Antimicrobial Peptides and Their Applications in Biomedical Sector.
In a report by WHO (2014), it was stated that antimicrobial resistance is an arising challenge that needs to be resolved. This resistance is a critical issue in terms of disease or infection treatment and is usually caused due to mutation, gene transfer, long-term usage or inadequate use of antimicrobials, survival of microbes after consumption of antimicrobials, and the presence of antimicrobials in agricultural feeds. One of the solutions to this problem is antimicrobial peptides (AMPs), which are ubiquitously present in the environment. These peptides are of concern due to their special mode of action against a wide spectrum of infections and health-related problems. The biomedical field has the highest need of AMPs as it possesses prominent desirable activity against HIV-1, skin cancer, breast cancer, in Behcet's disease treatment, as well as in reducing the release of inflammatory cells such as TNFα, IL-8, and IL-1β, enhancing the production of anti-inflammatory cytokines such as IL-10 and GM-CSF, and in wound healing properties. This review has highlighted all the major functions and applications of AMPs in the biomedical field and concludes the future potential of AMPs.


A hollow microshuttle-shaped capsule covalent organic framework for protein adsorption.
Covalent organic frameworks (COFs) are a class of crystalline porous materials utilized in various potential applications. However, the development of hollow-structured COFs with defined morphology is important for their further applications, which is rare. Herein, COF with unique hollow shuttle morphology was prepared by a Schiff condensation reaction between 4-(4-aldehyde phenyl)ethylene (TPE) and tetra-(4-aminophenyl) porphyrin (TAP). A detailed mechanistic investigation reveals that an initial self-assembly followed by a similar inside-out Ostwald ripening process is responsible for the hollow capsule formation. The hollow microshuttle-shaped capsule COF is used for studying hemoglobin adsorption, which shows an uptake of 550.82 mg g-1 of hemoglobin. These studies could foreshadow new avenues for the development of porous materials with defined morphologies for the adsorption of biomolecules.


The import of abdominal pain in adults with sickle cell disorder.
The aetiology, clinical correlates and outcome of abdominal pain in Nigerian adults with sickle cell disorder (SCD) have not been extensively reported. To determine the prevalence of abdominal vasoocclusive crisis in sickle cell patients with abdominal pain and their clinical correlates if any. Clinical records of adults with SCD (Hb SS and Hb SC) attending the Haematology Outpatients' Clinic of the Obafemi Awolowo University Teaching Hospitals Complex, Southwest Nigerian, over a ten-year period, were reviewed. Demographic, clinical and laboratory data with respect to abdominal pain were retrieved. Data were analysed using appropriate descriptive and inferential statistics. A total of 154 records (128 Hb SS and 26 Hb SC) were available for assessment. The patients mean ages were 22.5 +/- 7.3 years (Hb SS patients) and 24.2 +/- 9.7 years (Hb SC patients) (p > 0.05). The prevalence of abdominal pain was 39.1% and 30.8% in Hb SS and Hb SC respectively (p > 0.05). Pain was commonly in the epigastrium; dull in 35% Hb SS, but peppery/burning in 37.5% Hb SC. All patients with abdominal vaso-occlusive crisis (VOC) had diffuse/generalised dull abdominal pains. A diagnosis of gastritis/peptic ulcer disease was made in 50% of Hb SC patients and 28% of Hb SS patients. Abdominal VOC was diagnosed in 26% Hb SS, but none in Hb SC patients. The size of the liver or spleen and the haematocrit of Hb SS patients did not correlate with the frequency of abdominal pain generally or abdominal VOC specifically. The prevalence rates and patterns of abdominal pain in Hb SS and Hb SC patients appear similar. Abdominal VOC characterised by diffuse/generalised dull abdominal pain occurred in only Hb SS patients and may be a marker of disease severity in these patients.


Addressing the Perioperative Nursing Shortage Via a Perioperative Nursing Preceptorship for Baccalaureate Nursing Students.
A growing demand for perioperative nurses, insufficient interest in the perioperative nursing specialty, and nurse retirements have resulted in a perioperative nursing workforce shortage. Undergraduate nursing students' limited exposure to perioperative content, along with facility hiring practices that exclude recently graduated nurses, further contribute to this shortage. To address these concerns, a large health care system in the midwestern United States partnered with a college of nursing to institute a perioperative preceptorship for baccalaureate nursing students during their final semester. After completing the preceptorship, students reported increased understanding of perioperative nursing roles and responsibilities, time management, and patient safety skills; ability to work effectively as a part of an interdisciplinary team; and independence in the perioperative setting. Future study is needed to examine rates of matriculation among program graduates into perioperative nursing positions and the program's effect on the length of orientation for recently graduated nurses and nurse retention.


Full-Length Nucleotide Sequences of mcr-1-Harboring Plasmids Isolated from Extended-Spectrum-β-Lactamase-Producing Escherichia coli Isolates of Different Origins.
Here, we present the full sequences of three mcr-1-carrying plasmids isolated from extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli The plasmids belong to three different replicon types and are 34,640 bp, 209,401 bp, and 247,885 bp in size. We describe for the first time a composite transposon containing mcr-1 localized on a multidrug-resistant (MDR) IncHI2 plasmid harboring additional determinants of resistance to six different classes of antibiotics, including the ESBL gene blaCTX-M-1, and heavy metal resistance.


Near-Infrared Imaging Polarimetry of the GG Tauri Circumbinary Ring.
We present 1 µm Hubble Space Telescope/near-infrared camera and multiobject spectrometer resolved imaging polarimetry of the GG Tau circumbinary ring. We find that the ring displays east-west asymmetries in surface brightness as well as several pronounced irregularities but is smoother than suggested by ground-based adaptive optics observations. The data are consistent with a 37 degrees system inclination and a projected rotational axis at a position angle of 7 degrees east of north, determined from millimeter imaging. The ring is strongly polarized, up to approximately 50%, which is indicative of Rayleigh-like scattering from submicron dust grains. Although the polarization pattern is broadly centrosymmetric and clearly results from illumination of the ring by the central stars, departures from true centrosymmetry and the irregular flux suggest that binary illumination, scattering through unresolved circumstellar disks, and shading by these disks may all be factors influencing the observed morphology. We confirm a approximately 0&farcs;25 shift between the inner edges of the near-infrared and millimeter images and find that the global morphology of the ring and the polarimetry provide strong evidence for a geometrically thick ring. A simple Monte Carlo scattering simulation is presented that reproduces these features and supports the thick-ring hypothesis. We cannot confirm filamentary streaming from the binary to the ring, also observed in the ground-based images, although it is possible that there is material inside the dynamically cleared region that might contribute to filamentary deconvolution artifacts. Finally, we find a faint fifth point source in the GG Tau field that, if it is associated with the system, is almost certainly a brown dwarf.


APE1 is the major 3'-phosphoglycolate activity in human cell extracts.
DNA strand breaks containing 3'-phosphoglycolate (3'-PG) ends are the major lesions induced by ionizing radiation. The repair of this lesion is not completely understood and several activities are thought to be involved in processing of 3'-PG ends. In this study we examined activities in human whole cell extracts (WCE) responsible for removal of 3'-PG. Using a radiolabelled oligonucleotide containing a single nucleotide gap with internal 5'-phosphate and 3'-PG ends, we demonstrate that the major 3'-PG activity in human WCE is Mg2+ dependent and that this activity co-purifies with AP endonuclease 1 (APE1) over phosphocellulose and gel filtration chromatography. Furthermore, immunodepletion of APE1 from active gel filtration fractions using APE1 specific antibodies reveals that the major activity against 3'-PG in human WCE is APE1.


(Re)regulating gay sex in viral times: COVID-19 and the impersonal intimacy of the glory hole.
COVID-19 has transformed the way we live our lives, and sex has been a significant element of that transformation. Gay male sex in the UK has faced the most significant (re)criminalisation and (re)regulation in living memory with intimacy outside of the heteronormative framework of domestic coupledom at best discouraged and, at worst, made into a criminal offence. This criminalisation provides a temporal praxis in which gay men experience sex in the shadows once more, an echo of a historic legal and cultural regulation of desire. This history also provides a space for experiencing forms of impersonal intimacy and queer desire in a way that is arguably well-suited for viral times, namely the glory hole. These historic partitions and apertures - connecting gay men across legal and cultural boundaries of desire and affirmed through modes of anonymous and promiscuous sex - may once again provide a queer way to experience intimacy as impersonal. This article explores this potential and situates the glory hole as a cultural and legal site of this tension between the intimate and the impersonal, as well as considering how it is being recast as commercial artefact and performance space during these viral times.


Health risks, past usage, and intention to use weight loss products in normal weight women with high and low body dysphoria.
There are many health risks involved with the use of weight loss products by normal weight women. The mass media may compound this problem through the promotion of weight loss products and a thin body size. This study tested women's perceptions of different weight loss product ads to determine if body dysphoria (i.e., an over concern with body size and shape in normal weight people) was associated with risk beliefs, past behaviors, and intention toward using weight loss products. Normal weight women (age range = 18-41 yr), who were classified as either high (n=45) or low (n=43) on a measure of body dysphoria, rated different weight loss products according to their perception of health risks, past behavior, and their intention to consume the products. These products were a dietary fat substitute (olestra), a prescription obesity medication (sibutramine), and an over-the-counter appetite suppressant (phenylpropanolamine). High body dysphoric women reported higher intentions to use the products as well as increased prior use of two of the three weight loss products. High body dysphoric women did not believe that these weight loss products were harmless. They recognized potential health risks associated with using such products, but nonetheless, expressed intention to use these weight loss products at a higher frequency. Also, several variables related to body image were found to effectively discriminate normal weight women at risk for abusing weight loss products. This study found that women who do not need to lose weight but have significant body image concerns were willing to use potentially harmful weight loss products despite the knowledge that such products might pose significant health risks. Techniques utilized by advertising regulatory agencies such as warning labels did not have a strong deterrent effect for stated intentions to use the products. Implications of these findings for public health policy issues were discussed.


Mini-review of conventional and hypofractionated radiation therapy combined with immunotherapy for non-small cell lung cancer.
A successful antitumoral response requires immunological activation as well as an antigenic pool capable of stimulating both the innate and the adaptive immune system. Recent advances in immunotherapy have been aimed at boosting the activation status of the innate and adaptive immune system, including cytokine administration, monoclonal antibodies engineered to target high yield elements in oncogenic signaling pathways, cancer vaccines, and checkpoint inhibitors. Herein, we examine the ways that radiation therapy induced cell death provides a pool of stimulus antigen, and draw parallels from the immunobiology of autoimmunity to explore how the immunogenicity of antigen derived from radiation-induced cell death might augment the antitumoral response. We also review basic research into the ability of different radiation dose fractionation schedules to induce an antitumoral response. After a discussion of basic immunotherapeutic principles, we review the published literature in the field of non-small cell lung cancer (NSCLC) and examine the ways that combining radiation and immunotherapy have begun to change the therapeutic terrain. We provide a summary of ongoing clinical trials aimed at combining immunotherapy and radiation therapy in NSCLC while emphasizing the need for identification of biomarkers with predictive power and the assessment of efficacy as a function of fractionation strategy.


Centrifuge: rapid and sensitive classification of metagenomic sequences.
Centrifuge is a novel microbial classification engine that enables rapid, accurate, and sensitive labeling of reads and quantification of species on desktop computers. The system uses an indexing scheme based on the Burrows-Wheeler transform (BWT) and the Ferragina-Manzini (FM) index, optimized specifically for the metagenomic classification problem. Centrifuge requires a relatively small index (4.2 GB for 4078 bacterial and 200 archaeal genomes) and classifies sequences at very high speed, allowing it to process the millions of reads from a typical high-throughput DNA sequencing run within a few minutes. Together, these advances enable timely and accurate analysis of large metagenomics data sets on conventional desktop computers. Because of its space-optimized indexing schemes, Centrifuge also makes it possible to index the entire NCBI nonredundant nucleotide sequence database (a total of 109 billion bases) with an index size of 69 GB, in contrast to k-mer-based indexing schemes, which require far more extensive space.


CYP2C19 Polymorphism is Associated With Amputation Rates in Patients Taking Clopidogrel After Endovascular Intervention for Critical Limb Ischaemia.
Clopidogrel is a pro-drug requiring cytochrome P450 (CYP) 2C19 enzyme to be oxidised to its active form. This study evaluated the association between the CYP 2C19 genetic polymorphism and clinical outcomes in patients with critical limb ischaemia (CLI) taking clopidogrel after endovascular therapy (EVT). This was a retrospective study. Patients with CLI who had undergone EVT between August 2014 and January 2017 were included. The study subjects were divided into three groups according to the loss of function (LOF) CYP2C19 alleles: (1) extensive metaboliser (EM); (2) intermediate metaboliser (IM); and (3) poor metaboliser (PM). All patients underwent a platelet function test (VerifyNow). Amputation free survival and all cause mortality were estimated using the Kaplan-Meier method. The association between baseline characteristics and clinical outcomes was assessed with the Cox proportional hazard model. A total of 278 CLI patients (EM: 153, IM: 79, PM: 46) who underwent EVT were included. There were 180/278 (64.7%, EM: 107, IM: 45, PM: 28) patients who completed the 12 month follow up examination. Carriers of at least one CYP2C19 LOF allele (44.9%, 125/278) had diminished pharmacodynamic responses to clopidogrel as measured using VerifyNow (174 ± 27 platelet reactivity units (PRU), 216 ± 21 PRU, and 245 ± 35 PRU for patients with EM, IM, and PM CYP2C19 profiles, respectively; EM vs. IM, p < .0001 and EM vs. PM, p < .0001). The estimated amputation free 12 month survival rates were EM 82.1%, IM 66.1.0%, and PM 56.6% with significant differences between groups (log-rank test p = .0006, p for trend <.0001). The estimated all cause 12 month mortality rates were EM 83.7%, IM 72.2%, and PM 71.3% (log rank test p = .01, p for trend p = .007). The combined group consisting of IM and PM was associated with amputation free survival and all cause mortality based on a univariable analysis (hazard ratio [HR] = 2.23 [1.97-2.46], p = .011; HR = 1.43 [1.05-1.85], p = .043) and remained significant in a multivariable Cox analysis (HR = 2.65 [2.1-2.9], p = .009; HR = 1.39 [1.07-1.74], p = .037). CYP2C19 genetic profiles can significantly influence clinical outcomes (in both amputation free survival and all cause mortality) in CLI patients who are taking only clopidogrel after EVT.


2.1 μm waveguide laser fabricated by femtosecond laser direct-writing in Ho3+, Tm3+:ZBLAN glass.
We report the first Ho3+ doped waveguide laser, which was realized by femtosecond direct-writing of a depressed cladding structure into ZBLAN glass. Tm3+ sensitizing allows the 9 mm long Ho3+ gain medium to be conveniently pumped at 790 nm, achieving an optical-to-optical slope efficiency of 20% and a threshold of 20 mW. The potentially widely tunable laser produces up to 76 mW at 2052 nm and also operates at shorter wavelengths near 1880 nm and 1978 nm for certain cavity configurations.


Cranberry juice improved antioxidant status without affecting bone quality in orchidectomized male rats.
We reported that drinking citrus juice improves bone quality in orchidectomized senescent male rats. Because cranberry juice, like citrus, is rich in nutrients and phenolic compounds, beneficial effects of citrus juice might also be seen with cranberry juice. An experiment evaluated effect of drinking cranberry juice on bone quality in orchidectomized rats. Thirty-two 1-year-old male rats were randomized to two groups: a sham-control group (n=8) and an orchidectomized group (n=24). The treatments for the 4 months duration of the study were SHAM, orchidectomy (ORX), ORX+drinking either 27% or 45% cranberry juice concentrate added to drinking water. At the termination of the study, the rats were euthanized, blood was collected for plasma antioxidant status and IGF-I. The femur, tibia and the 4th lumbar were evaluated for bone quality. Total calcium and magnesium concentration in the femurs were also evaluated. ORX did not affect red blood cell (RBC)-induced hemolysis despite lowering (p<0.05) plasma antioxidant capacity; reduced (p<0.05) plasma IGF-I, femoral density, femoral strength, time-induced femoral fracture, bone mineral content, bone mineral area; numerically (p=0.07) lowered 4th lumbar density; decreased (p<0.05) trabecular connectivity, trabecular number, femoral ash; increased (p<0.05) trabecular separation in comparison to the SHAM group. Drinking cranberry juice increased (p<0.05) plasma antioxidant status, protected RBC against hemolysis, but had no positive effect on bone quality or bone mineral status. Cranberry juice increases plasma antioxidant status without affecting bone quality.


High fidelity medical simulation in the difficult environment of a helicopter: feasibility, self-efficacy and cost.
This study assessed the feasibility, self-efficacy and cost of providing a high fidelity medical simulation experience in the difficult environment of an air ambulance helicopter. Seven of 12 EM residents in their first postgraduate year participated in an EMS flight simulation as the flight physician. The simulation used the Laerdal SimMantrade mark to present a cardiac and a trauma case in an EMS helicopter while running at flight idle. Before and after the simulation, subjects completed visual analog scales and a semi-structured interview to measure their self-efficacy, i.e. comfort with their ability to treat patients in the helicopter, and recognition of obstacles to care in the helicopter environment. After all 12 residents had completed their first non-simulated flight as the flight physician; they were surveyed about self-assessed comfort and perceived value of the simulation. Continuous data were compared between pre- and post-simulation using a paired samples t-test, and between residents participating in the simulation and those who did not using an independent samples t-test. Categorical data were compared using Fisher's exact test. Cost data for the simulation experience were estimated by the investigators. The simulations functioned correctly 5 out of 7 times; suggesting some refinement is necessary. Cost data indicated a monetary cost of 440 dollars and a time cost of 22 hours of skilled instructor time. The simulation and non-simulation groups were similar in their demographics and pre-hospital experiences. The simulation did not improve residents' self-assessed comfort prior to their first flight (p > 0.234), but did improve understanding of the obstacles to patient care in the helicopter (p = 0.029). Every resident undertaking the simulation agreed it was educational and it should be included in their training. Qualitative data suggested residents would benefit from high fidelity simulation in other environments, including ground transport and for running codes in hospital. It is feasible to provide a high fidelity medical simulation experience in the difficult environment of the air ambulance helicopter, although further experience is necessary to eliminate practical problems. Simulation improves recognition of the challenges present and provides an important opportunity for training in challenging environments. However, use of simulation technology is expensive both in terms of monetary outlay and of personnel involvement. The benefits of this technology must be weighed against the cost for each institution.


Virtual Reality-Delivered Mirror Visual Feedback and Exposure Therapy for FND: A Midpoint Report of a Randomized Controlled Feasibility Study.
The aim was to provide preliminary feasibility, safety, and efficacy data for a personalized virtual reality-delivered mirror visual feedback (VR-MVF) and exposure therapy (VR-ET) intervention for functional neurological disorder (FND). Midpoint results of a single-blind, randomized controlled pilot are presented. Fourteen adults were randomly assigned to eight weekly 30-minute VR sessions-seven in the treatment arm and seven in the control arm. The treatment arm consisted of an immersive avatar-embodied VR-MVF treatment, plus optional weekly VR-ET starting at session 4 if participants had identifiable FND triggers. The control arm received equally immersive nonembodied sessions involving exploration of a virtual interactive space. Feasibility was measured by acceptability of randomization, completion rates, side effects, adverse events, and integrity of blinding procedures. Exploratory primary and secondary outcome measures were weekly symptom frequency and the Oxford Handicap Scale, respectively. Two early dropouts occurred in the treatment arm, resulting in an 86% completion rate (N=12/14). No side effects or adverse events were reported. Blind assessment at study end indicated that two of the seven treatment arm and three of the seven control arm participants incorrectly guessed their assignment. Changes in mean symptom frequency and disability were reported, but data will not be statistically analyzed until study end. This study is the first to report on MVF and VR for treatment of FND. Results generated thus far support feasibility and justify continuation of the study and further investigation into the efficacy of VR interventions for FND.


MTOR pathway in focal cortical dysplasia type 2: What do we know?
Focal cortical dysplasia (FCD) is the most commonly encountered developmental malformation that causes refractory epilepsy. Focal cortical dysplasia type 2 is one of the most usual neuropathological findings in tissues resected therapeutically from patients with drug-resistant epilepsy. Unlike other types of FCD, it is characterized by laminar disorganization and dysplastic neurons, which compromise the organization of the six histologically known layers in the cortex; the morphology and/or cell location can also be altered. A comprehensive review about the pathogenesis of this disease is important because of the necessity to update the results reported over the past years. Here, we present an updated review through Pubmed about the mammalian target of rapamycin (MTOR) pathway in FCD type 2. A wide variety of aspects was covered in 44 articles related to molecular and cellular biology, including experiments in animal and human models. The first publications appeared in 2004, but there is still a lack of studies specifically for one type of FCD. With the advancement of techniques and greater access to molecular and cellular experiments, such as induced pluripotent stem cells (iPSCs) and organoids, it is believed that the trend is increasing the number of publications contributing to the achievement of new discoveries.


Oregon physicians' attitudes about and experiences with end-of-life care since passage of the Oregon Death with Dignity Act.
The Oregon Death with Dignity Act, passed by ballot measure in 1994 and enacted in October 1997, legalized physician-assisted suicide for competent, terminally ill Oregonians, but little is known about the effects of the act on clinical practice or physician perspective. To examine Oregon physicians' attitudes toward and practices regarding care of dying patients since the passage of the Death with Dignity Act. A self-administered questionnaire was mailed in February 1999 to Oregon physicians eligible to prescribe under the act. Of 3981 eligible physicians, 2641 (66%) returned the questionnaire by August 1999. Physicians' reports of their efforts to improve care for dying patients since 1994, their attitudes, concerns, and sources of information about participating in the Death with Dignity Act, and their conversations with patients regarding assisted suicide. A total of 791 respondents (30%) reported that they had increased referrals to hospice. Of the 2094 respondents who cared for terminally ill patients, 76% reported that they made efforts to improve their knowledge of the use of pain medications in the terminally ill. Nine hundred forty-nine responding physicians (36%) had been asked by a patient if they were potentially willing to prescribe a lethal medication. Seven percent of all survey participants reported that 1 or more patients became upset after learning the physician's position on assisted suicide, and 2% reported that 1 or more patients left their care after learning the physician's position on assisted suicide. Of the 73 physicians who were willing to write a lethal prescription and who had received a request from a patient, 20 (27%) were not confident they could determine when a patient had less than 6 months to live. Most Oregon physicians who care for terminally ill patients report that since 1994 they have made efforts to improve their ability to care for these patients and many have had conversations with patients about assisted suicide.


Characterization of the Class I MHC Peptidome Resulting From DNCB Exposure of HaCaT Cells.
Skin sensitization following the covalent modification of proteins by low molecular weight chemicals (haptenation) is mediated by cytotoxic T lymphocyte (CTL) recognition of human leukocyte antigen (HLA) molecules presented on the surface of almost all nucleated cells. There exist 3 nonmutually exclusive hypotheses for how haptens mediate CTL recognition: direct stimulation by haptenated peptides, hapten modification of HLA leading to an altered HLA-peptide repertoire, or a hapten altered proteome leading to an altered HLA-peptide repertoire. To shed light on the mechanism underpinning skin sensitization, we set out to utilize proteomic analysis of keratinocyte presented antigens following exposure to 2,4-dinitrochlorobenzene (DNCB). We show that the following DNCB exposure, cultured keratinocytes present cysteine haptenated (dinitrophenylated) peptides in multiple HLA molecules. In addition, we find that one of the DNCB modified peptides derives from the active site of cytosolic glutathione-S transferase-ω. These results support the current view that a key mechanism of skin sensitization is stimulation of CTLs by haptenated peptides. Data are available via ProteomeXchange with identifier PXD021373.


Motion grouping impairs speed discrimination.
Discriminating between two speed signals is harder when they are seen as part of a single trajectory, compared to the case when they appear as distinct entities. Observers were asked to judge which half of a display had dots that were moving faster. This was done under two main conditions: when dot motion appeared to continue across the boundary between the two halves, and when it moved parallel to the boundary. Speed discrimination thresholds were elevated when motion in the two halves appeared to cross the boundary compared to the case when motion was parallel to the boundary. Extensive practice improved performance until speed discrimination in the two cases was virtually indistinguishable. The addition of noise caused the original effect to reappear, i.e., thresholds were elevated when motion continued across the border. Our results suggest that the local differences in velocity on either side of border are ignored when motion appears to cross the border. Instead the visual system seems to enforce an a priori assumption that when motion continues across a boundary it belongs to a common motion path.


Lymphogranuloma venereum in Zurich, Switzerland: Chlamydia trachomatis serovar L2 proctitis among men who have sex with men.
Whereas until 2003 Lymphogranuloma venereum (LGV) was rare in industrialised countries, there have been increasing reports of cases of LGV proctitis in men having sex with men (MSM) over the last six years in Europe, America and Australia. After the alarming message from the Netherlands in 2003, physicians in a dermatological and STI private clinic in Zurich started examining rectal swabs from patients with proctitis for LGV serovars of C. trachomatis on a regular basis. A test system based on PCR with sequencing and databank comparison was used. Clinical files of all patients with proctitis observed in this time period were examined. Since 2003 twelve cases of proctitis, all in MSM, caused by the LGV serovar L2 C. trachomatis were observed. Of the overall 11 patients the majority were HIV positive and only 2 were HIV negative. Only one patient reported previous sexual contacts outside Europe (Thailand) as the likely place of infection. The clinical presentation was characterised by anorectal pain, discharge, tenesmus and change in stool frequency. Four patients were successfully treated with a single dose of 1 g azithromycin. In all seven cases treated with doxycycline 2 x 100 mg for 10-20 days clinical cure and a negative PCR result after treatment were observed, except for one patient lost to follow-up. Zurich has not been spared by the recent outbreaks of LGV proctitis in MSM. Anorectal LGV infections may progress to severe destructive changes, with formation of granulomas, strictures, and perirectal abscesses. Increased awareness of this problem and establishment of reliable diagnostic tools are required.


Pharmacokinetics of fluoride in human adults: The effect of exercise.
The literature is sparse in terms of the effect of exercise on the pharmacokinetics of fluoride (F) in humans. In a 4-treatment repeated measures cross-over study, we investigated F pharmacokinetics following no exercise (control) and three exercise intensity conditions (light, moderate and vigorous) in healthy adults. At a pre-experimental session, 8 participants (18-30y) residing in a non-fluoridated-area, underwent a VO2 max test to guide the three exercise intensities for the experimental sessions. Participants were on a F-free regime one week before and throughout the four experimental weeks. We measured urinary F excretion (UFE), maximum plasma concentration (Cmax), lag time of Cmax (Tmax), and Area Under the Curve (AUC) for plasma F concentration against time, following F ingestion then no, light, moderate and vigorous exercise. Results showed no statistically significant difference in Tmax among all sessions; whereas Cmax for moderate exercise (226.2 ng/ml) was significantly higher than for no (27.0 ng/ml; p < 0.001), light (105.6 ng/ml; p = 0.016) and vigorous (94.2 ng/ml; p = 0.008) exercise. Mean AUC over 0-90 min following F ingestion was also significantly higher in moderate exercise than for no (p < 0.001), light (p = 0.004) and vigorous (p = 0.001) exercise. Mean UFE over 0-14h was 638.8, 718.7, 574.6 and 450.5 μg for no, light, moderate and vigorous exercise, with no statistically significant differences among different sessions. In conclusion, this human experimental study suggests that moderate exercise may increase the fraction of F absorbed systemically which is therefore available to produce a biological effect. Future studies should be conducted with larger samples, different age groups and using different F doses.


Echinococcus granulosus in farm dogs and dingoes in south eastern Queensland.
Twenty-nine farms with a prevalence of greater than 20% of hydatidosis in cattle were visited in south eastern Queensland between August and December 1982. All farms carried beef cattle but none sheep. Twenty-four had dingoes and wallabies but only 8 had feral pigs. On 17 farms either macropods were killed for dog food or dogs were suspected of hunting macropods or scavenging their carcases. Purge samples were collected from 45 dogs from 23 of the 29 farms visited. The Australian sylvatic strain of Echinococcus granulosus was found in low numbers in purged intestinal content from one dog from each of 2 farms. Also, 50 intestinal tracts from dingoes from southern Queensland were examined between October 1981 and November 1983. The sylvatic strain of E. granulosus was found in 36 dingoes, the Australian mainland domestic strain in 4, and a further 5 dingoes were infected but the strain was not identified. This work indicates that domestic dogs are probably not important definitive hosts for E. granulosus in south eastern Queensland but could be an occasional source of infection for man. Dingoes are the major definitive host and worm numbers can be very high. Small foci of the domestic strain of E. granulosus may be maintained in a cycle involving dingoes, macropods and possibly feral pigs in cattle raising areas of coastal Queensland.


In-Home Occupational Performance Evaluation for Providing Assistance (I-HOPE Assist): An Assessment for Informal Caregivers.
Home modification interventions have the potential to provide support to informal caregivers; however, the impact of these interventions on caregivers is understudied, and adequate assessments are lacking. This study describes the development and preliminary psychometric properties of a performance-based assessment that identifies environmental barriers to performance of daily caregiving activities. An existing assessment of person-environment fit was modified using key informant interviews and was administered to 31 informal caregivers. The In-Home Occupational Performance Evaluation for Providing Assistance demonstrated reliability across raters, good internal consistency for all subscales, and convergent validity with existing measures. This assessment has the potential to guide home modification interventions and measure the impact on informal caregiving in the home.


The ACE I/D polymorphism does not explain heterogeneity of natural course and response to enzyme replacement therapy in Pompe disease.
The majority of children and adults with Pompe disease in the population of European descent carry the leaky splicing GAA variant c.-32-13T>G (IVS1) in combination with a fully deleterious GAA variant on the second allele. The phenotypic spectrum of this patient group is exceptionally broad, with symptom onset ranging from early infancy to late adulthood. In addition, the response to enzyme replacement therapy (ERT) varies between patients. The insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) has been suggested to be a modifier of disease onset and/or response to ERT. Here, we have investigated the effect of the ACE I/D polymorphism in a relatively large cohort of 131 children and adults with Pompe disease, of whom 112 were followed during treatment with ERT for 5 years. We assessed the use of wheelchair and mechanical ventilation, muscle strength assessed via manual muscle testing and hand-held dynamometry (HHD), distance walked on the six-minute walk test (6MWT), forced vital capacity (FVC) in sitting and supine position and daily-life activities assessed by R-PAct. Cross sectional analysis at first visit showed no differences between the genotypes with respect to age at first symptoms, diagnosis, wheelchair use, or ventilator use. Also response to ERT over 5 years assessed by linear mixed model analyses showed no significant differences between ACE groups for any of the outcome measures. The patient cohort contained 24 families with 54 siblings. Differences in ACE genotype could neither explain inter nor intra familial differences. We conclude that the ACE I/D polymorphism does not explain the large variation in disease severity and response to ERT observed among Pompe patients with the same c.-32-13T>G GAA variant.


The factor structure of complex posttraumatic stress disorder in traumatized refugees.
The construct of complex posttraumatic stress disorder (CPTSD) has attracted much research attention in previous years, however it has not been systematically evaluated in individuals exposed to persecution and displacement. Given that CPTSD has been proposed as a diagnostic category in the ICD-11, it is important that it be examined in refugee groups. In the current study, we proposed to test, for the first time, the factor structure of CPTSD proposed for the ICD-11 in a sample of resettled treatment-seeking refugees. The study sample consisted of 134 traumatized refugees from a variety of countries of origin, with approximately 93% of the sample having been exposed to torture. We used confirmatory factor analysis to examine the factor structure of CPTSD in this sample and examined the sensitivity, specificity, positive predictive power and negative predictive power of individual items in relation to the CPTSD diagnosis. Findings revealed that a two-factor higher-order model of CPTSD comprising PTSD and Difficulties in Self-Organization (χ2 (47)=57.322, p=0.144, RMSEA=0.041, CFI=0.981, TLI=0.974) evidenced superior fit compared to a one-factor higher-order model of CPTSD (χ2 (48)=65.745, p=0.045, RMSEA=0.053, CFI=0.968, TLI=0.956). Overall, items evidenced strong sensitivity and negative predictive power, moderate positive predictive power, and poor specificity. Findings provide preliminary evidence for the validity of the CPTSD construct with highly traumatized treatment-seeking refugees.


Molecular hydrogen: An inert gas turns clinically effective.
Molecular hydrogen (H2) appeared as an experimental agent in biomedicine approximately 40 years ago, yet the past 5 years seem to confirm its medicinal value in the clinical environment. H2 improves clinical end-points and surrogate markers in several clinical trials, from metabolic diseases to chronic systemic inflammatory disorders to cancer. However, less information is available concerning its medicinal properties, such as dosage and administration, or adverse reactions and use in specific populations. The present paper overviews the clinical relevance of molecular hydrogen, and summarizes data from clinical trials on this innovative medical agent. Clinical profiles of H2 provide evidence-based direction for practical application and future research on molecular hydrogen for the wider health care community.


Relations of Preschoolers' Visual-Motor and Object Manipulation Skills With Executive Function and Social Behavior.
The purpose of this article was to examine specific linkages between early visual-motor integration skills and executive function, as well as between early object manipulation skills and social behaviors in the classroom during the preschool year. Ninety-two children aged 3 to 5 years old (Mage = 4.31 years) were recruited to participate. Comprehensive measures of visual-motor integration skills, object manipulation skills, executive function, and social behaviors were administered in the fall and spring of the preschool year. Our findings indicated that children who had better visual-motor integration skills in the fall had better executive function scores (B = 0.47 [0.20], p < .05, β = .27) in the spring of the preschool year after controlling for age, gender, Head Start status, and site location, but not after controlling for children's baseline levels of executive function. In addition, children who demonstrated better object manipulation skills in the fall showed significantly stronger social behavior in their classrooms (as rated by teachers) in the spring, including more self-control (B - 0.03 [0.00], p < .05, β = .40), more cooperation (B = 0.02 [0.01], p < .05, β = .28), and less externalizing/hyperactivity (B = - 0.02 [0.01], p < .05, β = - .28) after controlling for social behavior in the fall and other covariates. Children's visual-motor integration and object manipulation skills in the fall have modest to moderate relations with executive function and social behaviors later in the preschool year. These findings have implications for early learning initiatives and school readiness.


Effects of Prism Eyeglasses on Objective and Subjective Fixation Disparity.
In optometry of binocular vision, the question may arise whether prisms should be included in eyeglasses to compensate an oculomotor and/or sensory imbalance between the two eyes. The corresponding measures of objective and subjective fixation disparity may be reduced by the prisms, or the adaptability of the binocular vergence system may diminish effects of the prisms over time. This study investigates effects of wearing prisms constantly for about 5 weeks in daily life. Two groups of 12 participants received eyeglasses with prisms having either a base-in direction or a base-out direction with an amount up to 8 prism diopters. Prisms were prescribed based on clinical fixation disparity test plates at 6 m. Two dependent variables were used: (1) subjective fixation disparity was indicated by a perceived offset of dichoptic nonius lines that were superimposed on the fusion stimuli and (2) objective fixation disparity was measured with a video based eye tracker relative to monocular calibration. Stimuli were presented at 6 m and included either central or more peripheral fusion stimuli. Repeated measurements were made without the prisms and with the prisms after about 5 weeks of wearing these prisms. Objective and subjective fixation disparity were correlated, but the type of fusion stimulus and the direction of the required prism may play a role. The prisms did not reduce the fixation disparity to zero, but induced significant changes in fixation disparity with large effect sizes. Participants receiving base-out prisms showed hypothesized effects, which were concurrent in both types of fixation disparity. In participants receiving base-in prisms, the individual effects of subjective and objective effects were negatively correlated: the larger the subjective (sensory) effect, the smaller the objective (motor) effect. This response pattern was related to the vergence adaptability, i.e. the individual fusional vergence reserves.


A nonredundant role for canonical NF-κB in human myeloid dendritic cell development and function.
The plastic role of dendritic cells (DCs) in the regulation of immune responses has made them interesting targets for immunotherapy, but also for pathogens or tumors to evade immunity. Functional alterations of DCs are often ascribed to manipulation of canonical NF-κB activity. However, though this pathway has been linked to murine myeloid DC biology, a detailed analysis of its importance in human myeloid DC differentiation, survival, maturation, and function is lacking. The myeloid DC subsets include interstitial DCs and Langerhans cells. In this study, we investigated the role of canonical NF-κB in human myeloid DCs generated from monocytes (monocyte-derived DCs [mo-DCs]) or CD34(+) progenitors (CD34-derived myeloid DCs [CD34-mDCs]). Inhibition of NF-κB activation during and after mo-DC, CD34-interstitial DC, or CD34-Langerhans cell differentiation resulted in apoptosis induction associated with caspase 3 activation and loss of mitochondrial transmembrane potential. Besides regulating survival, canonical NF-κB activity was required for the acquisition of a DC phenotype. Despite phenotypic differences, however, Ag uptake, costimulatory molecule and CCR7 expression, as well as T cell stimulatory capacity of cells generated under NF-κB inhibition were comparable to control DCs, indicating that canonical NF-κB activity during differentiation is redundant for the development of functional APCs. However, both mo-DC and CD34-mDC functionality were reduced by NF-κB inhibition during activation. In conclusion, canonical NF-κB activity is essential for the development and function of mo-DCs as well as CD34-mDCs. Insight into the role of this pathway may help in understanding how pathogens and tumors escape immunity and aid in developing novel treatment strategies aiming to interfere with human immune responses.


Temporary right ventricular mechanical support in high-risk left ventricular assist device recipients versus permanent biventricular or total artificial heart support.
Early planned institution of temporary right ventricular assist device (RVAD) support with the CentriMag (Levitronix LLC, Waltham, MA, USA) in left ventricular assist device (LVAD) recipients was compared with permanent biventricular assist device (BVAD) or total artificial heart (TAH) support. Between 2007 and 2011, 77 patients (age range: 25-70 years) with preoperative evidence of biventricular dysfunction (University of Pennsylvania score >50; University of Michigan score >5) were included. Forty-six patients (38 men; median age 54.5 years, range: 25-70 years) underwent LVAD placement combined with temporary RVAD support (group A); in 31 patients (25 men; median age 56.7 years, range: 28-68 years), a permanent BVAD or TAH implantation (group B) was performed. Within 30 days, 12 patients from group A (26.08%) and 14 patients from group B (45.1%) died on mechanical support (P = 0.02). Thirty patients (65.2%) in group A were weaned from temporary RVAD support and three (6.5%) underwent permanent RVAD (HeartWare, Inc., Framingham, MA, USA) placement. A total of 26 patients (56.5%) were discharged home in group A versus 17 (54.8%) in group B (P = 0.56). Three patients (8.5%) received heart transplantation in group A and six (19.3%) in group B (P = 0.04). In group A, 90-day and 6-month survival was 54.3% (n = 25) versus 51.6% (n = 16) in group B (P = 0.66). In group A, 1-year survival was 45.6% (n = 21) versus 45.1% (n = 14) in group B (P = 0.81). The strategy of planned temporary RVAD support in LVAD recipients showed encouraging results if compared with those of a similar permanent BVAD/TAH population. Weaning from and removal of the temporary RVAD support may allow patients to be on LVAD support only despite preoperative biventricular dysfunction.


Creating chemical diversity to target protein kinases.
Protein kinases play crucial roles in regulating virtually every cellular process and are currently attracting tremendous interest as drug targets from the pharmaceutical industry. The major challenges facing the development of the potential kinase inhibitor drugs are: selectivity, physical properties (solubility, molecular weight), and pharmacological properties (bioavailability, half life, toxicity, etc.) This review focuses on how selective protein kinase inhibitors that target the ATP and allosteric binding sites are currently being identified and optimized.


Circadian occurrence of symptomatic paroxysmal supraventricular tachycardia in untreated patients.
Fifty-two patients with paroxysmal supraventricular tachycardia were studied to determine whether there was a circadian pattern to the occurrence of this arrhythmia. Antiarrhythmic therapy was discontinued, and patients were followed until they had one recurrence of tachycardia documented by telephone transmission of the electrocardiogram. By least-squares analysis, the times of day that the 52 attacks (one from each patient) occurred were fit to a sinusoidal density function with a period of 24 hr. The highest relative incidence of tachycardia was at 4 P.M.; tachycardia was five times more likely to occur at 4 P.M. than at 4 A.M., the time of the lowest relative incidence. A second attack of tachycardia was recorded from 35 of the 52 patients. The times of the two attacks in individual patients were found to be independent; thus the times of day at which the second attacks occurred were used as a test set for the distribution estimated from the first. The empirical distribution for the times from the 35 second attacks was compared with the distribution function estimated from the 52 first attacks, and there was no significant departure; this finding confirmed the circadian pattern. Since the relative incidence of attacks of paroxysmal supraventricular tachycardia is higher in the afternoon, it may be helpful to target antiarrhythmic therapy to that time of day.


miR-20b regulates expression of proteinase-activated receptor-1 (PAR-1) thrombin receptor in melanoma cells.
The proteinase-activated receptor 1 (PAR-1) plays a central role in melanoma progression and its expression level is believed to correlate with the degree of cancer invasiveness. Here, we show that PAR-1 is post-transcriptionally regulated by miR-20b microRNA in human melanoma cells. PAR-1 was found to be expressed in metastatic melanoma cells but was barely detectable in primary melanoma. By transducing primary melanoma cells with a lentivirus containing a 3'-UTR construct of PAR-1 mRNA, we could show that endogenous melanoma microRNAs interacted with PAR-1 3'-UTR and silenced a fused luciferase reporter. Transfection of an inhibitor against miR-20b into primary melanoma cells reversed this process. Finally, transfection of miR-20b mimic into metastatic melanoma cells caused downregulation of the luciferase reporter. We conclude that miR-20b regulates expression of melanoma PAR-1 receptor, which may explain the differential expression of PAR-1 observed in human melanoma.


Kaposi's Sarcoma-Associated Herpesvirus, but Not Epstein-Barr Virus, Co-infection Associates With Coronavirus Disease 2019 Severity and Outcome in South African Patients.
In South Africa, the Coronavirus Disease 2019 (COVID-19) pandemic is occurring against the backdrop of high Human Immunodeficiency Virus (HIV), tuberculosis and non-communicable disease burdens as well as prevalent herpesviruses infections such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). As part of an observational study of adults admitted to Groote Schuur Hospital, Cape Town, South Africa during the period June-August 2020 and assessed for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we measured KSHV serology and KSHV and EBV viral load (VL) in peripheral blood in relation to COVID-19 severity and outcome. A total of 104 patients with PCR-confirmed SARS-CoV-2 infection were included in this study. 61% were men and 39% women with a median age of 53 years (range 21-86). 29.8% (95% CI: 21.7-39.1%) of the cohort was HIV positive and 41.1% (95% CI: 31.6-51.1%) were KSHV seropositive. EBV VL was detectable in 84.4% (95% CI: 76.1-84.4%) of the cohort while KSHV DNA was detected in 20.6% (95% CI: 13.6-29.2%), with dual EBV/KSHV infection in 17.7% (95% CI: 11.1-26.2%). On enrollment, 48 [46.2% (95% CI: 36.8-55.7%)] COVID-19 patients were classified as severe on the WHO ordinal scale reflecting oxygen therapy and supportive care requirements and 30 of these patients [28.8% (95% CI: 20.8-38.0%)] later died. In COVID-19 patients, detectable KSHV VL was associated with death after adjusting for age, sex, HIV status and detectable EBV VL [p = 0.036, adjusted OR = 3.17 (95% CI: 1.08-9.32)]. Furthermore, in HIV negative COVID-19 patients, there was a trend indicating that KSHV VL may be related to COVID-19 disease severity [p = 0.054, unstandardized co-efficient 0.86 (95% CI: -0.015-1.74)] in addition to death [p = 0.008, adjusted OR = 7.34 (95% CI: 1.69-31.49)]. While the design of our study cannot distinguish if disease synergy exists between COVID-19 and KSHV nor if either viral infection is indeed fueling the other, these data point to a potential contribution of KSHV infection to COVID-19 outcome, or SARS-CoV-2 infection to KSHV reactivation, particularly in the South African context of high disease burden, that warrants further investigation.


Maximizing treatment efficacy through patient stratification in neuropathic pain trials.
Treatment of neuropathic pain remains inadequate despite the elucidation of multiple pathophysiological mechanisms and the development of promising therapeutic compounds. The lack of success in translating knowledge into clinical practice has discouraged pharmaceutical companies from investing in pain medicine; however, new patient stratification approaches could help bridge the translation gap and develop individualized therapeutic approaches. As we highlight in this article, subgrouping of patients according to sensory profiles and other baseline characteristics could aid the prediction of treatment success. Furthermore, novel outcome measures have been developed for patients with neuropathic pain. The extent to which sensory profiles and outcome measures can be employed in routine clinical practice and clinical trials and across distinct neuropathic pain aetiologies is yet to be determined. Improvements in animal models, drawing on our knowledge of human pain, and robust public-private partnerships will be needed to pave the way to innovative and effective pain medicine in the future.


The estimated effect of mass or footprint reduction in recent light-duty vehicles on U.S. societal fatality risk per vehicle mile traveled.
The National Highway Traffic Safety Administration (NHTSA) recently updated its 2003 and 2010 logistic regression analyses of the effect of a reduction in light-duty vehicle mass on US societal fatality risk per vehicle mile traveled (VMT; Kahane, 2012). Societal fatality risk includes the risk to both the occupants of the case vehicle as well as any crash partner or pedestrians. The current analysis is the most thorough investigation of this issue to date. This paper replicates the Kahane analysis and extends it by testing the sensitivity of his results to changes in the definition of risk, and the data and control variables used in the regression models. An assessment by Lawrence Berkeley National Laboratory (LBNL) indicates that the estimated effect of mass reduction on risk is smaller than in Kahane's previous studies, and is statistically non-significant for all but the lightest cars (Wenzel, 2012a). The estimated effects of a reduction in mass or footprint (i.e. wheelbase times track width) are small relative to other vehicle, driver, and crash variables used in the regression models. The recent historical correlation between mass and footprint is not so large to prohibit including both variables in the same regression model; excluding footprint from the model, i.e. allowing footprint to decrease with mass, increases the estimated detrimental effect of mass reduction on risk in cars and crossover utility vehicles (CUVs)/minivans, but has virtually no effect on light trucks. Analysis by footprint deciles indicates that risk does not consistently increase with reduced mass for vehicles of similar footprint. Finally, the estimated effects of mass and footprint reduction are sensitive to the measure of exposure used (fatalities per induced exposure crash, rather than per VMT), as well as other changes in the data or control variables used. It appears that the safety penalty from lower mass can be mitigated with careful vehicle design, and that manufacturers can reduce mass as a strategy to increase their vehicles' fuel economy and reduce greenhouse gas emissions without necessarily compromising societal safety.


Simultaneous quantification of active carbon- and nitrogen-fixing communities and estimation of fixation rates using fluorescence in situ hybridization and flow cytometry.
Understanding the interconnectivity of oceanic carbon and nitrogen cycles, specifically carbon and nitrogen fixation, is essential in elucidating the fate and distribution of carbon in the ocean. Traditional techniques measure either organism abundance or biochemical rates. As such, measurements are performed on separate samples and on different time scales. Here, we developed a method to simultaneously quantify organisms while estimating rates of fixation across time and space for both carbon and nitrogen. Tyramide signal amplification fluorescence in situ hybridization (TSA-FISH) of mRNA for functionally specific oligonucleotide probes for rbcL (ribulose-1,5-bisphosphate carboxylase/oxygenase; carbon fixation) and nifH (nitrogenase; nitrogen fixation) was combined with flow cytometry to measure abundance and estimate activity. Cultured samples representing a diversity of phytoplankton (cyanobacteria, coccolithophores, chlorophytes, diatoms, and dinoflagellates), as well as environmental samples from the open ocean (Gulf of Mexico, USA, and southeastern Indian Ocean, Australia) and an estuary (Galveston Bay, Texas, USA), were successfully hybridized. Strong correlations between positively tagged community abundance and (14)C/(15)N measurements are presented. We propose that these methods can be used to estimate carbon and nitrogen fixation in environmental communities. The utilization of mRNA TSA-FISH to detect multiple active microbial functions within the same sample will offer increased understanding of important biogeochemical cycles in the ocean.


Enablers and barriers to using two-way information technology in the management of adults with diabetes: A descriptive systematic review.
Background This systematic review aimed to explore the enablers and barriers faced by adults with diabetes using two-way information communication technologies to support diabetes self-management. Methods Relevant literature was obtained from five databases using search strategies combining four major constructs: adults with diabetes, biomedical technology, communication technology and patient utilisation. Results Of 8430 unique articles identified, 48 were included for review. Risk of bias was assessed using either the Newcastle-Ottowa or Cochrane risk of bias assessment tools. Seventy-one percent of studies were of cohort design with the majority of studies assessed at high or unclear risk of bias. Consistently identified barriers included poorly designed interfaces requiring manual data entry and systems that lacked functionalities valued by patients. Commonly cited enablers included access to reliable technology, highly automated data entry and transmission, graphical display of data with immediate feedback, and supportive health care professionals and family members. Conclusions People with diabetes face a number of potentially modifiable barriers in using technology to support their diabetes management. In order to address these barriers, end users should be consulted in the design process and consideration given to theories of technology adoption to inform design and implementation. Systems should be designed to solve clinical or behavioural problems that are identified by patients as priorities. Technology should be as automated, streamlined, mobile, low cost and integrated as possible in order to limit the burden of usage for the patient and maximise clinical usefulness.


The effect of A23187 concentration and exposure time on the outcome of the hamster egg penetration test.
We investigated the conditions required to enhance the performance of human sperm in the hamster egg penetration test with the free acid form of A23187. The best performance was observed after stimulation with 2 microM A23187 for 1 h when the median penetration rate with sperm from fertile donors was 100% of eggs with 5.8 decondensed sperm heads/egg. Extending the stimulation period with 2 microM A23187 to 2 or 3 h, resulted in a progressive decrease in the penetration rate. In the absence of A23187, the penetration rate was lower (0.7 decondensed sperm heads/egg after 1 h) but increased with stimulation time. A similar picture was observed with sperm from patients taken for an IVF programme. For a pool of cryopreserved semen, the coefficient of variation of the penetration rate after stimulation with 2 microM A23187 for 1 h, expressed as decondensed sperm heads/egg, was 11% within and 20% between assays. There was no correlation between the outcome of the hamster egg penetration test and the percentage motility, velocity or lateral head displacement of the sperm measured after the same stimulation regime. However, in IVF patients the initial velocity and lateral head displacement of the sperm (zero time) were correlated with the best result from the hamster egg penetration test (r = 0.62 and 0.57 respectively). No motility changes characteristic of capacitation were detected. We conclude that stimulation with 2 microM A23187 (free acid) for 1 h prior to the addition of the zona free hamster eggs can produce a high penetration rate with fertile samples and provides a convenient and robust protocol for the assay. However, when carried out in this way the test does not assess the ability of the sperm to capacitate.


Self-reported attitudes and behaviors of general surgery residents about ethical academic practices in test taking.
A correlation exists between people who engage in academic dishonesty as students and unethical behaviors later as professionals. Academic dishonesty has been assessed among medical students, but not among general surgery residents. We sought to describe the attitudes of general surgery residents with regard to ethical practices in test taking. A survey with 4 scenarios describing activities related to examination taking that may or may not be considered unethical was administered. Participants were asked about participation in the activities-either personally or any knowledge of others-and whether the activities were unethical. Fifty-seven of 62 residents (92%) participated. For each scenario, >70% indicated that neither they nor anyone else they knew had participated in the activities. Behaviors deemed unethical included memorizing or using memorized questions to prepare for future tests (52%), selling questions for financial gain (90%), and purchasing previously used questions (57%). No difference in attitudes was seen among incoming interns, junior-level (postgraduate year [PGY]1-3), or senior-level (PGY4-6) residents. Overall, general surgery residents indicated that they had not participated in activities they felt to be unethical. Defining what is unethical was less clear. This represents an area for further education.


Developing a predictive in vitro dissolution model based on gastrointestinal fluid characterisation in rats.
The influence of physiological factors on the solubility of drug compounds has been thoroughly investigated in humans. However, as these factors vary between species and since many in vivo studies are carried out in rats or mice, it has been difficult to establish sufficient in vitro in vivo relations. The aim of this study was to develop a physiologically relevant in vitro dissolution model simulating the gastrointestinal (GI) fluids of fasted rats and compare it to previously published in vitro and in vivo data. To develop the in vitro model, the pH was measured in situ in six segments of the GI tract of anesthetised rats, then the fluids from the stomach, the proximal and the distal small intestine were collected and characterized with regard to osmolality, and bile acid and phospholipid concentration. The pH and osmolality were found to increase throughout the GI tract. The bile acids and phospholipids were present in high concentrations in the proximal small intestine, and the bile acid concentration doubled in the distal part, where the phospholipid concentration decreased. Matrix-assisted laser desorption ionisation mass spectrometry imaging was applied on a cross section of the small intestine, to study which bile acids and phospholipid classes were present in the small intestine of rats. Both cholic acid, taurocholic acid and glycocholic acid were detected, and phosphatidylcholine (34:2) was found to be mainly present in the intestinal wall or mucus, whereas lysophosphatidylcholine (16:0) was also detected in the lumen. Based on these observations, biorelevant media were developed to simulate fluids in the stomach and the proximal part of the small intestine in fasted rats. The media were implemented in a two-step in vitro dissolution model, which was found to better predict the in vivo performance of furosemide, when compared to previously published in vitro and in vivo data.


(2R,6R)-hydroxynorketamine rescues chronic stress-induced depression-like behavior through its actions in the midbrain periaqueductal gray.
It has been widely reported that ketamine rescues chronic stress-induced depression-like behavior, but the underlying cellular mechanisms of the rapid antidepressant actions of ketamine remain largely unclear. Both male and female Sprague-Dawley rats were used and received modified learned helplessness paradigm to induce depression-like behavior. Depression-like behavior was assayed and manipulated using forced swim tests, sucrose preference tests and pharmacological microinjection. We conducted whole-cell patch-clamp electrophysiological recordings in the midbrain ventrolateral periaqueductal gray (vlPAG) neurons. Surface and cytosolic glutamate receptor 1 (GluR1) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression were analyzed using Western blotting. Phosphorylated GluR1 expression was quantified using Western blotting analysis. The results showed that a single systemic administration of a ketamine metabolite (2R,6R)-hydroxynorketamine (2R,6R-HNK) rapidly rescued chronic stress-induced depression-like behavior and persisted for up to 21 days. Consistently, the chronic stress-induced diminished glutamatergic transmission and surface GluR1 expression in the vlPAG were also reversed by a single systemic injection of (2R,6R)-HNK. Furthermore, bath application of (2R,6R)-HNK increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in the vlPAG. Further evidence for the antidepressant action of (2R,6R)-HNK is provided by the finding that microinjection of (2R,6R)-HNK into the vlPAG exhibited a rapid-acting and long-lasting antidepressant effect. This antidepressant effect of (2R,6R)-HNK was prevented by the intra-vlPAG microinjection of AMPA receptor antagonist CNQX. Together, the current results provide evidence that (2R,6R)-HNK rescues chronic stress-induced depression-like behavior with rapid-acting and long-lasting antidepressant effects through enhancement of AMPA receptor-mediated transmission in the vlPAG.


Excessive production of sex hormones in a cat with an adrenocortical tumor.
A 13-year-old neutered male domestic shorthair cat was evaluated because it was spraying urine that had a strong odor and had developed aggressive behavior. Physical examination did not detect any palpable testes within the scrotum; however, spines were detected on the penis. Abdominal ultrasonography revealed a mass in the region of the right adrenal gland. Results of adrenal hormonal analyses revealed considerable increases in serum concentrations of androstenedione and testosterone. A mass associated with the right adrenal gland was found during exploratory laparotomy. There was no invasion of the mass into the caudal vena cava. No ectopic gonadal tissue was seen within the abdomen. Adrenalectomy of the right adrenal gland was performed, and histologic evaluation of the mass revealed an adrenocortical adenoma. Two weeks after surgery, serum concentrations of androgens had decreased. Eight weeks after surgery, the cat was no longer spraying urine and was acting affectionate toward the owner. Adrenal gland tumors can produce a variety of hormones other than cortisol. An adrenal gland tumor should be considered in neutered cats with newly developed physical and behavioral changes of a sexual nature. In the absence of debilitating conditions that are often associated with hyperadrenocorticism, cats undergoing adrenalectomy for an adrenal gland tumor that is producing sex hormones may have resolution of clinical signs and a good prognosis.


Infrared measurements of atmospheric transmission at sea level.
Atmospheric transmittance spectra from 0.56 micro to 10.7 micro obtained over a 25-km horizontal path at sea level, are presented. The sources were six 150-cm diam carbon are searchlights. A radiometrically calibrated spectrometer equipped with a NaCl prism and a thermocouple detector was used to record the spectral distribution of the radiation transmitted through the atmosphere. The transmittance spectra were obtained for values of precipitable water vapor ranging from 21.5 cm to 43.3 cm. From these spectra the selective transmittance of four atmospheric windows was measured. A plot of selective transmittance as a function of the square root of the precipitable water vapor for the four windows shows that the transmittance in these windows is well described by the statistical model of band absorption.


Oxytocin modulates social distance between males and females.
In humans, interpersonal romantic attraction and the subsequent development of monogamous pair-bonds is substantially predicted by influential impressions formed during first encounters. The prosocial neuropeptide oxytocin (OXT) has been identified as a key facilitator of both interpersonal attraction and the formation of parental attachment. However, whether OXT contributes to the maintenance of monogamous bonds after they have been formed is unclear. In this randomized placebo-controlled trial, we provide the first behavioral evidence that the intranasal administration of OXT stimulates men in a monogamous relationship, but not single ones, to keep a much greater distance (~10-15 cm) between themselves and an attractive woman during a first encounter. This avoidance of close personal proximity occurred in the physical presence of female but not male experimenters and was independent of gaze direction and whether the female experimenter or the subject was moving. We further confirmed this unexpected finding using a photograph-based approach/avoidance task that showed again that OXT only stimulated men in a monogamous relationship to approach pictures of attractive women more slowly. Importantly, these changes cannot be attributed to OXT altering the attitude of monogamous men toward attractive women or their judgments of and arousal by pictures of them. Together, our results suggest that where OXT release is stimulated during a monogamous relationship, it may additionally promote its maintenance by making men avoid signaling romantic interest to other women through close-approach behavior during social encounters. In this way, OXT may help to promote fidelity within monogamous human relationships.


The P50 Research Center in Perioperative Sciences: How the investment by the National Institute of General Medical Sciences in team science has reduced postburn mortality.
Since the inception of the P50 Research Center in Injury and Peri-operative Sciences (RCIPS) funding mechanism, the National Institute of General Medical Sciences has supported a team approach to science. Many advances in critical care, particularly burns, have been driven by RCIPS teams. In fact, burns that were fatal in the early 1970s, prior to the inception of the P50 RCIPS program, are now routinely survived as a result of the P50-funded research. The advances in clinical care that led to the reduction in postburn death were made by optimizing resuscitation, incorporating early excision and grafting, bolstering acute care including support for inhalation injury, modulating the hypermetabolic response, augmenting the immune response, incorporating aerobic exercise, and developing antiscarring strategies. The work of the Burn RCIPS programs advanced our understanding of the pathophysiologic response to burn injury. As a result, the effects of a large burn on all organ systems have been studied, leading to the discovery of persistent dysfunction, elucidation of the underlying molecular mechanisms, and identification of potential therapeutic targets. Survival and subsequent patient satisfaction with quality of life have increased. In this review article, we describe the contributions of the Galveston P50 RCIPS that have changed postburn care and have considerably reduced postburn mortality.


Biomarkers predicting a need for intensive treatment in patients with early arthritis.
The heterogeneous nature of rheumatoid arthritis (RA) complicates early recognition and treatment. In recent years, a growing body of evidence has demonstrated that intervention during the window of opportunity can improve the response to treatment and slow- or even stop-irreversible structural changes. Advances in therapy, such as biologic agents, and changing approaches to the disease, such as the treat to target and tight control strategies, have led to better outcomes resulting from personalized treatment to patients with different prognostic markers. The various biomarkers identified either facilitate early diagnosis or make it possible to adjust management to disease activity or poor outcomes. However, no single biomarker can bridge the gap between disease onset and prescription of the first DMARD, and traditional biomarkers do not identify all patients requiring early aggressive treatment. Furthermore, the outcomes of early arthritis cohorts are largely biased by the treatment prescribed to patients; therefore, new challenges arise in the search for prognostic biomarkers. Herein, we discuss the value of traditional and new biomarkers and suggest the need for intensive treatment as a new surrogate marker of poor prognosis that can guide therapeutic decisions in the early stages of RA.


The lefty-related factor Xatv acts as a feedback inhibitor of nodal signaling in mesoderm induction and L-R axis development in xenopus.
In mouse, lefty genes play critical roles in the left-right (L-R) axis determination pathway. Here, we characterize the Xenopus lefty-related factor antivin (Xatv). Xatv expression is first observed in the marginal zone early during gastrulation, later becoming restricted to axial tissues. During tailbud stages, axial expression resolves to the neural tube floorplate, hypochord, and (transiently) the notochord anlage, and is joined by dynamic expression in the left lateral plate mesoderm (LPM) and left dorsal endoderm. An emerging paradigm in embryonic patterning is that secreted antagonists regulate the activity of intercellular signaling factors, thereby modulating cell fate specification. Xatv expression is rapidly induced by dorsoanterior-type mesoderm inducers such as activin or Xnr2. Xatv is not an inducer itself, but antagonizes both Xnr2 and activin. Together with its expression pattern, this suggests that Xatv functions during gastrulation in a negative feedback loop with Xnrs to affect the amount and/or character of mesoderm induced. Our data also provide insights into the way that lefty/nodal signals interact in the initiation of differential L-R morphogenesis. Right-sided misexpression of Xnr1 (endogenously expressed in the left LPM) induces bilateral Xatv expression. Left-sided Xatv overexpression suppresses Xnr1/XPitx2 expression in the left LPM, and leads to severely disturbed visceral asymmetry, suggesting that active 'left' signals are critical for L-R axis determination in frog embryos. We propose that the induction of lefty/Xatv in the left LPM by nodal/Xnr1 provides an efficient self-regulating mechanism to downregulate nodal/Xnr1 expression and ensure a transient 'left' signal within the embryo.


Predicting race performance in triathlon: the role of perfectionism, achievement goals, and personal goal setting.
The question of how perfectionism affects performance is highly debated. Because empirical studies examining perfectionism and competitive sport performance are missing, the present research investigated how perfectionism affected race performance and what role athletes' goals played in this relationship in two prospective studies with competitive triathletes (Study 1: N = 112; Study 2: N = 321). Regression analyses showed that perfectionistic personal standards, high performance-approach goals, low performance-avoidance goals, and high personal goals predicted race performance beyond athletes' performance level. Moreover, the contrast between performance-avoidance and performance-approach goals mediated the relationship between perfectionistic personal standards and performance, whereas personal goal setting mediated the relationship between performance-approach goals and performance. The findings indicate that perfectionistic personal standards do not undermine competitive performance, but are associated with goals that help athletes achieve their best possible performance.


Visualisation of exercise-induced ischaemia of the right ventricle by thallium-201 single photon emission computed tomography.
Exercise thallium-201 (201T1) single photon emission computed tomography (SPECT) has been used to detect potential ischaemia in the left ventricular myocardium but not in the right ventricle. The purpose of this study was to establish the clinical usefulness of a right ventricular polar map of 201T1 SPECT for visualisation of exercise-induced right ventricular ischaemia. Myocardial 201T1 SPECT was obtained immediately after treadmill exercise in 97 patients with suspected coronary artery disease. A region of interest was placed over the right ventricle (RV) on post-stress transaxial images. Short axis images of this region were generated and reconstructed as a bull's eye polar map. Normal ranges of RV 201T1 uptake were determined in 12 patients with normal coronary arteries. Scintigraphic criteria for identifying RV perfusion abnormality were derived from 25 patients with right coronary artery (RCA) stenosis greater than 75%. These criteria were applied to 60 consecutive patients with suspected coronary artery disease. Perfusion defects in the RV were larger in patients with proximal RCA stenosis than in those with distal RCA stenosis (mean (SD) 28 (16)% v 6 (5)%, P < 0.001). The sensitivity and specificity of the RV polar map for the detection of proximal RCA stenosis were 67% (8/12) and 98% (47/48), respectively. RV perfusion defects became undetectable in 9 patients who had successful percutaneous transluminal coronary angioplasty to a proximal RCA lesion. A right ventricular polar map display was useful for visualising exercise-induced right ventricular ischaemia.


Recall of Others' Actions after Incidental Encoding Reveals Episodic-like Memory in Dogs.
The existence of episodic memory in non-human animals is a debated topic that has been investigated using different methodologies that reflect diverse theoretical approaches to its definition. A fundamental feature of episodic memory is recalling after incidental encoding, which can be assessed if the recall test is unexpected [1]. We used a modified version of the "Do as I Do" method [2], relying on dogs' ability to imitate human actions, to test whether dogs can rely on episodic memory when recalling others' actions from the past. Dogs were first trained to imitate human actions on command. Next, they were trained to perform a simple training exercise (lying down), irrespective of the previously demonstrated action. This way, we substituted their expectation to be required to imitate with the expectation to be required to lie down. We then tested whether dogs recalled the demonstrated actions by unexpectedly giving them the command to imitate, instead of lying down. Dogs were tested with a short (1 min) and a long (1 hr) retention interval. They were able to recall the demonstrated actions after both intervals; however, their performance declined more with time compared to conditions in which imitation was expected. These findings show that dogs recall past events as complex as human actions even if they do not expect the memory test, providing evidence for episodic-like memory. Dogs offer an ideal model to study episodic memory in non-human species, and this methodological approach allows investigating memory of complex, context-rich events. VIDEO ABSTRACT.


Mortgage worries: young adults and the US housing crisis.
The 2008 housing crisis and the changes in lending practices that led up to it shook the status of home loans as secure debt in the United States. The crisis hit during a time when many young adults had recently bought their first home, making it a particularly consequential moment in their homeownership career. We investigate the effects of the housing crisis on the mental health of young homeowners using longitudinal data. We model levels of anxiety among young homeowners carrying mortgage debt before and after the recession as an early indicator of how the crisis affected the experience of home loans. The positive effects of being a mortgaged homeowner before the recession declined significantly after the housing crisis. We discuss whether this shift may portend a longer-term shift in American beliefs in the value of investing in housing, with significant implications for financial well-being and wealth stratification.


Intravenous glutamine decreases lung and distal organ injury in an experimental model of abdominal sepsis.
The protective effect of glutamine, as a pharmacological agent against lung injury, has been reported in experimental sepsis; however, its efficacy at improving oxygenation and lung mechanics, attenuating diaphragm and distal organ injury has to be better elucidated. In the present study, we tested the hypothesis that a single early intravenous dose of glutamine was associated not only with the improvement of lung morpho-function, but also the reduction of the inflammatory process and epithelial cell apoptosis in kidney, liver, and intestine villi. Seventy-two Wistar rats were randomly assigned into four groups. Sepsis was induced by cecal ligation and puncture surgery (CLP), while a sham operated group was used as control (C). One hour after surgery, C and CLP groups were further randomized into subgroups receiving intravenous saline (1 ml, SAL) or glutamine (0.75 g/kg, Gln). At 48 hours, animals were anesthetized, and the following parameters were measured: arterial oxygenation, pulmonary mechanics, and diaphragm, lung, kidney, liver, and small intestine villi histology. At 18 and 48 hours, Cytokine-Induced Neutrophil Chemoattractant (CINC)-1, interleukin (IL)-6 and 10 were quantified in bronchoalveolar and peritoneal lavage fluids (BALF and PLF, respectively). CLP induced: a) deterioration of lung mechanics and gas exchange; b) ultrastructural changes of lung parenchyma and diaphragm; and c) lung and distal organ epithelial cell apoptosis. Glutamine improved survival rate, oxygenation and lung mechanics, minimized pulmonary and diaphragmatic changes, attenuating lung and distal organ epithelial cell apoptosis. Glutamine increased IL-10 in peritoneal lavage fluid at 18 hours and bronchoalveolar lavage fluid at 48 hours, but decreased CINC-1 and IL-6 in BALF and PLF only at 18 hours. In an experimental model of abdominal sepsis, a single intravenous dose of glutamine administered after sepsis induction may modulate the inflammatory process reducing not only the risk of lung injury, but also distal organ impairment. These results suggest that intravenous glutamine may be a potentially beneficial therapy for abdominal sepsis.


Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning.
Mice carrying mutations in Wise (Sostdc1) display defects in many aspects of tooth development, including tooth number, size and cusp pattern. To understand the basis of these defects, we have investigated the pathways modulated by Wise in tooth development. We present evidence that, in tooth development, Wise suppresses survival of the diastema or incisor vestigial buds by serving as an inhibitor of Lrp5- and Lrp6-dependent Wnt signaling. Reducing the dosage of the Wnt co-receptor genes Lrp5 and Lrp6 rescues the Wise-null tooth phenotypes. Inactivation of Wise leads to elevated Wnt signaling and, as a consequence, vestigial tooth buds in the normally toothless diastema region display increased proliferation and continuous development to form supernumerary teeth. Conversely, gain-of-function studies show that ectopic Wise reduces Wnt signaling and tooth number. Our analyses demonstrate that the Fgf and Shh pathways are major downstream targets of Wise-regulated Wnt signaling. Furthermore, our experiments revealed that Shh acts as a negative-feedback regulator of Wnt signaling and thus determines the fate of the vestigial buds and later tooth patterning. These data provide insight into the mechanisms that control Wnt signaling in tooth development and into how crosstalk among signaling pathways controls tooth number and morphogenesis.


Molecular attochemistry in non-polar liquid environments: ultrafast charge migration dynamics through gold-thiolate and gold-selenolate linkages.
Molecular attosecond science has already started contributing to our fundamental understanding of ultrafast purely electron dynamics in isolated molecules under vacuum. Extending attosecond science to the liquid phase is expected to offer new insight into the influence of a surrounding solvent environment on the attosecond electron dynamics in solvated molecules. A systematic theoretical investigation of the attochemistry of solvated molecules would help one design attosecond experiments under ambient conditions to explore the attochemistry in a liquid environment. With this goal in mind, for the first time, we have explored the attochemistry of molecules surrounded by different non-polar solvent environments. For this work, we have focused on the attosecond charge conduction through gold-thiolate and gold-selenolate linkages following the vertical ionization of the S/Se(CH3)-CH2-phenyl-X unit anchored to a gold dimeric cluster (Au2), where X represents either a strong electron donating N(CH3)2 group or a strong electron withdrawing NO2 group. To model solvation effects on the attochemistry of molecules containing gold-chalcogen linkages, we have used an implicit solvent model (Polarizable Continuum Model) under the density functional theory (DFT) formalism for non-polar solvents. We have found that the charge migration time scale in molecules becomes faster in the presence of the solvent environment as compared to that under vacuum. Charge oscillation does not damp quickly in molecules surrounded by the solvent environment as compared to that under vacuum. Furthermore, the direction of the charge migration may change in molecules when they are surrounded by the solvent environment as compared to that under vacuum. Thus, the present work has laid the foundation, for the first time, for thinking of the attochemistry into the realm of liquids.


Interaction of amyotrophic lateral sclerosis (ALS)-related mutant copper-zinc superoxide dismutase with the dynein-dynactin complex contributes to inclusion formation.
An important consequence of protein misfolding related to neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), is the formation of proteinaceous inclusions or aggregates within the central nervous system. We have previously shown that several familial ALS-linked copper-zinc superoxide dismutase (SOD1) mutants (A4V, G85R, and G93A) interact and co-localize with the dynein-dynactin complex in cultured cells and affected tissues of ALS mice. In this study, we report that the interaction between mutant SOD1 and the dynein motor plays a critical role in the formation of large inclusions containing mutant SOD1. Disruption of the motor by overexpression of the p50 subunit of dynactin in neuronal and non-neuronal cell cultures abolished the association between aggregation-prone SOD1 mutants and the dynein-dynactin complex. The p50 overexpression also prevented mutant SOD1 inclusion formation and improved the survival of cells expressing A4V SOD1. Furthermore, we observed that two ALS-linked SOD1 mutants, H46R and H48Q, which showed a lower propensity to interact with the dynein motor, also produced less aggregation and fewer large inclusions. Overall, these data suggest that formation of large inclusions depends upon association of the abnormal SOD1s with the dynein motor. Whether the misfolded SOD1s directly perturb axonal transport or impair other functional properties of the dynein motor, this interaction could propagate a toxic effect that ultimately causes motor neuron death in ALS.


[Intravascular lymphomatosis of the nervous system--case report and review of the literature].
We report on a typical case of intravascular lymphomatosis, a rarely diagnosed, generalised intravascular lymphoma usually of the B-cell type. In most cases there is a lack of clear haematological findings but in more than 50% intravascular lymphomatosis presents with symptoms of the central nervous system. Every rapidly progressive neurological deficit, especially the association of a subacute dementia with a spinal syndrome may suggest IVL-NS. However, careful examination may detect minor features for a systemic process in 25-80% i.e. B-symptoms elevation of ESR and LDH. Neurological imaging demonstrates multifocal lesions in the CNS with affinity to the deep white matter consistent with a microvascular or demyelinating disease. Angiographically IVL-NS may mimic cerebral vasculitis. CSF findings are nonspecific. Because diagnosis can only be made histologically, a cerebral biopsy should be undertaken in suspected cases. Usually the course of the disease is fatal. Therapy involving steroids, combination polychemotherapy or radiation met with only minor success.


Prevalence and sociodemographic determinants of tobacco use in four countries of the World Health Organization: South-East Asia region: findings from the Global Adult Tobacco Survey.
Tobacco use is a leading cause of deaths and Disability Adjusted Life Years lost worldwide, particularly in South-East Asia. Health risks associated with exclusive use of one form of tobacco alone has a different health risk profile when compared to dual use. In order to tease out specific profiles of mutually exclusive categories of tobacco use, we carried out this analysis. The Global Adult Tobacco Survey (GATS) data was used to describe the profiles of three mutually exclusive tobacco use categories ("Current smoking only," "Current smokeless tobacco [SLT] use only," and "Dual use") in four World Health Organization South-East Asia Region countries, namely Bangladesh, India, Indonesia and Thailand. GATS was a nationally representative household-based survey that used a stratified multistage cluster sampling design proportional to population size. Prevalence of different forms of usage were described as proportions. Logistics regression analyses was performed to calculate odds ratios (OR) with 95% confidence intervals. All analyses were weighted, accounted for the complex sampling design and conducted using SPSS version 18. The prevalence of different forms of tobacco use varied across countries. Current tobacco use ranged from 27.2% in Thailand to 43.3% in Bangladesh. Exclusively smoking was more common in Indonesia (34.0%) and Thailand (23.4%) and less common in Bangladesh (16.1%) and India (8.7%). Exclusively using SLT was more common in Bangladesh (20.3%) and India (20.6%) and less common on Indonesia (0.9%) and Thailand (3.5%). Dual use of smoking and SLT was found in Bangladesh (6.8%) and India (5.3%), but was negligible in Indonesia (0.8) and Thailand (0.4%). Gender, age, education and wealth had significant effects on the OR for most forms of tobacco use across all four countries with the exceptions of SLT use in Indonesia and dual use in both Indonesia and Thailand. In general, the different forms of tobacco use increased among males and with increasing age; and decreased with higher education and wealth. The results for urban versus rural residence were mixed and frequently not significant once controlling for the other demographic factors. This study addressed the socioeconomic disparities, which underlie health inequities due to tobacco use. Tobacco control activities in these countries should take in account local cultural, social and demographic factors for successful implementation.


Enhanced kinetic stability of [Pd2L4](4+) cages through ligand substitution.
There is considerable interest in exploiting metallosupramolecular cages as drug delivery vectors. Recently, we developed a [Pd2L4](4+) cage capable of binding two molecules of cisplatin. Unfortunately, this first generation cage was rapidly decomposed by common biologically relevant nucleophiles. In an effort to improve the kinetic stability of these cage architectures here we report the synthesis of two amino substituted tripyridyl 2,6-bis(pyridin-3-ylethynyl)pyridine () ligands (with amino groups either in the 2-() or 3-() positions of the terminal pyridines) and their respective [Pd2()4](4+) cages. These systems have been characterised by (1)H, (13)C and DOSY NMR spectroscopies, high resolution electrospray mass spectrometry, elemental analysis and, in one case, by X-ray crystallography. It was established, using model palladium(ii) N-heterocyclic carbene (NHC) probe complexes, that the amino substituted compounds were stronger donor ligands than the parent system ( > > ). Competition experiments with a range of nucleophiles showed that these substitutions lead to more kinetically robust cage architectures, with [Pd2()4](4+) proving the most stable. Biological testing on the three ligands and cages against A549 and MDA-MB-231 cell lines showed that only [Pd2()4](4+) exhibited any appreciable cytotoxicity, with a modest IC50 of 36.4 ± 1.9 μM against the MDA-MB-231 cell line. Unfortunately, the increase in kinetic stability of the [Pd2()4](4+) cages was accompanied by loss of cisplatin-binding ability.


Effect of antibodies on the expression of Plasmodium falciparum circumsporozoite protein gene.
Antibodies are known to play an important role in the control of malaria infection. However, they can modulate parasite development enhancing infection. The effect of anti-Plasmodium antibodies on the expression of circumsporozoite protein gene (csp) was investigated. Plasmodium falciparum 3D7 in vitro cultures were submitted to: i) anti- circumsporozoite protein monoclonal antibody (anti-CSP-mAb) [1microg/ml, 0.1microg/ml, 0.01microg/ml and 0.001microg/ml] and ii) purified IgG Fab fragment from a pool of malaria patients [1mg/ml and 1microg/ml]; and compared to control cultures. After 24h the number of ring infected erythrocytes was determined in order to calculate invasion efficacy. At 48h culture supernatant was collected, and the amount of circumsporozoite protein determined by ELISA, parasitaemia was calculated and cells were processed for RNA preparation. Expression of csp gene was quantified using Real time RT-PCR. There was an increase in parasite growth when treated with lower anti-CSP-mAb concentration, which was associated with lower csp expression, while 1mug/ml anti-CSP-mAb treatment presented a growth inhibitory effect accompanied by high csp expression.


Effect of quercetin on bone formation.
Quercetin is a flavonol, also a phytoestrogen, available commonly in onions and apples. Our laboratory compared the amount of new bone produced by quercetin in a collagen matrix to that produced by bone grafts and a collagen matrix. Eighteen bone defects, 5 x 10 mm were created in the parietal bone of nine New Zealand White rabbits. In the experimental group, six defects were grafted with quercetin solution mixed with a collagen matrix. In the control groups, six defects were grafted with a collagen matrix alone (active control) and six were left empty (passive control). Animals were killed on day 14 and the defects were dissected and prepared for histological assessment. Serial sections were cut across each defect. Quantitative analysis of new bone formation was made on 100 sections (50 sections for each group) using image analysis. A total of 556% more new bone was present in defects grafted with quercetin in a collagen matrix than those grafted with a collagen matrix alone. No bone was formed in the passive control group. In conclusion, quercetin in a collagen matrix has the effect of increasing new bone formation locally, and can be used as a bone graft material.