appearance in the early 1980s, inspired a wealth of empirical research. Moving to the 1990s, psychophysical evidence for view-based accounts of recognition challenged some of the fundamental assumptions of structural-description theories. The 1990s also saw increased interest in the neurophysiological study of high-level visual cortex, the results of which provide some constraints on how objects may be represented. By 2000, neuroimaging arose as a viable means for connecting neurons to behavior. One of the most striking fMRI results has been category selectivity, which provided further constraints for models of object recognition. Despite this progress, the field is still faced with the challenge of developing a comprehensive theory that integrates this ever-increasing body of results and explains how we perceive and recognize objects.


Age- and diet-specific effects of variation at S6 kinase on life history, metabolic, and immune response traits in Drosophila melanogaster.
Life history theory hypothesizes that genetically based variation in life history traits results from alleles that alter age-specific patterns of energy allocation among the competing demands of reproduction, storage, and maintenance. Despite the important role that alleles with age-specific effects must play in life history evolution, few naturally occurring alleles with age-specific effects on life history traits have been identified. A recent mapping study identified S6 kinase (S6k) as a candidate gene affecting lipid storage in Drosophila. S6k is in the target of rapamycin pathway, which regulates cell growth in response to nutrient availability and has also been implicated to influence many life history traits from fecundity to life span. In this article, we used quantitative complementation tests to examine the effect of allelic variation at S6k on a range of phenotypes associated with metabolism and fitness in an age-, diet-, and sex-specific manner. We found that alleles of S6k have pleiotropic effects on total protein levels, glycogen storage, life span, and the immune response and demonstrate that these allelic effects are age, diet, and sex specific. As many of the genes in the target of rapamycin pathway are evolutionarily conserved, our data suggest that genes in this pathway could play a pivotal role in life history evolution in a wide range of taxa.


In vivo properties of KNT-127, a novel δ opioid receptor agonist: receptor internalization, antihyperalgesia and antidepressant effects in mice.
Activation of δ opioid (DOP) receptors regulates pain and emotional responses, and also displays ligand-biased agonism. KNT-127 (1,2,3,4,4a,5,12,12a-octahydro-2-methyl-4aβ,1β-([1,2]benzenomethano)-2,6-diazanaphthacene-12aβ,17-diol) is a novel DOP receptor agonist inducing analgesia and antidepressant effects in mice. Here, we have assessed KNT-127 for (i) analgesia against chronic inflammatory pain; (ii) effects on depression, locomotion and DOP receptor internalization; and (iii) for cross-tolerance to analgesic and antidepressant effects of acute treatment by other DOP receptor agonists. Inflammatory pain was induced by complete Freund's adjuvant injection into tail or hindpaw, and thermal and mechanical sensitivities were determined in mice. Locomotor and antidepressant-like effects were measured using actimetry and forced swim test respectively. In vivo KNT-127 selectivity and internalization were assessed using DOP receptor knockout mice and knock-in mice expressing fluorescent-tagged DOP receptors. KNT-127 was injected acutely at 0.1-10.0 mg·kg(-1) or administered chronically at 5 mg·kg(-1) daily over 5 days. Acute treatment with KNT-127 reversed inflammatory hyperalgesia, produced an antidepressant-like effect but induced neither hyperlocomotion nor receptor sequestration. Chronic treatment with KNT-127 induced tolerance and cross-tolerance to SNC80-induced analgesia, but no tolerance to SNC80-evoked hyperlocomotor or antidepressant-like effects. The DOP receptor agonist KNT-127 induced agonist-specific acute and chronic responses, at both behavioural and cellular levels. It displays activities similar to the other recently reported DOP agonists, AR-M1000390, ADL5747 and ADL5859, and differs from SNC80. SNC80 differs from the other DOP receptor agonists including KNT-127, by exhibiting ligand-biased tolerance at this receptor.


Delineating effect of headgroup and preparation method on transfection versus toxicity of DNA-loaded lipid nanocarriers.
Aim: To perform a parallel comparison of key parameters affecting the safety and efficiency of lipid-based nanovectors (i.e., complexing headgroups, composition and preparation method). Materials & methods: Various cationic and ionizable headgroups were screened for formulating lipoplexes with GFP-plasmid DNA. Ethanol injection and microfluidics were used to prepare nanoparticles with GFP-plasmid DNA complexed on the surface or within the interior of lipid bilayers. Results: Lipoplexes composed of sphingomyelin 102 exhibited the highest transfection efficiency given their higher cellular uptake in BRAF inhibitor-resistant melanoma cells. Lipid nanoparticles demonstrated acceptable transfection efficiency and high spheroid penetration while protecting plasmid DNA under simulated physiological conditions. Conclusion: Selecting the right complexing lipid and preparation method is critical for developing lipid nanocarriers to treat intractable diseases.


Nuclear DNA content of altered hepatic foci in a rat liver carcinogenesis model.
In individual altered hepatic foci (AHF), aneuploidy occurs before malignant changes can be diagnosed histologically (O. Sudilovsky and T. K. Hei. Fed. Proc., 42:2225, 1983). In the current experiments Sprague-Dawley rats of both sexes were given i.p. injections of diethylnitrosamine (50 mg/kg body weight) 18 h after partial hepatectomy and were given a choline-sufficient diet (CS) for 1 wk. Four treatment groups were then formed and fed CS, CS containing 0.05% phenobarbital (PHB), choline-deficient diet (CD), and CD with 0.05% PHB. An extra female group received infusions of saline after the hepatectomy and fared CD. Control animals were partially hepatectomized, inoculated i.p. with saline, and placed on CS. The rats were sacrificed 16 wk later, liver sections were stained with a combined Feulgen-gamma-glutamyl transpeptidase stain, and the DNA content of gamma-glutamyl transpeptidase-positive foci was measured cytospectrophotometrically. There were no AHF in the control animals. Hepatocytes from control livers and cells adjacent to foci in treated livers had peaks corresponding to the 2C, 4C, and 8C range. In AHF the ploidy, however, was predominantly diploid, tetraploid, or heterogeneous. The ratio of diploid to tetraploid cells in foci of rats provided with CS + PHB was 5.5 and in those supplied with CD + PHB was 0.09. This suggested that dietary manipulations change the nuclear DNA distribution of AHF. Aneuploidy was also present, as expected, in 4 of 33 AHF in the animals placed on CD + PHB. It was observed as well in 2 of 26 AHF of rats given CD but in none of the 20 AHF fed CS + PHB. These data indicate that CD (which acts as both initiator and promoter) may be responsible for the appearance of aneuploidy. A general model, based on these results and the clonality of each individual focus, is proposed for the development of cells through the preneoplastic stage.


The effect of benzyl beta-D-xyloside on keratan sulphate synthesis in ox articular cartilage.
Cartilage from adult bovine hock joints was incubated with [3H]galactose or [35S]sulphate in the presence of benzyl beta-D-xyloside. Radioisotope incorporation into proteoglycan was inhibited by the xyloside; the magnitude of this inhibition depended on the concentration of xyloside used. With 0.2mM xyloside radioisotope incorporation into keratan sulphate was not altered but inhibition was observed at xyloside concentrations of 1.0mM or higher. The decrease in radioisotope incorporation into keratan sulphate in the presence of 1.0mM benzyl beta-xyloside was directly related to a reduction in the average length of the keratan sulphate chains. This effect of beta-xyloside on keratan sulphate biosynthesis was markedly different from its effect on chondroitin sulphate biosynthesis.


Evaluating the reliability of gestalt quality ratings of medical education podcasts: A METRIQ study.
Podcasts are increasingly being used for medical education. Studies have found that the assessment of the quality of online resources can be challenging. We sought to determine the reliability of gestalt quality assessment of education podcasts in emergency medicine. An international, interprofessional sample of raters was recruited through social media, direct contact, and the extended personal network of the study team. Each participant listened to eight podcasts (selected to include a variety of accents, number of speakers, and topics) and rated the quality of that podcast on a seven-point Likert scale. Phi coefficients were calculated within each group and overall. Decision studies were conducted using a phi of 0.8. A total of 240 collaborators completed all eight surveys and were included in the analysis. Attendings, medical students, and physician assistants had the lowest individual-level variance and thus the lowest number of required raters to reliably evaluate quality (phi >0.80). Overall, 20 raters were required to reliably evaluate the quality of emergency medicine podcasts. Gestalt ratings of quality from approximately 20 health professionals are required to reliably assess the quality of a podcast. This finding should inform future work focused on developing and validating tools to support the evaluation of quality in these resources.


Responses of a bursting pacemaker to excitation reveal spatial segregation between bursting and spiking mechanisms.
Central pattern generators (CPGs) frequently include bursting neurons that serve as pacemakers for rhythm generation. Phase resetting curves (PRCs) can provide insight into mechanisms underlying phase locking in such circuits. PRCs were constructed for a pacemaker bursting complex in the pyloric circuit in the stomatogastric ganglion of the lobster and crab. This complex is comprised of the Anterior Burster (AB) neuron and two Pyloric Dilator (PD) neurons that are all electrically coupled. Artificial excitatory synaptic conductance pulses of different strengths and durations were injected into one of the AB or PD somata using the Dynamic Clamp. Previously, we characterized the inhibitory PRCs by assuming a single slow process that enabled synaptic inputs to trigger switches between an up state in which spiking occurs and a down state in which it does not. Excitation produced five different PRC shapes, which could not be explained with such a simple model. A separate dendritic compartment was required to separate the mechanism that generates the up and down phases of the bursting envelope (1) from synaptic inputs applied at the soma, (2) from axonal spike generation and (3) from a slow process with a slower time scale than burst generation. This study reveals that due to the nonlinear properties and compartmentalization of ionic channels, the response to excitation is more complex than inhibition.


Chronotype, Sleep Characteristics, and Musculoskeletal Disorders Among Hospital Nurses.
Work-related musculoskeletal disorders (WMSDs) persist as the leading occupational injury, accounting for nearly half of nurses' total occupational injuries. Musculoskeletal pain is a known cause of sleep disruption, and individuals with WMSDs that interfere with sleep often report more pain. Evening chronotype has been associated with poor sleep among nurses. However, the associations among chronotype, sleep, and WMSDs are still unclear, and were explored in the present study. A cross-sectional survey was administered to 397 nurses, with 47.4% reporting WMSDs. Robust Poisson regression modeling suggested that evening type (PR = 1.32, p < .05), prolonged sleep onset latency (PR = 1.37, p < .05), and using sleep-promoting substances (PR = 1.35, p < .01) were associated with increased risk of WMSDs among nurses, after adjusting for shift work, regular exercise, body mass index, and other covariates. This study suggests that well-designed evidence-based nonpharmacological interventions to improve sleep may reduce the risk of WMSDs among nurses.


Molecular imprinting of proteins emerging as a tool for protein recognition.
This article gives the recent developments in molecular imprinting for proteins. Currently bio-macromolecules such as antibodies and enzymes are mainly employed for protein recognition purposes. However, such bio-macromolecules are sometimes difficult to find and/or produce, therefore, receptor-like synthetic materials such as protein-imprinted polymers have been intensively studied as substitutes for natural receptors. Recent advances in protein imprinting shown here demonstrate the possibility of this technique as a future technology of protein recognition.


Effect of chronic tobacco use on salivary concentrations of sodium and potassium.
Most of the methods of tobacco are use linked to the oral cavity where the taste receptors, a primary site for stimulation of salivary secretion, are constantly exposed to tobacco. It is generally believed that repeated exposure of a receptor to a stimulus results in inactivation (suppression) of the receptor. The present study was designed to document changes in salivary concentrations of sodium (Na+) and potassium (K+) in response to this effect in chronic tobacco users. Subjects of the study were divided into smokers, pan (tobacco-betel-lime quid) chewers, niswar (moist oral snuff) differs and non tobacco users as controls. The saliva of each subject was collected under resting condition and following application of crude nicotine and citric acid solutions to the tip of his tongue. After stimulation with nicotine all groups exhibited an increase in sodium concentration but the increase was significant (p < 0.05) in pan chewers only. However all groups showed a highly significant (p < 0.005) increase in sodium concentration after citric acid stimulation. No statistically significant (p > 0.05) decrease in potassium concentration was observed in any group after nicotine stimulation but all chronic tobacco user groups showed a highly significant (p < 0.005) decrease after citric acid stimulation. We conclude the sodium concentration increases and that of potassium decreases with the increase in salivary flow rates and this observation in chronic tobacco users was not much different from that in non tobacco users.


The source of methadone in overdose deaths in Western Virginia in 2004.
Methadone-related overdose deaths increased in the United States by 468% from 1999 to 2005. Current studies associate the nonmedical use of methadone with methadone-related deaths. This study describes medical examiner cases in rural Virginia in 2004 with methadone identified by toxicology and compares cases according to source of methadone. In 2004, all intentional and unintentional poisoning deaths from the Office of The Chief Medical Examiner, Western District of Virginia, were reviewed to identify cases in which methadone was a direct or contributing cause of death. The Virginia Prescription Monitoring Program was reviewed for prescription opioids in the name of these identified decedents. Decedent participation in local opioid treatment programs (OTP) was also assessed. The source of methadone in the 61 methadone-related overdose deaths was mostly nonprescribed (67%), although 28% of decedents were prescribed methadone for analgesia. Only 5% of decedents were actively enrolled in an OTP. The majority of deaths were attributed to polysubstance overdose. The majority of methadone overdose deaths in this study were related to illicit methadone use, rather than prescribed or OTP uses. Interventions to decrease methadone-related deaths should focus on reduction of nonprescription use of methadone.


Selective percutaneous "biopsy" of atheromatous plaque tissue for cell culture.
The combination of percutaneous atherectomy and angioscopy enabled a selective "biopsy" of protruding atheromatous plaque material from 11 patients with arterial occlusive disease. The removed specimens were cultivated as adhering explants or single cells were obtained by enzymatic disintegration. The vast majority of the cultivated cells resembled fibroblasts, but could be identified as smooth muscle cells by their smooth muscle alpha-actin content. Proliferation rate was slow with 0.1 doublings per day. Endothelial cells were not observed by immunologic criteria. The described biopsy technique and in vitro evaluation of cultured human atheromatous plaque material may be useful for a better understanding of atherogenesis.


Inhibition of TRPV1 for the treatment of sensitive skin.
During the past years, the topic sensitive skin became one of the most important fields in dermatology. The tremendous interest is based on several studies showing that about 50% of the population declares to have sensitive skin. The human thermoreceptor hTRPV1 was previously identified to contribute to this skin condition while facilitating neurogenic inflammation leading to hyperalgesia. Furthermore, skin sensitivity towards capsaicin, a natural activator of TRPV1, was shown to correlate with sensitive skin. In a screening campaign based on recombinant HEK293-cells stably transfected with hTRPV1, the selective antagonist trans-4-tert-butylcyclohexanol was identified. This antagonist is able to inhibit capsaicin-induced hTRPV1 activation with an IC(50) value of 34 ± 5 μm tested in HEK293-cells as well as in electrophysiological recordings performed in oocytes expressing hTRPV1. Strikingly, in a clinical study with 30 women using topical treatment with o/w emulsions containing 31.6 ppm capsaicin, we were able to show that 0.4% of this inhibitor significantly reduces capsaicin-induced burning (P < 0.0001) in vivo. Thus trans-4-tert-butylcyclohexanol has the potential as a novel bioactive for the treatment of sensitive skin.


GADD34 is a modulator of autophagy during starvation.
Cells respond to starvation by shutting down protein synthesis and by activating catabolic processes, including autophagy, to recycle nutrients. This two-pronged response is mediated by the integrated stress response (ISR) through phosphorylation of eIF2α, which represses protein translation, and by inhibition of mTORC1 signaling, which promotes autophagy also through a stress-responsive transcriptional program. Implementation of such a program, however, requires protein synthesis, thus conflicting with general repression of translation. How is this mismatch resolved? We found that the main regulator of the starvation-induced transcriptional program, TFEB, counteracts protein synthesis inhibition by directly activating expression of GADD34, a component of the protein phosphatase 1 complex that dephosphorylates eIF2α. We discovered that GADD34 plays an essential role in autophagy by tuning translation during starvation, thus enabling lysosomal biogenesis and a sustained autophagic flux. Hence, the TFEB-GADD34 axis integrates the mTORC1 and ISR pathways in response to starvation.


Donnan-exclusion-driven distribution of catalytic ferromagnetic nanoparticles synthesized in polymeric fibers.
One of the routes to overcome the high instability of metal nanoparticles (MNPs) lies in the use of polymeric materials for their synthesis and stabilization. Besides, one of the most serious concerns associated with the growing production and use of MNPs is the possibility of their uncontrollable escape into the medium under treatment and the environment. A possible solution to this problem could be the synthesis of ferromagnetic MNPs with desired functionality, that might not only prevent their escape by using simple magnetic traps but also allow their recovery and reuse. In our work we report the results obtained by the development of environmentally-safe polymer-metal nanocomposite materials containing polymer-stabilized MNPs (PSMNPs) with properties. This material consists of a functional polymer with immobilized Pd@Co core-shell PSMNPs distributed mainly near the surface of the polymer which makes PSMNPs maximally accessible for reagents in catalytic applications. The material was characterized by different techniques to evaluate the total metal content, the size and the magnetic properties of MNPs and their distribution inside the polymer. All nanocomposites were tested as catalysts in Suzuki cross-coupling reactions between arylboronic acids and aryl halides to produce biphenyls as a reference reaction.


D-stem: a parallel electron diffraction technique applied to nanomaterials.
An electron diffraction technique called D-STEM has been developed in a transmission electron microscopy/scanning transmission electron microscopy (TEM/STEM) instrument to obtain spot electron diffraction patterns from nanostructures, as small as ∼3 nm. The electron ray path achieved by configuring the pre- and postspecimen illumination lenses enables the formation of a 1-2 nm near-parallel probe, which is used to obtain bright-field/dark-field STEM images. Under these conditions, the beam can be controlled and accurately positioned on the STEM image, at the nanostructure of interest, while sharp spot diffraction patterns can be simultaneously recorded on the charge-coupled device camera. When integrated with softwares such as GatanTM STEM diffraction imaging and Automated Crystallography for TEM or DigistarTM, NanoMEGAS, the D-STEM technique is very powerful for obtaining automated orientation and phase maps based on diffraction information acquired on a pixel by pixel basis. The versatility of the D-STEM technique is demonstrated by applying this technique to nanoparticles, nanowires, and nano interconnect structures.


Impact of intraoperative adverse events during branched and fenestrated aortic stent grafting on postoperative outcome.
Fenestrated and branched endovascular devices are increasingly used for complex aortic diseases, and despite the challenging nature of these procedures, early experiences from pioneering centers have been encouraging. The objectives of this retrospective study were to report our experience of intraoperative adverse events (IOAEs) during fenestrated and branched stent grafting and to analyze the impact on clinical outcomes. Consecutive patients treated with fenestrated and branched stent grafting in a tertiary vascular center between February 2006 and October 2013 were evaluated. A prospectively maintained computerized database was scrutinized and updated retrospectively. Intraoperative angiograms were reviewed to identify IOAEs, and adverse events were categorized into three types: target vessel cannulation, positioning of graft components, and intraoperative access. Clinical consequences of IOAEs were analyzed to ascertain whether they were responsible for death or moderate to severe postoperative complications. During the study period, 113 consecutive elective patients underwent fenestrated or branched stent grafting. Indications for treatment were asymptomatic complex abdominal aortic aneurysms (CAAAs, n = 89) and thoracoabdominal aortic aneurysms (TAAAs, n = 24). Stent grafts included fenestrated (n = 79) and branched (n = 17) Cook stent grafts (Cook Medical, Bloomington, Ind), Ventana (Endologix, Irvine, Calif) stent grafts (n = 9), and fenestrated Anaconda (Vascutek Terumo, Scotland, UK) stent grafts (n = 8). In-hospital mortality rates for the CAAA and TAAA groups were 6.7% (6 of 89) and 12.5% (3 of 24), respectively. Twenty-eight moderate to severe complications occurred in 21 patients (18.6%). Spinal cord ischemia was recorded in six patients, three of which resolved completely. A total of 37 IOAEs were recorded in 34 (30.1%) patients (22 CAAAs and 12 TAAAs). Of 37 IOAEs, 15 (40.5%) resulted in no clinical consequence in 15 patients; 17 (45.9%) were responsible for moderate to severe complications in 16 patients, and five (13.5%) led to death in four patients. The composite end point death/nonfatal moderate to severe complication occurred more frequently in patients with IOAEs compared with patients without IOAEs (20 of 34 vs 12 of 79; P < .0001). In this contemporary series, IOAEs were relatively frequent during branched or fenestrated stenting procedures and were often responsible for significant complications.


Temperature sensitivity patterns of carbon and nitrogen processes in decomposition of boreal organic soils - Quantification in different compounds and molecule sizes based on a multifactorial experiment.
Climate warming and organic matter decomposition are connected in a recursive manner; this recursion can be described by temperature sensitivity. We conducted a multifactorial laboratory experiment to quantify the temperature sensitivity of organic carbon (C) and nitrogen (N) decomposition processes of common boreal organic soils. We incubated 36 mor and 36 slightly decomposed Carex-Sphagnum peat samples in a constant moisture and ambient temperature for 6 months. The experiment included three temperature and two moisture levels and two food web manipulations (samples with and without fungivore enchytraeid worms). We determined the release of carbon dioxide (CO2) and dissolved organic carbon (DOC) in seven molecular size classes together with ammonium N and dissolved organic N in low molecular weight and high molecular weight fractions. The temperature sensitivity function Q10 was fit to the data. The C and N release rate was almost an order of magnitude higher in mor than in peat. Soil fauna increased the temperature sensitivity of C release. Soil fauna played a key role in N release; when fauna was absent in peat, the N release was ceased. The wide range of the studied C and N compounds and treatments (68 Q10 datasets) allowed us to recognize five different temperature sensitivity patterns. The most common pattern (37 out of 68) was a positive upwards temperature response, which was observed for CO2 and DOC release. A negative downward pattern was observed for extractable organic nitrogen and microbial C. Sixteen temperature sensitivity patterns represented a mixed type, where the Q10function was not applicable, as this does not allow changing the sign storage change rate with increasing or decreasing temperature. The mixed pattern was typically connected to intermediate decomposition products, where input and output fluxes with different temperature sensitivities may simultaneously change the storage. Mixed type was typical for N processes. Our results provide useful parameterization for ecosystem models that describe the feedback loop between climate warming, organic matter decomposition, and productivity of N-limited vegetation.


[Molecular genetic and biochemical studies of human inherited diseases].
The paper gives the results of complex studies of human inherited diseases, which involved reverse genetics for the analysis of mutant genes, biochemical and immunological studies of anomalous proteins, the products of these genes. It describes the main results of the studies which used this complex approach to examining the etiology and pathogenesis of Wilson's disease, alpha 1-antitrypsin deficiency, familial hypercholesterolemia and cystic fibrosis.


Multisite collaboration using REDCap to capture library data.
In January 2018, library services at Providence St. Joseph Health merged to form a single, unified system, incorporating nine libraries and sixteen full-time staff. As a small, nonclinical team of librarians, we needed to make sure our work and value were visible to clinicians, administrators, and other nonlibrary stakeholders. Using REDCap, we developed a form to seamlessly collect statistics about our services.


Preferences for Sun Protection With a Self-Monitoring App: Protocol of a Discrete Choice Experiment Study.
The incidence of sun-exposure-related skin conditions, such as melanoma, is a gradually increasing and largely preventable public health problem. Simultaneously, the availability of mobile apps that enable the self-monitoring of health behavior and outcomes is ever increasing. Inevitably, recent years have seen an emerging volume of electronic patient-generated health data (PGHD), as well as their targeted application across primary prevention areas, including sun protection and skin health. Despite their preventive potential, the actual impact of these apps relies on the engagement of health care consumers, who are primarily responsible for recording, sharing, and using their PGHD. Exploring preferences is a key step toward facilitating consumer engagement and ultimately realizing their potential. This paper describes an ongoing research project that aims to elicit the preferences of health care consumers for sun protection via app-based self-monitoring. A discrete choice experiment (DCE) will be conducted to explore how healthy consumers choose between two alternative preventive self-monitoring apps. DCE development and attribute selection were built on extensive qualitative work, consisting of the secondary use of a previously conducted scoping review, a rapid review of reviews, 13 expert interviews, and 12 health care consumer interviews, the results of which are reported in this paper. Following D-optimality criteria, a fractional factorial survey design was generated. The final DCE will be administered in the waiting room of a travel clinic, targeting a sample of 200 participants. Choice data will be analyzed with conditional logit and multinomial logit models, accounting for individual participant characteristics. An ethics approval was waived by the Ethics Committee Zurich. The study started in September 2019 and estimated data collection and completion is set for January 2020. Five two-level attributes have been selected for inclusion in the DCE, addressing (1) data generation methods, (2) privacy control, (3) data sharing with general practitioner, (4) reminder timing, and (5) costs. Data synthesis, analysis, and reporting are planned for January and February 2020. Results are expected to be submitted for publication by February 2020. Our results will target technology developers, health care providers, and policy makers, potentially offering some guidance on how to design or use sun-protection-focused self-monitoring apps in ways that are responsive to consumer preferences. Preferences are ultimately linked to engagement and motivation, which are key elements for the uptake and success of digital health. Our findings will inform the design of person-centered apps, while also inspiring future preference-eliciting research in the field of emerging and complex eHealth services. PRR1-10.2196/16087.


Production of Purified CasRNPs for Efficacious Genome Editing.
CRISPR-Cas systems have been harnessed as modular genome editing reagents for functional genomics and show promise to cure genetic diseases. Directed by a guide RNA, a Cas effector introduces a double stranded break in DNA and host cell DNA repair leads to the introduction of errors (e.g., to knockout a gene) or a programmed change. Introduction of a Cas effector and guide RNA as a purified Cas ribonucleoprotein complex (CasRNP) has recently emerged as a powerful approach to alter cell types and organisms. Not only does CasRNP editing exhibit increased efficacy and specificity, it avoids optimization and iteration of species-specific factors such as codon usage, promoters, and terminators. CasRNP editing has been rapidly adopted for research use in many contexts and is quickly becoming a popular method to edit primary cells for therapeutic application. This article describes how to make a Cas9 RNP and outlines its use for gene editing in human cells. © 2017 by John Wiley & Sons, Inc.


Plant Growth-Promoting Methylobacteria Selectively Increase the Biomass of Biotechnologically Relevant Microalgae.
Microalgae, a diverse group of single-celled organisms exhibiting versatile traits, find broad applications in industry. However, high production costs require further efforts to optimize their production and to enhance biomass yields. In the present study, co-occurrence of algae and methylobacteria was observed when naturally occurring microalgae biofilms were subjected to 16S rRNA gene fragment amplicon sequencing. This bacterial group is so far less explored than other microalgae-associated bacteria in terms of mutualistic relationships that might be exploitable for biotechnological applications. In order to assess the potential of four plant growth-promoting strains from the genus Methylobacterium for increased algae biomass production, co-cultivation experiments were conducted with three industrially relevant microalgae (Chlorella vulgaris, Scenedesmus vacuolatus, and Haematococcus lacustris). For S. vacuolatus and H. lacustris, a significant increase in algal biomass formation of 1.3-fold to up to 14-fold was observed after 7 days of co-incubation. Visualization of mixed cultures using confocal laser scanning microscopy revealed a high abundance of methylobacteria in the phycosphere of H. lacustris and S. vacuolatus, visually attached to the algae's surface forming a biofilm-like assemblage. Genome analyses revealed that features attributable to enhanced algal growth include genes involved in the synthesis of vitamins, siderophores and plant hormones. Our results provide evidence for the constructability of novel symbiotic algae-bacteria relationships with inter-kingdom supportive capacities, underlining the potential of microbial consortia as promising tool for sustainable biotechnology and agriculture.


Control of shoot apical development via cell division.
Cell division in plants not only partitions the protoplast but also provides the architectural framework for plant form. The shape of the shoot apical meristem is produced and maintained by gradients in the rate and plane of cell division, from the summit to the base of the apical dome, which also determine the region in which primordia can be formed. In Pisum leaf initiation is mainly the result of changes in the frequency of periclinal divisions at the leaf site whereas in Silene an increase in the rate of cell division seems more important since periclinal divisions are always present. Periclinal divisions may be permissive of primordium initiation rather than causal and may define the maximum area over which primordia can form. The occurrence in Pisum and Silene of periclinal divisions which do not seem to be related to concurrent outward growth suggests that the plane of division and the direction of growth may be controlled separately and in different ways. The control of outward growth during primordium initiation may lie in the epidermis, which necessarily grows faster at the leaf site. The initial orientation of epidermal growth at the primordial site, inferred as being normal to the plane of cell division, is predominantly longitudinal in Pisum but transverse in Silene. Longitudinal growth becomes dominant later in leaf development in Silene, as in Pisum. Several lines of evidence suggest a crucial role for the epidermis in the initial stages of primordium formation although the initial orientation of division planes in it may be concerned more with the shape of the young leaf than with initiation itself. In flower initiation primordial size becomes reduced, and in Silene there are alternations of higher and lower rates of cell division in successively initiated primordial types. A fuller understanding of the role of cell division in apical growth depends on better knowledge of the functional relationships between the plane of cell division, the orientation of microtubules and wall microfibrils, and the effect that division in one cell has on its neighbours.


The effect of postoperative gastrointestinal complications in patients undergoing coronary artery bypass surgery.
Gastrointestinal (GI) complications after coronary artery bypass graft surgery (CABG) are uncommon but associated with a disproportionate share of mortality. We thus identified variables associated with GI complications and analyzed their effect on postoperative mortality in patients undergoing isolated CABG. Information from patients who underwent isolated CABG at our institution during a 12-year period was obtained from the Anesthesiology Institute patient registry. Patients who experienced one or more postoperative GI complication(s) during their initial intensive care unit stay were identified. Multivariable logistic regression with backward variable selection was used to determine variables associated with GI complications and to evaluate their effect on mortality. Among 16,043 patients who underwent isolated CABG, 213 (1.43%) had one or more GI complication(s). The main patient variables associated with postoperative GI complications included preoperative (odds ratio, 2.43; 95% confidence interval [CI], 1.39 to 4.23; p < 0.001) and intraoperative (odds ratio, 5.07; 95% CI, 3.08 to 8.35; p < 0.001) intraaortic balloon pump insertion, patient age (odds ratio, 1.65; 95% CI, 1.41 to 1.94; p < 0.001), intraoperative fresh-frozen plasma transfusion (odds ratio, 3.38; 95% CI, 2.12 to 5.41; p < 0.001), and cardiogenic shock (odds ratio, 3.04; 95% CI, 1.12 to 8.24). No difference was detected in complication rates between off-pump and on-pump CABG procedures (1.50% versus 1.30%, respectively; p = 0.63). Postoperative GI complication(s) after CABG was associated with a 12.98 times increase in mortality (p < 0.001). This single-center cohort study indicates that GI complications after isolated CABG remain rare with an incidence 1.43%. However, GI complications portend a significant mortality. The implications of intraoperative administration of fresh-frozen plasma and insertion of an intraaortic balloon pump deserve further investigation as they are associated with GI complications.


Investing in Health to Create a Third Demographic Dividend.
The world is aging as a result of unprecedented successes worldwide adding 30 years of life expectancy and presenting great opportunities for all of society, but only if we invest effectively. This article, written as a requested background article for the World Health Organization 2015 World Report on Aging, proposes that creating health into the oldest ages could lay the basis for a third demographic dividend resulting from the societal benefits from the generative social capital of older adults, on top of the second demographic dividend's savings associated with longer lives. The combination would contribute to stronger and wealthier societies, greater success of the young, and increased societal ability to provide the humane supports needed at the end of life, plus a dividend that would endure. We now know that prevention works at every age and into the oldest ages. A life-course approach to prevention and health promotion is the key investment. The creation of geriatrically knowledgeable and integrated public health, medical and social care systems has the potential to amplify capabilities and well-being to the end of life. Healthy older populations bring both desire for engagement and unique talents. Institutions designed to create impactful roles for older adults to contribute to the success of the young can activate the societal benefits and further enhance health at older ages. Creating a new vision for the opportunities of an older age is the first critical step toward experiencing the benefits of our longer lives and creating a sustained third demographic dividend.


Collagen fiber alignment and biaxial mechanical behavior of porcine urinary bladder derived extracellular matrix.
The collagen fiber alignment and biomechanical behavior of naturally occurring extracellular matrix (ECM) scaffolds are important considerations for the design of medical devices from these materials. Both should be considered in order to produce a device to meet tissue specific mechanical requirements (e.g., tendon vs. urinary bladder), and could ultimately affect the remodeling response in vivo. The present study evaluated the collagen fiber alignment and biaxial mechanical behavior of ECM scaffold material harvested from porcine urinary bladder tunica mucosa and basement membrane (together referred to as urinary bladder matrix (UBM)) and ECM harvested from urinary bladder submucosa (UBS). Since the preparation of UBM allows for control of the direction of delamination, the effect of the delamination method on the mechanical behavior of UBM was determined by delaminating the submucosa and other abluminal layers by scraping along the longitudinal axis of the bladder (apex to neck) (UBML) or along the circumferential direction (UBMC). The processing of UBS does not allow for similar directional control. UBML and UBS had similar collagen fiber distributions, with a preferred collagen fiber alignment along the longitudinal direction. UBMC showed a more homogenous collagen fiber orientation. All samples showed a stiffer mechanical behavior in the longitudinal direction. Despite similar collagen fiber distributions, UBML and UBS showed quite different mechanical behavior for the applied loading patterns with UBS showing a much more pronounced toe region. The mechanical behavior for UBMC in both directions was similar to the mechanical behavior of UBML. There are distinct differences in the mechanical behavior of different layers of ECM from the porcine urinary bladder, and the processing methods can substantially alter the mechanical behavior observed.


Health across generations: findings from the Australian Longitudinal Study on Women's Health.
Interpretation of changes in health and health care utilization patterns across the life span depends on an understanding of the effects of age, period, and cohort. The purpose of this article is to illustrate differences among three generations of women in demographic factors, health risk factors, and health status indicators from 1996 to 2008. The article examines data from the Australian Longitudinal Study on Women's Health, a broad-ranging project funded by the Australian Government Department of Health and Ageing (DoHA) and involving three age groups of women (born in the periods 1973-1978, 1946-1951, and 1921-1926) who were first surveyed in 1996 and will be surveyed every 3 years until at least 2015. Patterns in selected demographic factors (marital status and level of educational qualification), health risk factors (smoking, alcohol consumption, physical activity, and body mass index [BMI]), and health status indicators (asthma, hypertension, diabetes and depression; physical functioning and mental health scores from the SF-36) were examined to illustrate examples of biological age, generational differences, or period effects that affect all age groups and generations simultaneously. The results can be used to inform the development of responsive and effective models for both prevention and management of chronic disease, including health and aged-care systems that will meet the needs of different generations of women across their life span.


Effects of age on the physiological and mechanical characteristics of human femoropopliteal arteries.
Surgical and interventional therapies for peripheral artery disease (PAD) are notorious for high rates of failure. Interactions between the artery and repair materials play an important role, but comprehensive data describing the physiological and mechanical characteristics of human femoropopliteal arteries are not available. Fresh femoropopliteal arteries were obtained from 70 human subjects (13-79 years old), and in situ vs. excised arterial lengths were measured. Circumferential and longitudinal opening angles were determined for proximal superficial femoral, proximal popliteal and distal popliteal arteries. Mechanical properties were assessed by multi-ratio planar biaxial extension, and experimental data were used to calculate physiological stresses and stretches, in situ axial force and anisotropy. Verhoeff-Van Gieson-stained axial and transverse arterial sections were used for histological analysis. Most specimens demonstrated nonlinear deformations and were more compliant longitudinally than circumferentially. In situ axial pre-stretch decreased 0.088 per decade of life. In situ axial force and axial stress also decreased with age, but circumferential physiological stress remained constant. Physiological circumferential stretch decreased 55-75% after 45 years of age. Histology demonstrated a thickened external elastic lamina with longitudinally oriented elastin that was denser in smaller, younger arteries. Axial elastin likely regulates axial pre-stretch to help accommodate the complex deformations required of the artery wall during locomotion. Degradation and fragmentation of elastin as a consequence of age, cyclic mechanical stress and atherosclerotic arterial disease may contribute to decreased in situ axial pre-stretch, predisposing to more severe kinking of the artery during limb flexion and loss of energy-efficient arterial function.


The carpal tunnel syndrome. A study of carpal canal pressures.
We measured intracarpal canal pressures with the wick catheter in fifteen patients with carpal tunnel syndrome and in twelve control subjects. The mean pressure in the carpal canal was elevated significantly in the patients. When the wrist was in neutral position, the mean pressure was thirty-two millimeters of mercury. With 90 degrees of wrist flexion the pressure increased to ninety-four millimeters of mercury, while with 90 degrees of wrist extension the mean pressure was 110 millimeters of mercury. The pressure in the control subjects with the wrist in neutral position was 2.5 millimeters of mercury; with wrist flexion the pressure rose to thirty-one millimeters of mercury, and with wrist extension it increased to thirty millimeters of mercury. Carpal tunnel release brought about an immediate and sustained reduction in pressure.


Image Fusion Technology in Interventional Radiology.
Image fusion technology aims to improve patient outcomes for image-guided interventions by leveraging the strengths of multimodality imaging datasets. This most commonly involves the overlay or co-display of advanced cross-sectional imaging permitting freedom of device placement via conventional image guidance such as ultrasound, fluoroscopy, and computed tomography. This can allow the interventionalist to target and treat lesions that would otherwise be difficult or impossible to visualize and access using conventional imaging guidance. Furthermore, the use of image fusion can allow for procedures traditionally performed with cross-sectional imaging to be performed under ultrasound or fluoroscopy, by importing the data from preacquired cross-sectional imaging into the interventional procedure. This manuscript provides an overview of image fusion technologies used for interventional radiology (IR) guidance, with an emphasis on technical considerations.


Scoring protein relationships in functional interaction networks predicted from sequence data.
The abundance of diverse biological data from various sources constitutes a rich source of knowledge, which has the power to advance our understanding of organisms. This requires computational methods in order to integrate and exploit these data effectively and elucidate local and genome wide functional connections between protein pairs, thus enabling functional inferences for uncharacterized proteins. These biological data are primarily in the form of sequences, which determine functions, although functional properties of a protein can often be predicted from just the domains it contains. Thus, protein sequences and domains can be used to predict protein pair-wise functional relationships, and thus contribute to the function prediction process of uncharacterized proteins in order to ensure that knowledge is gained from sequencing efforts. In this work, we introduce information-theoretic based approaches to score protein-protein functional interaction pairs predicted from protein sequence similarity and conserved protein signature matches. The proposed schemes are effective for data-driven scoring of connections between protein pairs. We applied these schemes to the Mycobacterium tuberculosis proteome to produce a homology-based functional network of the organism with a high confidence and coverage. We use the network for predicting functions of uncharacterised proteins. Protein pair-wise functional relationship scores for Mycobacterium tuberculosis strain CDC1551 sequence data and python scripts to compute these scores are available at http://web.cbio.uct.ac.za/~gmazandu/scoringschemes.


Hypothalamic POMC neurons promote cannabinoid-induced feeding.
Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide α-melanocyte-stimulating hormone, and the opioid peptide β-endorphin. CB1R activation selectively increases β-endorphin but not α-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.


Loss of Interleukin-13-Receptor-Alpha-1 Induces Apoptosis and Promotes EMT in Pancreatic Cancer.
In search of new therapies for pancreatic cancer, cytokine pathways have attracted increasing interest in recent years. Cytokines play a vital role in the crosstalk between tumour cells and the tumour microenvironment. The related inflammatory cytokines IL-4 and IL-13 can regularly be detected at increased levels in the microenvironment of pancreatic cancer. They share a receptor heterodimer consisting of IL-4Rα and IL-13Rα1. While IL-4Rα induces a more oncogenic phenotype, the role of IL-13Rα1 was yet to be determined. ShRNA-based knockdown of IL-13Rα1 was performed in Capan-1 and MIA PaCa-2. We assessed cell growth and migratory capacities under the influence of IL-13Rα1. Pathway alterations were detected by immunoblot analysis. We now have demonstrated that the loss of IL-13Rα1 induces apoptosis in pancreatic cancer cells. This was associated with an epithelial-to-mesenchymal transition. Loss of IL-13Rα1 also abolished the effects of exogenous IL-4 and IL-13 stimulation. Interestingly, in wild type cells, cytokine stimulation caused a similar increase in migratory capacities as after IL-13Rα1 knockdown. Overall, our results indicate the vital role of IL-13Rα1 in the progression of pancreatic cancer. The differential expression of IL-4Rα and IL-13Rα1 has to be taken into account when considering a cytokine-targeted therapy in pancreatic cancer.


Antibodies to Tp67 and Tp44 augment and sustain proliferative responses of activated T cells.
We have shown previously that binding of a monoclonal antibody (MAb) to Tp44 molecules increased the proliferation of anti-CD3-activated T cells by causing enhanced IL 2 receptor expression and IL 2 release. We now show that anti-CD5 (Tp67) antibodies have a similar effect under conditions in which monocytes are suboptimally activated or where monocytes are not present. The activity did not depend on antibody isotype or on the precise CD5 epitope recognized. Functional experiments indicated that both IL 2 production and IL 2 receptor expression were enhanced by antibody binding. Anti-Tp67 and anti-Tp44 appear to augment proliferation through distinct mechanisms, because both antibodies together had greater activity than either antibody alone. In neither system is the Fc portion of the antibody required, because F(ab')2 fragments had activity equivalent to that of the intact antibody and were effective at concentrations as low as 10 ng/ml. Fab fragments of anti-Tp67 were active, but Fab fragments of anti-Tp44 had no effect. Anti-Tp67 and anti-Tp44 were able to sustain continuous proliferation of anti-CD3-Sepharose-stimulated T cells for up to 2.5 wk without exogenous IL 2 or feeder cells. These experiments suggest that Tp67 and Tp44 are receptors that play a critical regulatory role in the control of T cell proliferation.


Drastic alteration of ribosomal RNA and ribosomal proteins in showdomycin-resistant Escherichia coli.
In a mutant of Escherichia coli resistant to showdomycin, both the 50S and 30S ribosomal subunits contain RNA species in which the purine concentration greatly exceeds that of pyrimidines. The same is true for total rapidly-labeled RNA. The modified ribosomal RNA hybridizes poorly with homologous DNA, which is apparently unchanged in base composition. Acrylamide gel electrophoresis of mutant ribosomal proteins shows a highly altered protein pattern for both ribosomal subunits, although the activity of these ribosomes is not decreased.


Engineering mesoporous silica nanoparticles towards oral delivery of vancomycin.
Vancomycin (Van) is a key antibiotic of choice for the treatment of systemic methicillin resistant Staphylococcus aureus (MRSA) infections. However, due to its poor membrane permeability, it is administered parenterally, adding to the cost and effort of treatment. The poor oral bioavailability of Van is mainly due to its physico-chemical properties that limit its paracellular and transcellular transport across gastrointestinal (GI) epithelium. Herein we report the development of silica nanoparticles (SNPs)-based formulations that are able to enhance the epithelial permeability of Van. We synthesized SNPs of different pore sizes (2 nm and 9 nm) and modified their surface charge and polarity by attaching different functional groups (-NH2, -PO3, and -CH3). Van was loaded within these SNPs at a loading capacity in the range of ca. 18-29 wt%. The Van-loaded SNPs exhibited a controlled release behaviour when compared to un-encapsulated Van which showed rapid release due to its hydrophilic nature. Among Van-loaded SNPs, SNPs with large pores showed a prolonged release compared to SNPs with small pores while SNPs functionalised with -CH3 groups exhibited a slowest release among the functionalised SNPs. Importantly, Van-loaded SNPs, especially the large pore SNPs with negative charge, enhanced the permeability of Van across an epithelial cell monolayer (Caco-2 cell model) by up to 6-fold, with Papp values up to 1.716 × 10-5 cm s-1 (vs. 0.304 × 10-5 cm s-1 for un-encapsulated Van) after 3 h. The enhancement was dependent on both the type of SNPs and their surface functionalisation. The permeation enhancing effect of SNPs was due to its ability to transiently open the tight junctions measured by decrease in transepithelial resistance (TEER) which was reversible after 3 h. All in all, our data highlights the potential of SNPs (especially SNPs with large pores) for oral delivery of Van or other antimicrobial peptides.


Hyperpolarised 13C-MRI identifies the emergence of a glycolytic cell population within intermediate-risk human prostate cancer.
Hyperpolarised magnetic resonance imaging (HP 13C-MRI) is an emerging clinical technique to detect [1-13C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1-13C]pyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating [1-13C]lactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP 13C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour [1-13C]lactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP 13C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments.


The historical evolution of the concept of apoptosis in rheumatic diseases.
Even if the idea of apoptosis may probably be detected for the first time in a Hippocratic treatise, it was Rudolph Virchow, the founder of cellular pathology in the XIX century, who gave the first structured description of the processes underlying the term. In the course of the XX century a body of systematic observations on cell death was elaborated in an organic way. In 1908 Mechnikov won the Nobel Prize for his studies on phagocytosis, while in the '30s and '40s many studies on metamorphosis were carried out, and Fell and Canti identified cell death in chondrocytes in culture. At the end of the '40s Saunders began to observe cell death in chick limbs, and Hamburger and Levi Montalcini began their exploration of nerve growth factors. In mid '50s research on lysosomes began, and in the '60s Kerr defined shrinkage necrosis. The term apoptosis was definitely introduced by Kerr in 1972 to indicate a particular form of death in which cells commit suicide by dissolving themselves into membrane-bounded apoptotic bodies. In the '80s ced-3 was described and at the beginning of the '90s apoptosis genes were identified. In more recent times new instruments have allowed a wide range of cellular deaths to be described, including apoptosis as currently defined. Extremely interesting are its role and function in many different diseases; in particular in rheumatic ones recent evidence indicates that, far from being simple, brief and monomorphic, apoptosis is a complex, long-lasting, and pleiomorphic process.


Low-level accelerations applied in the absence of weight bearing can enhance trabecular bone formation.
High-frequency whole body vibrations can be osteogenic, but their efficacy appears limited to skeletal segments that are weight bearing and thus subject to the induced load. To determine the anabolic component of this signal, we investigated whether low-level oscillatory displacements, in the absence of weight bearing, are anabolic to skeletal tissue. A loading apparatus, developed to shake specific segments of the murine skeleton without the direct application of deformations to the tissue, was used to subject the left tibia of eight anesthesized adult female C57BL/6J mice to small (0.3 g or 0.6 g) 45 Hz sinusoidal accelerations for 10 min/day, while the right tibia served as an internal control. Video and strain analysis revealed that motions of the apparatus and tibia were well coupled, inducing dynamic cortical deformations of less than three microstrain. After 3 weeks, trabecular metaphyseal bone formation rates and the percentage of mineralizing surfaces (MS/BS) were 88% and 64% greater (p < 0.05) in tibiae accelerated at 0.3 g than in their contralateral controls. At 0.6 g, bone formation rates and mineral apposition rates were 66% and 22% greater (p < 0.05) in accelerated tibiae. Changes in bone morphology were evident only in the epiphysis, where stimulated tibiae displayed significantly greater cortical area (+8%) and thickness (+8%). These results suggest that tiny acceleratory motions--independent of direct loading of the matrix--can influence bone formation and bone morphology. If confirmed by clinical studies, the unique nature of the signal may ultimately facilitate the stimulation of skeletal regions that are prone to osteoporosis even in patients that are suffering from confinement to wheelchairs, bed rest, or space travel.


Hierarchical modelling of polystyrene melts: from soft blobs to atomistic resolution.
We demonstrate that hierarchical backmapping strategies incorporating generic blob-based models can equilibrate melts of high-molecular-weight polymers, described with chemically specific, atomistic models. The central idea is first to represent polymers by chains of large soft blobs (spheres) and efficiently equilibrate the melt on large scales. Then, the degrees of freedom of more detailed models are reinserted step by step. The procedure terminates when the atomistic description is reached. Reinsertions are feasible computationally because the fine-grained melt must be re-equilibrated only locally. We consider polystyrene (PS) which is sufficiently complex to serve method development because of stereo-chemistry and bulky side groups. Our backmapping strategy bridges mesoscopic and atomistic scales by incorporating a blob-based, a moderately coarse-grained (CG), and a united-atom model of PS. We demonstrate that the generic blob-based model can be parameterised to reproduce the mesoscale properties of a specific polymer - here PS. The moderately CG model captures stereo-chemistry. To perform backmapping we improve and adjust several fine-graining techniques. We prove equilibration of backmapped PS melts by comparing their structural and conformational properties with reference data from smaller systems, equilibrated with less efficient methods.