Sjögren's Syndrome Antigen B Acts as an Endogenous Danger Molecule to Induce Interleukin-8 Gene Expression in Polymorphonuclear Neutrophils.
Sjögren's syndrome antigen B is expressed in the nucleus and surface membrane of human polymorphonuclear neutrophils and is released after cell death. However, its biological role is not clear. This study is aimed to investigate the effect of Sjögren's syndrome antigen B on human polymorphonuclear neutrophils. Human recombinant Sjögren's syndrome antigen B (rSSB) purified from E. coli was incubated with human polymorphonuclear neutrophils as well as retinoid acid-induced granulocytic differentiated HL-60 cells, HL-60 (RA). Interleukin (IL)-8 protein production and mRNA expressions were measured by enzyme-linked immunosorbent assay and quantitative-polymerase chain reaction, respectively. Uptake of fluorescein isothiocyanate (FITC)-rSSB was assessed by flow cytometry and fluorescence microscopy. Moreover, mitogen-activated protein kinase (MAPK) pathways and nuclear factor-kappaB activation were investigated. Human rSSB stimulated IL-8 production from normal human neutrophils and HL-60 (RA) cells in a time- and dose-dependent manner. This IL-8-stimulated activity was blocked by chloroquine and NH4Cl, indicating that endosomal acidification is important for this effect. We found rSSB activated both MAPK pathway and nuclear factor-kappaB signaling to transcribe the IL-8 gene expression of cells. Furthermore, tumor necrosis factor-α exerted an additive effect and rSSB-anti-SSB immune complex exhibited a synergistic effect on rSSB-induced IL-8 production. Sjögren's syndrome antigen B might act as an endogenous danger molecule to enhance IL-8 gene expression in human polymorphonuclear neutrophils.


Testing the Effectiveness of a Blended Intervention to Reduce Suicidal Ideation among School Adolescents in Chile: A Protocol for a Cluster Randomized Controlled Trial.
Suicidal ideation is prevalent in adolescents and is a marker for subsequent psychiatric vulnerability and symptom severity. Literature shows that blended care (integrating online and offline components in a treatment process) could improve the effectiveness and adherence of interventions targeting suicidal ideation in adolescents, but the evidence is inconclusive. Thus, we will test the effectiveness of a blended intervention to reduce suicidal ideation (primary outcome) in school settings using a single-blind two-armed cluster randomized controlled trial (cRCT). The internet-based component corresponds to the Reframe-IT, a program encompassing eight online sessions based on cognitive-behavioral therapy (CBT) principles. The face-to-face intervention will be delivered through four CBT sessions. Additionally, we will assess the effect of the intervention on the following secondary outcomes: suicidal attempts, depressive symptoms, hopelessness, emotional regulation, and problem-solving skills. Primary and secondary outcomes will be assessed at post-intervention, 3-month, 6-month, and 12-month follow-up. Finally, we will explore the mediation role of cognitive, emotional, and behavioral correlates of suicide on the effect of the intervention. Results will inform whether the intervention can reduce suicide among school adolescents and be implemented on a large scale in Chile.


RECPAM analysis of prognostic factors in patients with stage III breast cancer.
A retrospective chart review was conducted of women with stage III breast cancer seen at the Princess Margaret Hospital between January 1977 and December 1980. Three hundred and sixty-nine patients were available for analysis. These cases were evaluated to determine the prognostic factors of patients presenting with this stage of the disease using a recursive partitioning technique, RECPAM, and a Cox regression model. A non-mathematical description of RECPAM is presented and the advantages of RECPAM over Cox analysis are discussed. The results identify primary tumour size, axillary node involvement, internal mammary node involvement, and estrogen receptor status as the most important prognostic variables. RECPAM identified 3 prognostic groups and simultaneously provided rules based on the prognostic variables to assign patients to poor, intermediate, or good prognosis categories. Patients with estrogen receptor negative tumours, or those with axillary node involvement, primary tumours greater than 5 cm, and serum alkaline phosphatase greater than 60 IU/L, or those with internal mammary node involvement, no skin changes, and serum alkaline phosphatase greater than 60 IU/L, define a group with a poor prognosis. Patients with estrogen receptor positive tumours, no axillary node involvements, and primary tumours greater than 5 cm, or estrogen receptor positive tumours, axillary node involvement, primary tumours greater than 5 cm, but serum alkaline phosphatase less than or equal to 60 U/L, have an intermediate prognosis. The good prognosis group consists of those patients with estrogen receptor positive tumours who have either skin changes or primary tumours less than or equal to 5 cm. The effect of loco-regional and systemic therapy was assessed and there was no association between treatment assignment and prognostic group. On the basis of this RECPAM analysis, we have defined important prognostic variables to be used in the design of clinical trials, and three major patient subgroups which can be used in routine oncologic practice as a guide to patient management.


Radioprotective effect of American ginseng on human lymphocytes at 90 minutes postirradiation: a study of 40 cases.
Ionizing radiation (IR) initiates intracellular oxidative stress through enhanced formation of reactive oxygen species (ROS) that attack DNA leading to cell death. Because of the diversity of IR applied in medicine, agriculture, industry, and the growing threats of global terrorism, the acquisition of radioprotectors is an urgent need for the nation. However, the applicability of radioprotectors currently under investigation is limited due to their inherent toxicity. This study investigated the effect of a standardized North American ginseng extract (NAGE, total ginsenoside content: 11.7%) on DNA damage in human lymphocytes at 90 minutes postirradiation. With the application of NAGE (250-1000 microg mL(-1)) at 90 minutes postirradiation (1 and 2 Gy), DNA damage in lymphocytes obtained from 40 healthy individuals was evaluated by cytokinesis-block micronucleus assay. Similar experiments were also performed in lymphocytes treated with WR-1065 (1 mmol/L or 3 mmol/L). In addition, before and after irradiation, lymphocytes obtained from 10 individuals were measured for their total antioxidant capacity (TAC) and the reactive oxygen species (ROS). The significant effect of NAGE against (137)Cs-induced micronuclei (MN) in lymphocytes is concentration dependent. NAGE (750 microg mL(-1)) reduced MN yield by 50.7% after 1 Gy and 35.9% after 2 Gy exposures, respectively; these results were comparable to that of WR-1065. Furthermore, we also found that NAGE reduces MN yield and ROS but increases TAC in lymphocytes. Our results suggest that NAGE is a relatively nontoxic natural compound that holds radioprotective potential in human lymphocytes even when applied at 90 minutes postirradiation. One of the radioprotective mechanisms may be mediated through the scavenging of free radicals and enhancement of the intracellular TAC.


Energy Landscapes of a Pair of Adsorbed Peptides.
The wide relevance of peptide adsorption in natural and synthetic contexts means it has attracted much attention. Molecular dynamics (MD) simulation has been widely used in these endeavors. Much of this has focused on single peptides due to the computational effort required to capture the rare events that characterize their adsorption. This focus is, however, of limited practical relevance as in reality, most systems of interest operate in the nondilute regime where peptides will interact with other adsorbed peptides. As an alternative to MD simulation, we have used energy landscape mapping (ELM) to investigate two met-enkephalin molecules adsorbed at a gas/graphite interface. Major conformations of the adsorbed peptides and the connecting transition states are elucidated along with the associated energy barriers and rates of exchange. The last of these makes clear that MD simulations are currently of limited use in probing the co-adsorption of two peptides, let alone more. The constant volume heat capacity as a function of temperature is also presented. Overall, this study represents a significant step toward characterizing peptide adsorption beyond the dilute limit.


Carotid artery endoscopy (autopsy).
Intra-arterial endoscopy of the common carotid artery and its bifurcation was accomplished in 100 random autopsy cases. Resulting still photographs and movies reveal fatty dots and streaks, elevated gelatinous plaques, mural thrombi, thrombosis, ulcerations and ulcers with or without organizing thrombi, boulder and stalagmite-shaped lesions, bridging and elevated plaques in the carotid artery. These findings suggest possible explanations for some surgical and angiographic complications, bruits, transient ischemic attacks or strokes following reportedly normal carotid angiograms. Endoscopy aids in understanding the theories of inception, progression and sequelae of atherosclerosis,the role of risk factors, trauma and hemodynamics.


Ethical considerations in design of a study to evaluate a US Food and Drug Administration-approved indication: antivenom versus placebo for copperhead envenomation.
In 2000, the US Food and Drug Administration approved CroFab(®) Crotalidae Polyvalent Immune Fab, ovine (FabAV), which had received orphan drug designation, for use in patients with minimal to moderate North American crotaline envenomations including copperhead snakes. As existing evidence on the effectiveness of FabAV for this indication is limited, wide practice variation in its use exists. In order to provide more definitive clinical evidence as to the role of this treatment, a new randomized, placebo-controlled trial of FabAV specifically for copperhead bites was initiated. In light of the existing US Food and Drug Administration approval, ethical considerations of participation in this trial have been raised. We discuss the ethical principles pertinent to this randomized, placebo-controlled trial with placebo arm. We apply an accepted framework for ethical research to this trial. Due to the evidence gap in the literature, wide-ranging treatment recommendations by medical experts, and broad practice variation, clinical equipoise exists in the treatment of copperhead envenomation with FabAV. The impact of this clinical equipoise on the value and scientific validity of the trial is discussed. The trial's risk-benefit ratio is also considered. Potential risks to the patients are minimized as the protocol includes a plan for rescue therapy in the event that patients progress to severe envenomation symptoms. Overall, risks are further minimized by the inclusion of an interim analysis with stopping rules based on demonstrated efficacy should the therapy clearly prove to be beneficial. Although a post-marketing clinical study of this nature is unusual for an approved indication, this trial adheres to all ethical preconditions found in existing guidelines for clinical research involving human subjects.


Individuality of the Extremely Premature Infant Gut Microbiota Is Driven by Ecological Drift.
The initial contact between humans and their colonizing gut microbiota after birth is thought to have expansive and long-lasting consequences for physiology and health. Premature infants are at high risk of suffering from lifelong impairments, due in part to aberrant development of gut microbiota that can contribute to early-life infections and inflammation. Despite their importance to health, the ecological assembly and succession processes governing gut microbiome composition in premature infants remained incompletely understood. Here, we quantified these ecological processes in a spatiotemporally resolved 16S rRNA gene amplicon sequencing data set of 60 extremely premature neonates using an established mathematical framework. We found that gut colonization during the first months of life is predominantly stochastic, whereby interindividual diversification of microbiota is driven by ecological drift. Dispersal limitations are initially small but have increasing influence at later stages of succession. Furthermore, we find similar trends in a cohort of 32 healthy term-born infants. These results suggest that the uniqueness of individual gut microbiota of extremely premature infants is largely due to stochastic assembly. IMPORTANCE Our knowledge concerning the initial gut microbiome assembly in human neonates is limited, and scientific progression in this interdisciplinary field is hindered due to the individuality in composition of gut microbiota. Our study addresses the ecological processes that result in the observed individuality of microbes in the gastrointestinal tract between extremely premature and term-born infants. We find that initial assembly is mainly driven by neutral ecological processes. Interestingly, while this progression is predominantly random, limitations to the dispersal of microbiota between infants become increasingly important with age and are concomitant features of gut microbiome stability. This indicates that while we cannot predict gut microbiota assembly due to its random nature, we can expect the establishment of certain ecological features that are highly relevant for neonatal health.


Cigarette Smoking and Intracranial Aneurysms: A Pilot Analysis of SNPs in the CYP2A6 Gene in the Italian Population.
Cigarette smoking is a modifiable risk factor associated with formation and rupture of intracranial aneurysms (IAs). Cytochrome P450 2A6 (CYP2A6) is the main enzyme implied in catabolism of nicotine and xenobiotics, giving rise to oxidative stress products. Our study investigated the associations between specific single-nucleotide polymorphisms (SNPs) in the CYP2A6 gene and the presence of sporadic IAs in a cluster of Italian patients, as well as their rupture regarding cigarette smoking habit. Three hundred and thirty-one Italian patients with sporadic IAs were recruited in a single institution. We recorded data on clinical onset with subarachnoid hemorrhage (SAH) and smoking habit. Genetic analysis was performed with a standard procedure on peripheral blood samples: CYP2A6 ∗1B2, CYP2A6 ∗2, and CYP2A6 ∗14 SNPs were analyzed in the study group along with 150 healthy control subjects. Statistical analysis was conducted according to genetic association study guidelines. In the patient cohort, the frequency of aSAH was significantly higher in current smokers (P < 0.001; OR=17.45), regardless of the pattern of CYP2A6 SNPs. There was a correlation between IA rupture and cigarette smoking in patients with the heterozygous CYP2A6 ∗1B2 allele (P < 0.001; OR=15.47). All patients carrying the heterozygous CYP2A6 ∗14 allele had an aSAH event (100%), regardless of smoking habit, although this correlation was not statistically significant (P = 1). According to our findings, a cigarette smoker carrying a fully active CYP2A6 enzyme (heterozygous ∗1B2 allele) may have an increased risk of IA rupture compared to those with functionally less active variants: further investigation on a larger sample is needed to verify this result. The role of the heterozygous CYP2A6 ∗14 allele in aSAH is yet to be clarified.


Quality of life and fear of COVID-19 in 2600 baccalaureate nursing students at five universities: a cross-sectional study.
The COVID-19 pandemic has caused significant disruptions in the implementation of programs across educational institutions. Nursing students, being both young adults and by practical training, part of the health care system, may be particularly vulnerable during the COVID-19 pandemic. The purpose of this study was to explore the associations between self-reported fear of COVID-19, general health, psychological distress and overall quality of life (QoL) in a sample of Norwegian baccalaureate nursing students compared to reference data. The survey targeted baccalaureate nursing students from five universities in February 2021. An electronic questionnaire consisted of the Fear of COVID-19 Scale (FCV-19S), the Hopkins Symptom Checklist 5 (SCL-5), one general health and one overall QoL question. The respondents' mean scores were compared to reference data. Hierarchical regression analyses were conducted, and effect sizes (Cohen's d) were evaluated. In total, 2605 out of 6088 (43%) students responded. Their FCV-19S scores (mean 2.45, CI 2.42, 2.48) were significantly higher than those of the reference population (mean 1.8, P < 0.001). Nursing students scores showed significantly lower general health (mean 3.50 ± 0.93 SD, population mean = 3.57, Cohen's d = 0.07), higher levels of psychological distress (mean 2.68 ± 1.03 SD, population mean = 2.12, Cohen's d = 0.55) and lower overall QoL (mean 5.50 ± 2.16 SD, population mean = 8.00, Cohen's d = 1.16) compared to pre-pandemic reference data. FCV-19S scores were significantly associated with levels of general health (Cohen's d = 0.26), psychological distress (Cohen's d = 0.76) and overall QoL (Cohen's d = 0.18). Baccalaureate nursing students reported worse outcomes during the Covid-19 pandemic on general health, psychological distress and overall QoL compared to the reference population. Level of fear of Covid-19, however, accounted for few of these differences. Other factors related to the pandemic may have reduced nursing students' overall QoL.


Spatial representation and attention in toddlers with Williams syndrome and Down syndrome.
The nature of the spatial representations that underlie simple visually guided actions early in life was investigated in toddlers with Williams syndrome (WS), Down syndrome (DS), and healthy chronological age- and mental age-matched controls, through the use of a "double-step" saccade paradigm. The experiment tested the hypothesis that, compared to typically developing infants and toddlers, and toddlers with DS, those with WS display a deficit in using spatial representations to guide actions. Levels of sustained attention were also measured within these groups, to establish whether differences in levels of engagement influenced performance on the double-step saccade task. The results showed that toddlers with WS were unable to combine extra-retinal information with retinal information to the same extent as the other groups, and displayed evidence of other deficits in saccade planning, suggesting a greater reliance on sub-cortical mechanisms than the other populations. Results also indicated that their exploration of the visual environment is less developed. The sustained attention task revealed shorter and fewer periods of sustained attention in toddlers with DS, but not those with WS, suggesting that WS performance on the double-step saccade task is not explained by poorer engagement. The findings are also discussed in relation to a possible attention disengagement deficit in WS toddlers. Our study highlights the importance of studying genetic disorders early in development.


Metamaterial perfect absorbers with solid and inverse periodic cross structures for optoelectronic applications.
Metamaterial based on a metal/insulator/metal (MIM) tri-layer structure provides an agile platform to realize high absorption efficiency for a variety of applications including semiconductor optoelectronic detectors. In this work, we use the finite time domain difference (FDTD) method and coupled mode theory (CMT) to numerically study metal/semiconductor/metal (MSM) structures and discuss their effective absorption for optoelectronic application. We compare MSM structures with a different top metal layer design and find that cross shaped absorber (CSA) and it's complementary cross shaped absorber (CCSA) exhibit different phase diagrams due to a distinctive dependence of radiation loss on geometrical parameters. Our results show that CSA (CCSA) structures are suitable for thinner (thicker) sandwiched semiconductor with a larger (smaller) imaginary part of its dielectric constant. The necessary condition to realize a maximum figure of merit (FOM) value for effective absorption is discussed in comparison with the perfect absorber condition. Our work may provide guidelines to design the general light-harvesting optoelectronic devices with high efficiencies based on metamaterial-semiconductor hybrid systems.


[Monitoring of contamination of foodstuffs with elements noxious to human health. Part II. Mineral waters, soft drinks, fruits, nuts, rice, soybeans, fish and seafood].
Results of the 5-years cycle (2004-2008) monitoring investigations on food contamination with elements noxious to human health, involving testing of mineral waters and soft drinks (226 samples), fruits (467 samples), rice (234 samples), soybeans (236 samples), nuts and peanuts (237 samples), fish and seafood (237 samples) are discussed. The parties involved in testing were: laboratories of State Sanitary Inspection and the national reference laboratory of the Department of Food and Consumer Articles Research of National Institute of Public Health - National Institute of Hygiene. The reported metals contents did not give rise to health concerns, remaining generally below the levels set forth in food legislation and being comparable with contamination levels reported in other European countries; and for cadmium--often lower. Health hazard assessment was performed taking into account the mean contamination levels obtained and average domestic consumption of these food products groups in Poland. The highest intake expressed as the percentage of provisional tolerable weekly intake (PTWI) was obtained for mercury in fish, which has reached mean 3.2% PTWI. Controlled fish consumption recommendations should be adhered to by prospective mothers, pregnant women, breast-feeding women and young children. Lead and arsenic intake with mineral waters and soft drinks comprises approx. 15% of total intake of these elements with food.


The leptin defense against wasting is abolished in the IL-2-deficient mouse model of inflammatory bowel disease.
Anorexia is a major complication of inflammatory bowel disease (IBD). We postulated that chronic intestinal inflammation with increased proinflammatory cytokines elevates serum leptin concentration, thereby contributing to anorexia. This hypothesis was studied in interleukin-2-deficient (IL-2(-/-)) mice, a model of IBD with elevated proinflammatory cytokine production. IL-2(-/-), wild-type pair-fed and wild-type control male mice (8 wk old) were fed regular laboratory mouse food for 2 wk. The IL-2(-/-) and pair-fed groups consumed less food and lost weight. Serum leptin concentrations in the IL-2(-/-) mice in the fed state were lower than controls, but not different from pair-fed mice, and paradoxically increased in the starved state to levels significantly higher than both starved control and pair-fed groups. This result did not change when serum leptin was adjusted for amount of body fat. These data show abnormal leptin responses in IL-2(-/-) mice with increased leptin concentrations disproportionate to fat mass and prevention of the normal decline in leptin with food restriction.


HPLC-DAD-ESI-MS(2) analytical profile of extracts obtained from purple sweet potato after green ultrasound-assisted extraction.
Ultrasound pre-treatment (UAE) was applied to assist the extraction of valuable compounds (polyphenols (especially anthocyanins), and proteins) from purple sweet potato (PSP). Under optimum conditions (ultrasound time (40min); supplementary hot extraction (80°C) up to 120min; pH: 2.5; ethanol concentration: 58%), the highest concentrations of polyphenols (3.877mg/g), anthocyanins (0.293mg/g), and proteins (0.753mg/g) were found, with minimal specific energy consumption (8406J/mg). Moreover, anthocyanin and non-anthocyanin polyphenols in PSP extract from optimized extraction temperature were identified using HPLC-DAD-ESI-MS(2). The major identified anthocyanins were peonidin-3-caffeoyl-p-hydroxybenzoyl sophoroside-5-glucoside, peonidin-3-(6″-caffeoyl-6‴-feruloyl sophoroside)-5-glucoside, cyanidin-3-caffeoyl-p-hydroxybenzoyl sophoroside-5-glucoside, whereas the major identified non-anthocyanin molecules were quinic acid, chlorogenic acid, caffeic acid, and chlorogenic acid-3-glucose. The amount of the predominant anthocyanin and non-anthocyanin compounds from PSP extract obtained after UAE was higher than that extracted after conventional solvent extraction. The results obtained in this work demonstrated the efficiency of UAE for the recovery of anthocyanins from PSP.


MRI findings in 77 children with non-syndromic autistic disorder.
The clinical relevance of MR scanning in children with autism is still an open question and must be considered in light of the evolution of this technology. MRI was judged to be of insufficient value to be included in the standard clinical evaluation of autism according to the guidelines of the American Academy of Neurology and Child Neurology Society in 2000. However, this statement was based on results obtained from small samples of patients and, more importantly, included mostly insufficient MRI sequences. Our main objective was to evaluate the prevalence of brain abnormalities in a large group of children with a non-syndromic autistic disorder (AD) using T1, T2 and FLAIR MRI sequences. MRI inspection of 77 children and adolescents with non-syndromic AD (mean age 7.4+/-3.6) was performed. All met the DSM-IV and ADI -R criteria for autism. Based on recommended clinical and biological screenings, we excluded patients with infectious, metabolic or genetic diseases, seizures or any other neurological symptoms. Identical MRI inspections of 77 children (mean age 7.0+/-4.2) without AD, developmental or neurological disorders were also performed. All MRIs were acquired with a 1.5-T Signa GE (3-D T1-FSPGR, T2, FLAIR coronal and axial sequences). Two neuroradiologists independently inspected cortical and sub-cortical regions. MRIs were reported to be normal, abnormal or uninterpretable. MRIs were judged as uninterpretable in 10% (8/77) of the cases. In 48% of the children (33/69 patients), abnormalities were reported. Three predominant abnormalities were observed, including white matter signal abnormalities (19/69), major dilated Virchow-Robin spaces (12/69) and temporal lobe abnormalities (20/69). In all, 52% of the MRIs were interpreted as normal (36/69 patients). An unexpectedly high rate of MRI abnormalities was found in the first large series of clinical MRI investigations in non-syndromic autism. These results could contribute to further etiopathogenetic research into autism.


Iron sucrose in hemodialysis patients: safety of replacement and maintenance regimens.
Parenteral iron replacement and maintenance are frequently required in hemodialysis patients. However, serious adverse events have been reported after single doses of some intravenous iron products. This multicenter phase IV clinical trial examined the safety of iron sucrose for the treatment of iron deficiency and for the maintenance of iron sufficiency in hemodialysis patients. In this safety study, iron sucrose was given in two dosing regimens. Iron deficient patients were treated with intravenous iron sucrose, 100 mg, during 10 consecutive hemodialysis sessions (replacement regimen). Iron replete patients were given iron sucrose, 100 mg intravenous (iv) over 5 minutes, weekly for 10 weeks (maintenance regimen). At the end of each 10-dose cycle, iron status was reassessed, and dosing during the subsequent cycle was based on the adequacy of iron stores as per Dialysis Outcome Quality Initiative (K/DOQI) Guidelines. With each dosing regimen, adverse events, if any, were recorded and described. Six hundred and sixty-five hemodialysis patients, including 80 who had experienced previous intolerance to other parenteral iron preparations, received a total of 8583 doses of iron sucrose. One hundred eighty-eight patients received more than one iv iron cycle (replacement, maintenance, or both). There were no serious or life-threatening drug-related adverse events. Iron sucrose is safe when given as treatment for iron deficiency or for maintenance of iron stores.


Axonopathy is a compounding factor in the pathogenesis of Krabbe disease.
Loss-of-function of the lysosomal enzyme galactosyl-ceramidase causes the accumulation of the lipid raft-associated sphingolipid psychosine, the disruption of postnatal myelination, neurodegeneration and early death in most cases of infantile Krabbe disease. This work presents a first study towards understanding the progression of axonal defects in this disease using the Twitcher mutant mouse. Axonal swellings were detected in axons within the mutant spinal cord as early as 1 week after birth. As the disease progressed, more axonopathic profiles were found in other regions of the nervous system, including peripheral nerves and various brain areas. Isolated mutant neurons recapitulated axonal and neuronal defects in the absence of mutant myelinating glia, suggesting an autonomous neuronal defect. Psychosine was sufficient to induce axonal defects and cell death in cultures of acutely isolated neurons. Interestingly, axonopathy in young Twitcher mice occurred in the absence of demyelination and of neuronal apoptosis. Neuronal damage occurred at later stages, when mutant mice were moribund and demyelinated. Altogether, these findings suggest a progressive dying-back neuronal dysfunction in Twitcher mutants.


Photophysical and electrochemical properties, and molecular structures of organic dyes for dye-sensitized solar cells.
Dye-sensitized solar cells (DSSCs) based on organic dyes adsorbed on oxide semiconductor electrodes, such as TiO(2), ZnO, or NiO, which have emerged as a new generation of sustainable photovoltaic devices, have attracted much attention from chemists, physicists, and engineers because of enormous scientific interest in not only their construction and operational principles, but also in their high incident-solar-light-to-electricity conversion efficiency and low cost of production. To develop high-performance DSSCs, it is important to create efficient organic dye sensitizers, which should be optimized for the photophysical and electrochemical properties of the dyes themselves, with molecular structures that provide good light-harvesting features, good electron communication between the dye and semiconductor electrode and between the dye and electrolyte, and to control the molecular orientation and arrangement of the dyes on a semiconductor surface. The aim of this Review is not to make a list of a number of organic dye sensitizers developed so far, but to provide a new direction in the epoch-making molecular design of organic dyes for high photovoltaic performance and long-term stability of DSSCs, based on the accumulated knowledge of their photophysical and electrochemical properties, and molecular structures of the organic dye sensitizers developed so far.


Hard surface biocontrol in hospitals using microbial-based cleaning products.
Healthcare-Associated Infections (HAIs) are one of the most frequent complications occurring in healthcare facilities. Contaminated environmental surfaces provide an important potential source for transmission of many healthcare-associated pathogens, thus indicating the need for new and sustainable strategies. This study aims to evaluate the effect of a novel cleaning procedure based on the mechanism of biocontrol, on the presence and survival of several microorganisms responsible for HAIs (i.e. coliforms, Staphyloccus aureus, Clostridium difficile, and Candida albicans) on hard surfaces in a hospital setting. The effect of microbial cleaning, containing spores of food grade Bacillus subtilis, Bacillus pumilus and Bacillus megaterium, in comparison with conventional cleaning protocols, was evaluated for 24 weeks in three independent hospitals (one in Belgium and two in Italy) and approximately 20000 microbial surface samples were collected. Microbial cleaning, as part of the daily cleaning protocol, resulted in a reduction of HAI-related pathogens by 50 to 89%. This effect was achieved after 3-4 weeks and the reduction in the pathogen load was stable over time. Moreover, by using microbial or conventional cleaning alternatively, we found that this effect was directly related to the new procedure, as indicated by the raise in CFU/m2 when microbial cleaning was replaced by the conventional procedure. Although many questions remain regarding the actual mechanisms involved, this study demonstrates that microbial cleaning is a more effective and sustainable alternative to chemical cleaning and non-specific disinfection in healthcare facilities. This study indicates microbial cleaning as an effective strategy in continuously lowering the number of HAI-related microorganisms on surfaces. The first indications on the actual level of HAIs in the trial hospitals monitored on a continuous basis are very promising, and may pave the way for a novel and cost-effective strategy to counteract or (bio)control healthcare-associated pathogens.


Factors affecting the in vitro release of recombinant human interferon-gamma (rhIFN-gamma) from PLGA microspheres.
A long-acting depot formulation of recombinant human interferon-gamma (rhIFN-gamma) was achieved by microencapsulation of rhIFN-gamma in polylactic-coglycolic acid (PLGA) microspheres by a water-in-oil-in-water technique. The release of protein was assessed with different release devices and buffer systems. The quality of the released protein was quantitated by sodium dodecyl sulfate-size exclusion chromatography, ELISA, and bioactivity assays. The microencapsulation process resulted in an encapsulation efficiency of 100% and the initial release of bioactive, native protein with no subsequent release. Further investigation suggested that the protein did not bind to the PLGA, but a constant and small amount of protein adsorbed to the filter device used for the release studies. The composition of the release media (pH, buffer species, salt concentration, ionic strength, and type and concentration of surfactants) had a profound effect on the in vitro release rate. The effect was mainly due to the differential solubility, stability, and aggregation of rhIFN-gamma in the various systems for protein inside the microspheres or released into the bulk solution. The quality of the protein released from the microspheres was also affected by the buffer media upon storage at 5 degrees C, which, in turn, affected the quantification of released protein. The bicinchoninic acid method typically used to quantitate protein release underestimated protein release because of aggregation. Protein released after several days was less active than the starting material and had lost activity as a result of the inherent instability of rhIFN-gamma at 37 degrees C. The release device, buffer species, pH, and excipients must be assessed in release studies of proteins from polymer matrices because the protein stability and release is dependent on these variables. These studies also indicated that rhIFN-gamma was encapsulated and released from PLGA in a bioactive form, but its stability at 37 degrees C, which was greatly affected by the release conditions, limits the duration of release of native, bioactive protein to 7 days or less.


The SUMO E3 ligase CBX4 is identified as a poor prognostic marker of gastric cancer through multipronged OMIC analyses.
Gastric cancer (GC) is one of the most common malignancies, with an ever-increasing incidence and high mortality rate. Chromobox4 (CBX4), also named hPC2, is a small ubiquitin-related modifier (SUMO) E3 ligase. Previous studies have found that high CBX4 expression is associated with tumor size, pathologic differentiation and decreased patient survival in hepatocellular carcinoma (HCC). However, the expression and prognostic value of CBX4 in GC have not been clarified. In our study, ONCOMINE, UALCAN, Kaplan-Meier Plotter, cBioPortal, DAVID 6.8 and TIMER were utilized. RT-PCR, immunohistochemistry (IHC), Western blot, CCK-8 assay, cell apoptosis assay, cell cycle assay were used to further verify in GC tissue samples or cell line. The transcriptional and protein level of CBX4 in GC tissues was found significantly elevated and a significant association between the expression of CBX4 and clinicopathological parameters was found in GC patients. Low expression of CBX4 in GC patients were correlated with a significantly improved prognosis. The functions of CBX4 are primarily related to the stem cell pluripotency signaling pathway, Hippo signaling pathway, HTLV-I infection, Notch signaling pathway, and N-glycan biosynthesis. Our results may provide novel insights for the selection of therapeutic targets and prognostic biomarkers for GC.


Reversed phase ion-pair liquid chromatographic determination of nicotine in commercial tobacco products. 2. Cigarettes.
A reversed phase ion-pair liquid chromatographic method for the determination of nicotine in commercial tobacco products was previously developed and optimized (Ciolino, L. A.; Turner, J. A.; McCauley, H. A.; Smallwood, A. W.; Yi, T. Y. J. Chromatogr. 1999a, 852 (2), 451-463) and provided reliable results for the determination of nicotine in commercial moist snuff (Ciolino, L. A.; McCauley, H. A.; Fraser, D. B.; Barnett, D. Y.; Yi, T. Y.; Turner, J. A. J. Agric. Food Chem. 1999b, 47, 3706-3712). The method uses an aqueous-based sample extraction and provides rapid separation of nicotine from the minor tobacco alkaloids and other commercial tobacco components. In the present work, the method is evaluated for the determination of nicotine in commercial cigarettes and compared to both an official AOAC method for total alkaloids in tobacco (AOAC, AOAC Official Methods of Analysis of AOAC International, 16th ed.; AOAC International: Gaithersburg, MD, 1995; pp 30-31), and a published GC method (Lyerly, L. A.; Greene, G. H. Beitr. Tabakforsch. 1976, 8 (6), 359-361). Good agreement was obtained between the ion-pair LC method and the GC method with relative differences in determined nicotine contents of 0.6 to 5% for a series of commercial and reference cigarettes.


Switchable LED-based laparoscopic multispectral system for rapid high-resolution perfusion imaging.
Multispectral imaging (MSI) is an approach for real-time, quantitative, and non-invasive tissue perfusion measurements. Current laparoscopic systems based on mosaic sensors or filter wheels lack high spatial resolution or acceptable frame rates. To develop a laparoscopic system for MSI-based color video and tissue perfusion imaging during gastrointestinal surgery without compromising spatial or temporal resolution. The system was built with 14 switchable light-emitting diodes in the visible and near-infrared spectral range, a 4K image sensor, and a 10 mm laparoscope. Illumination patterns were created for tissue oxygenation and hemoglobin content monitoring. The system was calibrated to a clinically approved laparoscopic hyperspectral system using linear regression models and evaluated in an occlusion study with 36 volunteers. The root mean squared errors between the MSI and reference system were 0.073 for hemoglobin content, 0.039 for oxygenation in deeper tissue layers, and 0.093 for superficial oxygenation. The spatial resolution at a working distance of 45 mm was 156 μm. The effective frame rate was 20 fps. High-resolution perfusion monitoring was successfully achieved. Hardware optimizations will increase the frame rate. Parameter optimizations through alternative illumination patterns, regression, or assumed tissue models are planned. Intraoperative measurements must confirm the suitability during surgery.


Mycotic and non-mycotic coronary artery aneurysms-A review of the rarity.
Sir William Osler coined the term "mycotic" to identify aneurysms secondary to an infectious cause, which may not be necessarily fungal and are caused mainly by bacteria. The literature's reported incidence of coronary artery aneurysms (CAA) is from 1.5-5%. The right coronary artery (RCA) is mainly involved, followed by the left side coronary circulation. Mycotic aneurysms are more commonly associated with infective endocarditis. More recently, coronary artery stents, particularly drug-eluting stents, are typically causing mycotic coronary aneurysms. CT angiography (CTA) has been the forefront diagnostic modality, showing both the lumen and wall of the coronary arteries. It also aids in preoperative planning. MRI is useful in diagnosing and following children with Kawasaki's disease. Smaller mycotic coronary aneurysms may resolve with antibiotic therapy; however, aneurysms more significant than 1-2 cm diameter needs corrective surgery. Early diagnosis and appropriate management are the critical factors in the successful treatment of infective coronary artery aneurysms.


Reduced-intensity modified constraint-induced movement therapy versus conventional therapy for upper extremity rehabilitation after stroke: a multicenter trial.
Constraint-induced movement therapy (CIMT) is a rehabilitation approach for arm paresis consisting of an intensive schedule of treatment (6 h/d). The high demand of resources for CIMT is a critical issue for its implementation in the Italian health system. To compare the effects of a reduced-intensity modified CIMT (mCIMT) program that included splinting the unaffected arm for 12 hours daily with the effects of a conventional rehabilitation program for arm paresis in patients with stroke. Sixty-six participants with hemiparesis (3-24 months poststroke) who could extend the wrist and several fingers at least 10° were randomly assigned to mCIMT or conventional rehabilitation. Each group underwent 10 (2 h/d) treatment sessions (5 d/wk for 2 weeks). Patients were assessed with the Wolf Motor Function Test (WMFT-FA and WMFT-T), the Motor Activity Log (MAL-AOU and MAL-QOM), and the Ashworth Scale before and after treatment and 3 months later. Between-groups analysis showed that the mCIMT group overall had greater improvement than the control group in terms of the WMFT-FA (P = .010), MAL-AOU (P < .001), and MAL-QOM (P < .001). Differences between groups were significant both after treatment (P < .01) and at the 3-month follow-up (P < .01), although 40% of participants did not complete the 3-month assessment. Furthermore, the mCIMT group showed a greater decrease of Ashworth Scale score than the control group at 3 months (P = .021). Two hours of CIMT may be more effective than conventional rehabilitation in improving motor function and use of the paretic arm in patients with chronic stroke.


Nature and properties of lateritic soils derived from different parent materials in Taiwan.
The objective of this study was to investigate the physical, chemical, and mineralogical composition of lateritic soils in order to use these soils as potential commercial products for industrial application in the future. Five lateritic soils derived from various parent materials in Taiwan, including andesite, diluvium, shale stone, basalt, and Pleistocene deposit, were collected from the Bt1 level of soil samples. Based on the analyses, the Tungwei soil is an alfisol, whereas other lateritic soils are ultisol. Higher pH value of Tungwei is attributed to the large amounts of Ca(2+) and Mg(2+). Loupi and Pingchen soils would be the older lateritic soils because of the lower active iron ratio. For the iron minerals, the magnetic iron oxides such as major amounts of magnetite and maghemite were found for Tamshui and Tungwei lateritic soils, respectively. Lepidocrocite was only found in Soka soil and intermediate amounts of goethite were detected for Loupi and Pingchen soils. After Mg-saturated and K-saturated processes, major amounts of mixed layer were observed in Loupi and Soka soils, whereas the montmorillonite was only detected in Tungwei soil. The investigation results revealed that the parent materials would play an important role during soil weathering process and physical, chemical, and mineralogy compositions strongly affect the formation of lateritic soils.


Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women.
The possibility that the heightened cardiovascular risk associated with the menopause, which is said to be ameliorated by soybeans, can be reduced with soy isoflavones was tested in 21 women. Although several were perimenopausal, all have been included. A placebo-controlled crossover trial tested the effects of 80-mg daily isoflavones (45 mg genistein) over 5- to 10-week periods. Systemic arterial compliance (arterial elasticity), which declined with age in this group, improved 26% (P < .001) compared with placebo. Arterial pressure and plasma lipids were unaffected. The vasodilatory capacity of the microcirculation was measured in nine women; high acetylcholine-mediated dilation in the forearm vasculature was similar with active and placebo treatments. LDL oxidizability measured in vitro was unchanged. Thus, one important measure of arterial health, systemic arterial compliance, was significantly improved in perimenopausal and menopausal women taking soy isoflavones to about the same extent as is achieved with conventional hormone replacement therapy.


Under-coracoid-around-clavicle (UCAC) loop in type II distal clavicle fractures.
In Neer type II (Robinson type 3B) fractures of the distal clavicle the medial fragment is detached from the coracoclavicular ligaments and displaced upwards, whereas the lateral fragment, which is usually small, maintains its position. Several fixation techniques have been suggested to treat this fracture. The aim of this study was to assess the outcome of patients with type II distal clavicle fractures treated with coracoclavicular suture fixation using three loops of Ethibond. This prospective study included 14 patients with Neer type II fractures treated with open reduction and coracoclavicular fixation. Ethibond sutures were passed under the coracoid and around the clavicle (UCAC loop) without making any drill holes in the proximal or distal fragments. There were 11 men and three women with a mean age of 34.57 years (29 to 41). Patients were followed for a mean of 24.64 months (14 to 31) and evaluated radiologically and clinically using the Constant score. Fracture union was obtained in 13 patients at a mean of 18.23 weeks (13 to 23) and the mean Constant score was 96.07 (91 to 100). One patient developed an asymptomatic fibrous nonunion at one year. This study suggests that open reduction and internal fixation of unstable distal clavicle fractures using UCAC loops can provide rigid fixation and lead to bony union. This technique avoids using metal hardware, preserves the acromioclavicular joint and provides adequate stability with excellent results.


Sperm DNA Integrity in Leukocytospermia and Its Association with Seminal Adenosine Deaminase.
The study aimed to examine the effect of leukocytospermia on sperm quality and the levels of seminal adenosine deaminase (ADA) enzyme in males attending an infertility clinic in a tertiary hospital and to detect the association, if any, between seminal ADA and sperm quality. Consenting male subjects, between 21 and 45 years, attending the infertility clinic and qualifying the eligibility criteria were recruited following informed consent. The collected semen samples were analyzed for the routine parameters based on the WHO protocols and for sperm DNA fragmentation. The seminal leukocyte count was detected using the peroxidase method, and the seminal ADA was assessed using spectrophotometry. Samples from 110 participants were included in the study; leukocytospermia was detected in 33% of the samples. A significant reduction in the sperm quality with respect to conventional semen parameters (sperm motility and sperm vitality) and sperm DNA fragmentation index (SDFI) was noted in the presence of leukocytospermia. Furthermore, a significant positive correlation between the levels of seminal ADA and SDFI was noted (P = 0.000, r = 0.412). The sperm motility and DNA integrity are significantly compromised in the presence of leukocytospermia when the leukocyte count is > 1 million/mL of semen as well as 0.5-1 million/mL of semen. The positive correlation noted between seminal ADA levels and increased sperm DNA damage paves way for the possibility of seminal ADA to be an indicator of silent male genital tract inflammation as well as low-quality semen.


Effect of mutations on binding of ligands to guanine riboswitch probed by free energy perturbation and molecular dynamics simulations.
Riboswitches can regulate gene expression by direct and specific interactions with ligands and have recently attracted interest as potential drug targets for antibacterial. In this work, molecular dynamics (MD) simulations, free energy perturbation (FEP) and molecular mechanics generalized Born surface area (MM-GBSA) methods were integrated to probe the effect of mutations on the binding of ligands to guanine riboswitch (GR). The results not only show that binding free energies predicted by FEP and MM-GBSA obtain an excellent correlation, but also indicate that mutations involved in the current study can strengthen the binding affinity of ligands GR. Residue-based free energy decomposition was applied to compute ligand-nucleotide interactions and the results suggest that mutations highly affect interactions of ligands with key nucleotides U22, U51 and C74. Dynamics analyses based on MD trajectories indicate that mutations not only regulate the structural flexibility but also change the internal motion modes of GR, especially for the structures J12, J23 and J31, which implies that the aptamer domain activity of GR is extremely plastic and thus readily tunable by nucleotide mutations. This study is expected to provide useful molecular basis and dynamics information for the understanding of the function of GR and possibility as potential drug targets for antibacterial.


Aged red garlic extract reduces cigarette smoke extract-induced cell death in human bronchial smooth muscle cells by increasing intracellular glutathione levels.
Increasing antioxidant capacity has been proposed as a promising strategy to prevent cigarette smoke-induced lung diseases. This study tested whether garlic extracts prevented cigarette smoke extract (CSE)-induced cell death in human bronchial smooth muscle cells (HBSMCs). Garlic extracts were prepared from fresh raw garlic (FRG), aged black garlic (ABG) and aged red garlic (ARG). Treatment of HBSMCs with 10% CSE induced cell death accompanied by activation of caspase. Of the garlic extracts, treatment with ARG extract reduced CSE-induced cell death. The combination of ARG extract with CSE attenuated the CSE-induced reduction in glutathione (GSH) content, generation of reactive oxygen species (ROS) and induction of heme oxygenase-1 expression compared with CSE treatment without ARG extract. Furthermore, the combination of L-BSO, a GSH synthesis inhibitor, with ARG and CSE extracts failed to increase the intracellular GSH content and cell viability. Taken together, these results demonstrate that ARG extract reduces CSE-induced cell death by increasing GSH content and reducing ROS generation in HBSMCs.


Anti-thrombosis repertoire of blood-feeding horsefly salivary glands.
Blood-feeding arthropods rely heavily on the pharmacological properties of their saliva to get a blood meal and suppress immune reactions of hosts. Little information is available on antihemostatic substances in horsefly salivary glands although their saliva has been thought to contain wide range of physiologically active molecules. In traditional Eastern medicine, horseflies are used as anti-thrombosis material for hundreds of years. By proteomics coupling transcriptome analysis with pharmacological testing, several families of proteins or peptides, which exert mainly on anti-thrombosis functions, were identified and characterized from 60,000 pairs of salivary glands of the horsefly Tabanus yao Macquart (Diptera, Tabanidae). They are: (I) ten fibrin(ogen)olytic enzymes, which hydrolyze specially alpha chain of fibrin(ogen) and are the first family of fibrin(ogen)olytic enzymes purified and characterized from arthropods; (II) another fibrin(ogen)olytic enzyme, which hydrolyzes both alpha and beta chain of fibrin(ogen); (III) ten Arg-Gly-Asp-motif containing proteins acting as platelet aggregation inhibitors; (IV) five thrombin inhibitor peptides; (V) three vasodilator peptides; (VI) one apyrase acting as platelet aggregation inhibitor; (VII) one peroxidase with both platelet aggregation inhibitory and vasodilator activities. The first three families are belonging to antigen five proteins, which show obvious similarity with insect allergens. They are the first members of the antigen 5 family found in salivary glands of blood sucking arthropods to have anti-thromobosis function. The current results imply a possible evolution from allergens of blood-sucking insects to anti-thrombosis agents. The extreme diversity of horsefly anti-thrombosis components also reveals the anti-thrombosis molecular mechanisms of the traditional Eastern medicine insect material.


Disulfide formation in plant storage vacuoles permits assembly of a multimeric lectin.
The ER (endoplasmic reticulum) has long been considered the plant cell compartment within which protein disulfide bond formation occurs. Members of the ER-located PDI (protein disulfide isomerase) family are responsible for oxidizing, reducing and isomerizing disulfide bonds, as well as functioning as chaperones to newly synthesized proteins. In the present study we demonstrate that an abundant 7S lectin of the castor oil seed protein storage vacuole, RCA (Ricinus communis agglutinin 1), is folded in the ER as disulfide bonded A-B dimers in both vegetative cells of tobacco leaf and in castor oil seed endosperm, but that these assemble into (A-B)2 disulfide-bonded tetramers only after Golgi-mediated delivery to the storage vacuoles in the producing endosperm tissue. These observations reveal an alternative and novel site conducive for disulfide bond formation in plant cells.


Information from physicians and retention of information by patients - obstacles to the awareness of patients of progressing disease when life is near the end.
Discrepancies between the information that patients have received and the patients' awareness of their condition have frequently been observed in literature and given a number of different explanations. The chief contribution of this study is that by following patients over time it is possible not only to notice any changes in the patients' knowledge or awareness of their disease, but also to investigate the interview material for possible reasons for those changes. Since the study is based on two different groups of patients it will also be possible to notice if the category of disease matters for patients' awareness of their condition. Twelve patients with malign haematological diseases or lung cancer were followed with interviews from diagnosis to cure or death, or at most for two years. The method is qualitative. Semi-structured interviews were conducted, transcribed into written text, and then used for a qualitative content analysis. During the process of analysis four different expressions (subcategories) emerged about the awareness of patients concerning their health status: informed and aware, not informed and not aware, aware though not informed, or not aware though informed. Then the search started for obstacles to the awareness of patients regarding their progressing disease and approaching death. Four kinds of obstacles were found: due to the physician, the patient, the physician and the patient in collusion, or neither to the physician nor the patient but the insidious way in which lung cancer (mostly) and haematological malignancies (occasionally) progress. To optimize the care of patients who wish to be informed and aware during their disease, it is important that the health care staff recognizes potential obstacles to the awareness of patients in order to minimize such obstacles. The physicians could improve their communication with patients with life-threatening diseases, and avoid having a narrow focus on the treatment calendar. The patients could be encouraged to have a more proactive attitude in their communication with their physician.


Diel periodicity in the landing of Aedes aegypti on man.
The dynamics of transmission of disease agents by vectors depends, in part, on the probability of host-vector contact, which can vary with fluctuations of both host and vector. As important as seasonal variations is 24-hour periodicity in activity. Periodicity in the landing of males and females of Aedes aegypti on man has been assessed by means of catches of 15 hours or longer, with several persons as a bait. The assessments were made in a suburban area of Tanzania and continued throughout one year. Activity was observed to be almost entirely diurnal and diphasic. Whereas the detailed activity pattern of males agreed closely with that found elsewhere in East Africa, that of the females was unusual on account of the symmetry of the morning and afternoon peaks. Possible causes of differences among studies are discussed.


Protection from radiation-induced DNA single-strand breaks by induction of nuclear metallothionein.
To examine the extent to which nuclear metallothionein protects from radiation-induced DNA damage under aerobic and hypoxic conditions. A semiquantitative fluorescence image analysis method measured the nuclear content of metallothionein (MT) in ME180 and SiHa human squamous cervical carcinoma cell lines under normal growth conditions, and following MT induction by zinc. The extent of initial DNA damage following 60Co irradiation under aerobic and hypoxic conditions was assessed using the alkaline comet assay. Provided that cells were maintained at 37 degrees C, most of the cellular content of MT was in the nucleus. Incubation at 4 degrees C caused the rapid translocation of MT from the nucleus into the cytoplasm in both cell lines, with no net loss of cellular MT. Baseline nuclear MT levels were about four times greater in ME180 cells, and were much more readily induced by treatment with 100 microM zinc acetate, compared with SiHa cells. Under aerobic conditions, MT induction by zinc resulted in no protection in either of the cell lines. Under hypoxic conditions, however, the number of DNA single-strand breaks in zinc-treated cells was reduced by approximately 40% in ME180, but not in SiHa cells, when compared with non-induced controls. Nuclear MT can exert a significant level of protection from radiation by a mechanism that involves competition with oxygen for DNA radical sites and/or scavenging of free radicals. Because increased MT levels have been reported in hypoxic micro-regions of some solid tumours, this protective mechanism might have clinical relevance.


Right ventricular regional deformation analysis in patients operated for tetralogy of Fallot.
We aimed to compare the findings of a segmental speckle-tracking strain of right ventricle with those of cardiac magnetic resonance imaging in this setting. In 26 patients with operated tetralogy of Fallot (mean age, 15.35 ± 2.3 years; range 11-18 years), right ventricular segmental speckle-straining (the basal, mid, apical segments of right ventricular septum and lateral free wall, and right ventricular apex) were determined using two-dimensional echocardiography. The echocardiographic findings were compared to right ventricular ejection fraction, right ventricular indexed end-diastolic volume, indexed end-systolic volume and pulmonary regurgitation fraction at cardiac magnetic resonance. Right ventricular global speckle strain was -18.6 ± 3.7and lateral free wall strain was -17.8 ± 4.9. Indexed right ventricular end diastolic volume was 171.7 ± 23.3 ml/m2, indexed right ventricular end systolic volume was 95.1 ± 35.0 ml/m2 and right ventricular ejection fraction was 44.76 ± 9.39%. Basal inferior septum is correlated with indexed right ventricular end-diastolic volume (RVEDV; r = -0.521, p = 0.015) and pulmonary regurgitation fraction (r = -0.584, p = 0.015). Cardiac magnetic resonance (CMR)-derived RVEDV is correlated with lateral free wall (r = -0.465, p = 0.034) and Global RV (r = 0.442, p = 0.045). Right ventricular basal inferior septal and apical longitudinal strain correlates with the measures of right ventricular performance on CMR. These parameters would be useful to monitor right ventricular performance in patients after tetralogy of Fallot repair.


p21 as a transcriptional co-repressor of S-phase and mitotic control genes.
It has been previously described that p21 functions not only as a CDK inhibitor but also as a transcriptional co-repressor in some systems. To investigate the roles of p21 in transcriptional control, we studied the gene expression changes in two human cell systems. Using a human leukemia cell line (K562) with inducible p21 expression and human primary keratinocytes with adenoviral-mediated p21 expression, we carried out microarray-based gene expression profiling. We found that p21 rapidly and strongly repressed the mRNA levels of a number of genes involved in cell cycle and mitosis. One of the most strongly down-regulated genes was CCNE2 (cyclin E2 gene). Mutational analysis in K562 cells showed that the N-terminal region of p21 is required for repression of gene expression of CCNE2 and other genes. Chromatin immunoprecipitation assays indicated that p21 was bound to human CCNE2 and other p21-repressed genes gene in the vicinity of the transcription start site. Moreover, p21 repressed human CCNE2 promoter-luciferase constructs in K562 cells. Bioinformatic analysis revealed that the CDE motif is present in most of the promoters of the p21-regulated genes. Altogether, the results suggest that p21 exerts a repressive effect on a relevant number of genes controlling S phase and mitosis. Thus, p21 activity as inhibitor of cell cycle progression would be mediated not only by the inhibition of CDKs but also by the transcriptional down-regulation of key genes.


[The thromboembolic risk of atrial fibrillation].
The assessment of the thrombo-embolic risk is currently well defined in case of atrial fibrillation, in the general population as well as in several subgroups. Predictive factors of thrombo-embolism have been identified, they are clinical and echocardiographic criteria. They allow to stratify the individual risk of each patient and to establish the therapeutic attitude best suited to its thrombo-embolic and haemorrhagic risk profile. Recent clinical trials have demonstrated that oral anticoagulation with coumarinics, adjusted at an INR between 2 and 3, provided a greater protection for patients at higher risk, compared to aspirin, with an acceptable low rate of haemorrhagic complications. When atrial fibrillation is of recent onset, the therapeutic attitude will take into account the time delay between onset of the arrhythmia and the medical consultation, 48 h representing the maximal delay allowed to perform cardioversion without prolonged anticoagulation.


ATRX Loss in the Development and Prognosis of Conjunctival Melanoma.
Metastatic disease is linked to TERT promoter mutations in conjunctival melanomas (CM). Both TERT promoter and ATRX mutations are associated with faulty telomere maintenance. This study aimed to determine the prognostic value of ATRX loss in conjunctival melanocytic lesions. Eighty-six conjunctival melanocytic lesions from the Rotterdam Ocular Melanoma Study group were collected. ATRX status and TERT promoter status were determined using immunohistochemical staining and molecular diagnostics, respectively. None of the nevi (n = 16) and primary acquired melanosis (PAM) without atypia (n = 6) showed ATRX loss. ATRX loss was found in 2/5 PAM with atypia without CM and in 8/59 CM. No cases with a TERT promoter mutation (n = 26) showed ATRX loss. Eight/eleven metastatic CM harbored a TERT promoter mutation, two other metastatic CM showed ATRX loss and one metastatic case showed no TERT promoter/ATRX alterations. In conclusion ATRX loss and TERT promoter mutations are only found in (pre)malignant conjunctival melanocytic lesions, with most metastatic cases harboring one of these alterations, suggesting that both alterations are associated with adverse behavior. Similar to TERT promoter mutations, ATRX loss may be used as a diagnostic tool in determining whether a conjunctival melanocytic lesion is prone to having an adverse course.


The Evaluation of 17 Gastrointestinal Tumor Markers Reveals Prognosis Value for MUC6, CK17, and CD10 in Gallbladder-Cancer Patients.
Gallbladder cancer (GBC) is an aggressive and highly lethal disease with relatively low global incidence, but one that constitutes a major health problem in Asian and Latin American countries, particularly in Chile. The identification of new tumor-associated markers with potential prognosis value is required for GBC clinical practice. Using immunohistochemistry/tumor tissue microarray, we evaluated the expression of 17 gastrointestinal tumor-associated protein markers (CK7, CK17, CK19, CK20, CKLMW, CKHMW, MUC1, MUC2, MUC5AC, MUC6, CA125, CD10, CEA, vimentin, villin, claudin-4, and CDX2) in primary gallbladder adenocarcinomas from 180 Chilean patients and analyzed potential associations with their pathological and clinical characteristics. Younger female patients with well- to moderately differentiated tumors had a better prognosis than that of older female or male patients with tumors with a similar tumor differentiation grade. Among all analyzed markers, MUC6 expression was associated with better prognosis in patients with well- to moderately differentiated tumors, whereas CK17 or CD10 was associated with worse prognosis in patients with poorly differentiated tumors. In addition, the MUC6+CK17- expression pattern was strongly associated with better prognosis in patients with well- to moderately differentiated tumors, whereas patients with poorly differentiated tumors and with the CK17+CD10+ expression pattern showed worse prognosis. Our results suggest that tumor MUC6, CK17, and CD10 can be considered as potential prognosis markers for GBC.


Learning From Synthetic CT Images via Test-Time Training for Liver Tumor Segmentation.
Automatic liver tumor segmentation could offer assistance to radiologists in liver tumor diagnosis, and its performance has been significantly improved by recent deep learning based methods. These methods rely on large-scale well-annotated training datasets, but collecting such datasets is time-consuming and labor-intensive, which could hinder their performance in practical situations. Learning from synthetic data is an encouraging solution to address this problem. In our task, synthetic tumors can be injected to healthy images to form training pairs. However, directly applying the model trained using the synthetic tumor images on real test images performs poorly due to the domain shift problem. In this paper, we propose a novel approach, namely Synthetic-to-Real Test-Time Training (SR-TTT), to reduce the domain gap between synthetic training images and real test images. Specifically, we add a self-supervised auxiliary task, i.e., two-step reconstruction, which takes the output of the main segmentation task as its input to build an explicit connection between these two tasks. Moreover, we design a scheduled mixture strategy to avoid error accumulation and bias explosion in the training process. During test time, we adapt the segmentation model to each test image with self-supervision from the auxiliary task so as to improve the inference performance. The proposed method is extensively evaluated on two public datasets for liver tumor segmentation. The experimental results demonstrate that our proposed SR-TTT can effectively mitigate the synthetic-to-real domain shift problem in the liver tumor segmentation task, and is superior to existing state-of-the-art approaches.


Promoting Sketching in Introductory Geoscience Courses: CogSketch Geoscience Worksheets.
Research from cognitive science and geoscience education has shown that sketching can improve spatial thinking skills and facilitate solving spatially complex problems. Yet sketching is rarely implemented in introductory geosciences courses, due to time needed to grade sketches and lack of materials that incorporate cognitive science research. Here, we report a design-centered, collaborative effort, between geoscientists, cognitive scientists, and artificial intelligence (AI) researchers, to characterize spatial learning challenges in geoscience and to design sketch activities that use a sketch-understanding program, CogSketch. We developed 26 CogSketch worksheets that use cognitive science-based principles to scaffold problem solving of spatially complex geoscience problems and report observations of an implementation in an introductory geoscience course where students used CogSketch or human-graded paper worksheets. Overall, this research highlights the principles of interdisciplinary design between cognitive scientists, geoscientists, and AI researchers that can inform the collaborative design process for others aiming to develop effective educational materials.


Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway.
The ubiquitin-proteasome system and autophagy are crucially important for proteostasis in cells. These pathways are interdependent, and dysfunction in either pathway causes accumulation of ubiquitin-positive aggregates, a hallmark of human pathological conditions. To elucidate in vivo compensatory action(s) against proteasomal dysfunction, we developed mice with reduced proteasome activity in their livers. The mutant mice exhibited severe liver damage, accompanied by formation of aggregates positive for ubiquitin and p62/Sqstm1, an adaptor protein for both selective autophagy and the anti-oxidative Keap1-Nrf2 pathway. These aggregates were selectively entrapped by autophagosomes, and pathological features of livers with impaired proteasome activity were exacerbated by simultaneous suppression of autophagy. In contrast, concomitant loss of p62/Sqstm1 had no apparent effect on the liver pathology though p62/Sqstm1 was indispensable for the aggregates formation. Furthermore, defective proteasome function led to transcriptional activation of the Nrf2, which served as a physiological adaptation. Our in vivo data suggest that cells contain networks of cellular defense mechanisms against defective proteostasis.


Functional Role of Non-Coding RNAs during Epithelial-To-Mesenchymal Transition.
Epithelial-to-mesenchymal transition (EMT) is a key biological process involved in a multitude of developmental and pathological events. It is characterized by the progressive loss of cell-to-cell contacts and actin cytoskeletal rearrangements, leading to filopodia formation and the progressive up-regulation of a mesenchymal gene expression pattern enabling cell migration. Epithelial-to-mesenchymal transition is already observed in early embryonic stages such as gastrulation, when the epiblast undergoes an EMT process and therefore leads to the formation of the third embryonic layer, the mesoderm. Epithelial-to-mesenchymal transition is pivotal in multiple embryonic processes, such as for example during cardiovascular system development, as valve primordia are formed and the cardiac jelly is progressively invaded by endocardium-derived mesenchyme or as the external cardiac cell layer is established, i.e., the epicardium and cells detached migrate into the embryonic myocardial to form the cardiac fibrous skeleton and the coronary vasculature. Strikingly, the most important biological event in which EMT is pivotal is cancer development and metastasis. Over the last years, understanding of the transcriptional regulatory networks involved in EMT has greatly advanced. Several transcriptional factors such as Snail, Slug, Twist, Zeb1 and Zeb2 have been reported to play fundamental roles in EMT, leading in most cases to transcriptional repression of cell⁻cell interacting proteins such as ZO-1 and cadherins and activation of cytoskeletal markers such as vimentin. In recent years, a fundamental role for non-coding RNAs, particularly microRNAs and more recently long non-coding RNAs, has been identified in normal tissue development and homeostasis as well as in several oncogenic processes. In this study, we will provide a state-of-the-art review of the functional roles of non-coding RNAs, particularly microRNAs, in epithelial-to-mesenchymal transition in both developmental and pathological EMT.


Frequent concomitant presence of Desulfitobacterium spp. and "Dehalococcoides" spp. in chloroethene-dechlorinating microbial communities.
The presence of chloroethene dechlorination activity as well as several bacterial genera containing mainly organohalide-respiring members was investigated in 34 environmental samples from 18 different sites. Cultures inoculated with these environmental samples on tetrachloroethene and amended weekly with a seven organic electron donor mixture resulted in 11 enrichments with cis-DCE, ten with VC, and 11 with ethene as dechlorination end product, and only two where no dechlorination was observed. "Dehalococcoides" spp. and Desulfitobacterium spp. were detected in the majority of the environmental samples independently of the dechlorination end product formed. The concomitant presence of Dehalococcoides spp. and Desulfitobacterium spp. in the majority of the enrichments suggested that chloroethene dechlorination was probably the result of catalysis by at least two organohalide-respiring genera either in parallel or by stepwise catalysis. A more detailed study of one enrichment on cis-DCE suggested that in this culture Desulfitobacterium spp. as well as Dehalococcoides spp. dechlorinated cis-DCE whereas dechlorination of VC was only catalyzed by the latter.


Anaerobic osteomyelitis in sickle cell disease: association and pathophysiology.
A 10-year-old boy with sickle cell disease developed osteomyelitis of the humerus associated with blood cultures positive for Bacteroides fragilis. Clinical and radiological resolution followed a 10-day course of intravenous clindamycin. Attention is drawn to the definite but poorly recognized association between sickle cell disease and anaerobic osteomyelitis, and the probable pathophysiology is described.


[The detection of streptococcal cell-wall proteins that form complexes with human macroglobulins].
The composition of the extracts of the cultures of individual streptococcal strains, studied by immunoblotting techniques, has been shown to contain proteins with a molecular weight of 70-80 KD. These proteins have pronounced affinity to human macroglobulins: alpha-macroglobulin, alpha-glycoprotein associated with pregnancy and protein A. The significance of this phenomenon on the cellular and somatic levels is discussed.


Comparison of intranasal versus intravenous midazolam for management of status epilepticus in dogs: A multi-center randomized parallel group clinical study.
The intranasal (IN) route for rapid drug administration in patients with brain disorders, including status epilepticus, has been investigated. Status epilepticus is an emergency, and the IN route offers a valuable alternative to other routes, especially when these fail. To compare IN versus IV midazolam (MDZ) at the same dosage (0.2 mg/kg) for controlling status epilepticus in dogs. Client-owned dogs (n = 44) with idiopathic epilepsy, structural epilepsy, or epilepsy of unknown origin manifesting as status epilepticus. Randomized parallel group clinical trial. Patients were randomly allocated to the IN-MDZ (n = 21) or IV-MDZ (n = 23) group. Number of successfully treated cases (defined as seizure cessation within 5 minutes and lasting for ≥10 minutes), seizure cessation time, and adverse effects were recorded. Comparisons were performed using the Fisher's exact and Wilcoxon rank sum tests with statistical significance set at α < .05. IN-MDZ and IV-MDZ successfully stopped status epilepticus in 76% and 61% of cases, respectively (P = .34). The median seizure cessation time was 33 and 64 seconds for IN-MDZ and IV-MDZ, respectively (P = .63). When the time to place an IV catheter was taken into account, IN-MDZ (100 seconds) was superior (P = .04) to IV-MDZ (270 seconds). Sedation and ataxia were seen in 88% and 79% of the dogs treated with IN-MDZ and IV-MDZ, respectively. Both routes are quick, safe, and effective for controlling status epilepticus. However, the IN route demonstrated superiority when the time needed to place an IV catheter was taken into account.


Cancer risk in patients with pyogenic liver abscess: a nationwide cohort study.
There has been no large-scale population-based study on the relationship between pyogenic liver abscesses (PLA) and subsequent cancer risk. To estimate all cancer risk following a diagnosis of PLA. Based on Taiwan's National Health Insurance Research Database, 1257 patients with PLA without prior cancers in the period 1996-2008 were identified and followed-up. The standard incidence ratio (SIR) of each cancer was calculated as the number of observed cancer cases arising among the PLA patients divided by the expected case number of cancer cases according to the national cancer rates. Of the 1257 PLA patients identified, 598 (47.6%) had diabetes mellitus. After a median (±s.d.) follow-up of 3.33 ± 3.45 years, 186 were diagnosed with cancers, including 56 liver cancer, 22 biliary tract cancer and 40 colorectal cancer patients. Patients with PLA had a higher risk of all cancers (SIR, 3.83; 95% CI, 3.30-4.42), liver cancer (SIR, 7.87; 95% CI, 5.94-10.21), biliary tract cancer (SIR, 34.58; 95% CI, 21.67-52.36) and colorectal cancer (SIR, 5.27; 95% CI, 3.76-7.18). The highest SIRs of all cancers, liver cancer, biliary tract cancer and colorectal cancer occurred within 90 days of follow-up (360.82; 95% CI, 278.46-459.91, 257.28; 95% CI, 186.17-346.56, 1153.38; 95% CI 694.08-1801.24, and 52.63; 95% CI 25.2-96.8 respectively). Pyogenic liver abscesses may herald the onset of cancer, especially hepato-biliary and colon cancer. Further surveys should be conducted for the detection of occult cancers in such patients.


Selective extraction of recombinant membrane proteins from Hansenula polymorpha by pulsed electric field and lytic enzyme pretreatment.
In yeast, recombinant membrane proteins including viral scaffold proteins used for the formation of enveloped Virus-like particles (eVLPs) typically accumulate intracellularly. Their recovery is carried out by mechanical disruption of the cells, often in combination with detergent treatment. Cell permeabilization is an attractive alternative to mechanical lysis because it allows for milder and more selective recovery of different intracellular products. Here, we present a novel approach for extraction of integral membrane proteins from yeast based on cell envelope permeabilization through a combination of pulsed electric field and lytic enzyme pretreatment of the cells. Our primary experiments focused on Hansenula polymorpha strain #25-5 co-expressing the integral membrane small surface protein (dS) of the duck hepatitis B virus and a fusion protein of dS with a trimer of a Human papillomavirus (HPV) L2-peptide (3xL2-dS). Irreversible plasma membrane permeabilization was induced by treating the cell suspension with monopolar rectangular pulses using a continuous flow system. The permeabilized cells were incubated with lyticase and dithiothreitol. This treatment increased the cell wall permeability, resulting in the release of over 50% of the soluble host proteins without causing significant cell lysis. The subsequent incubation with Triton X-100 resulted in the solubilization and release of a significant portion of 3xL2-dS and dS from the cells. By applying two steps: (i) brief heating of the cells before detergent treatment, and (ii) incubation of the extracts with KSCN, an 80% purity on the protein level has been achieved. Experiments performed with H. polymorpha strain T#3-3, co-expressing dS and the fusion protein EDIIIWNV-dS consisting of dS and the antigen from the West Nile virus (WSV), confirmed the applicability of this approach for recovering dS. The treatment, optimal for solubilization of 3xL2-dS and a significant part of dS, was not effective in isolating the fused protein EDIIIWNV-dS from the membranes, resulting in its retention within the cells. This study presents an alternative approach for the recovery and partial purification of viral membrane proteins expressed in H. polymorpha. The factors influencing the effectiveness of this procedure and its potential use for the recovery of other integral membrane proteins are discussed.


Discovery of a Novel Antifungal Agent in the Pathogen Box.
Human fungal pathogens cause over 2 million infections per year and are major drivers of morbidity and mortality. Cryptococcus neoformans and Candida albicans are two of the most common fungal pathogens of humans, together accounting for a staggering 1.4 million infections annually, with very high mortality rates. Patients with dysfunctional immune systems, such as individuals with HIV/AIDS, are particularly susceptible to fungal infections. Unfortunately, relatively few antifungal drugs are currently available and fungi frequently develop resistance, further complicating treatment approaches. In this study, we screened the Pathogen Box chemical library (Medicines for Malaria Venture, Switzerland) in an effort to identify novel antifungal compounds. This approach led to the discovery of a novel, highly potent antifungal agent with activity against both C. neoformans and C. albicans. Our initial study of the mechanism of action suggested that this novel compound prevents fungal proliferation by targeting the ability of C. neoformans to withstand stress at the plasma membrane and cell wall. Because this compound had previously been shown to have low toxicity for mammalian cells, we propose that it represents an attractive lead compound for further antifungal drug development. IMPORTANCECryptococcus neoformans and Candida albicans are two major human fungal pathogens and together account for over 1.4 million infections annually, with very high mortality rates. These fungi often infect immunocompromised individuals, such as HIV/AIDS patients. In an effort to identify novel drugs with antifungal activity, we have screened the Pathogen Box for compounds with anticryptococcal and anticandidal activities. This approach led to the discovery of a promising lead compound (MMV688271) with strong antifungal potency under nutrient-limited conditions.


The erythropoietin receptor transmembrane domain mediates complex formation with viral anemic and polycythemic gp55 proteins.
Erythropoietin receptor (EpoR) activation is crucial for mature red blood cell production. The murine EpoR can also be activated by the envelope protein of the polycythemic (P) spleen focus forming virus (SFFV), gp55-P. Due to differences in the TM sequence, gp55 of the anemic (A) strain SFFV, gp55-A, cannot efficiently activate the EpoR. Using antibody-mediated immunofluorescence co-patching, we show that the majority of EpoR forms hetero-oligomers at the cell surface with gp55-P and, surprisingly, with gp55-A. The EpoR TM domain is targeted by gp55-P and -A, as only chimeric receptors containing EpoR TM sequences oligomerized with gp55 proteins. Both gp55-P and gp55-A are homodimers on the cell surface, as shown by co-patching. However, when the homomeric interactions of the isolated TM domains were assayed by TOXCAT bacterial reporter system, only the TM sequence of gp55-P was dimerized. Thus, homo-oligomerization of gp55 proteins is insufficient for full EpoR activation, and a correct conformation of the dimer in the TM region is required. This is supported by the failure of gp55-A-->P, a mutant protein whose TM domain can homo-oligomerize, to fully activate EpoR. As unliganded EpoR forms TM-dependent but inactive homodimers, we propose that the EpoR can be activated to different extents by homodimeric gp55 proteins, depending on the conformation of the gp55 protein dimer in the TM region.


The Provision of Abortion Care via Telehealth in the United States: A Rapid Review.
The recent Supreme Court decision Dobbs v. Jackson Women's Health that has overruled Roe v. Wade has resulted in severe limitations of abortion access throughout the United States. Telehealth has been put forth as one solution for improving access for reproductive health care, including abortion services. Telehealth has demonstrated safety and efficacy in several health care disciplines; however, its use for abortion care and services has not been explored and synthesized. As part of a larger review on telehealth and general reproductive health, our team identified a moderate amount of literature on telehealth and abortion care. We conducted a rapid review searching for eligible studies in MEDLINE, Embase, and CINAHL. Information was extracted from each included study to explore 4 key areas of inquiry: (1) clinical effectiveness, (2) patient and provider experiences, (3) barriers and facilitators, and (4) the impact of the coronavirus disease 2019 (COVID-19) pandemic. Twenty-five studies on the use of telehealth for providing abortion services published between 2011 and 2022 were included. Telehealth for medical abortion increased during the COVID-19 pandemic and was found to be safe and clinically effective, with high patient satisfaction. Overall, telehealth improved access and removed barriers for patients including lack of transportation. Legal restrictions in certain states were cited as the primary barriers. Studies contained limited information on the perspectives and experiences of health care providers and diverse patient populations. Abortion care via telehealth is safe and effective with high satisfaction and may also remove barriers to care including transportation and fear. Removing restrictions on telehealth for the provision of abortion services may further improve access to care and promote greater health equity.


Structural basis for flagellin-induced NAIP5 activation.
The NAIP (NLR family apoptosis inhibitory protein)/NLRC4 (NLR family CARD containing protein 4) inflammasome senses Gram-negative bacterial ligand. In the ligand-bound state, the winged helix domain of NAIP forms a steric clash with NLRC4 to open it up. However, how ligand binding activates NAIP is less clear. Here, we investigated the dynamics of the ligand-binding region of inactive NAIP5 and solved the cryo-EM structure of NAIP5 in complex with its specific ligand, FliC from flagellin, at 2.9-Å resolution. The structure revealed a "trap and lock" mechanism in FliC recognition, whereby FliC-D0C is first trapped by the hydrophobic pocket of NAIP5, then locked in the binding site by ID (insertion domain) and C-terminal tail of NAIP5. The FliC-D0N domain further inserts into ID to stabilize the complex. According to this mechanism, FliC triggers the conformational change of NAIP5 by bringing multiple flexible domains together.


High species richness of Chironomidae (Diptera) in temporary flooded wetlands associated with high species turn-over rates.
Species richness and species turn-over of Chironomidae was studied in irregularly flooded wetlands of the River Dalälven flood-plains in central Sweden. The chironomid fauna, sampled with emergence traps in six wetlands over six summers, contained as much as 135 species, and the cumulative species curves indicated that the regional species pool contain several more species. Recurrent irregular floods may have induced this high chironomid species richness and the high species turn-over in the temporary wetlands, as the dominance between terrestrial and aquatic species shifted between years. Half of the wetlands were treated with Bacillus thuringiensis var. israelensis (Bti) against larvae of the flood-water mosquito Aedes sticticus. These treatments had no significant effect on chironomid species richness, but there was a higher species turn-over between years of primarily low abundance species in the treated wetlands. The cumulative number of species was also higher in the Bti-treated experimental wetlands than in the untreated reference wetlands. Thus, Bti treatment against mosquito larvae seemed to have only small effects on chironomid species richness but seemed to increase the colonisation-extinction dynamics.


Towards Principles-Based Approaches to Governance of Health-related Research using Personal Data.
Technological advances in the quality, availability and linkage potential of health data for research make the need to develop robust and effective information governance mechanisms more pressing than ever before; they also lead us to question the utility of governance devices used hitherto such as consent and anonymisation. This article assesses and advocates a principles-based approach, contrasting this with traditional rule-based approaches, and proposes a model of principled proportionate governance. It is suggested that the approach not only serves as the basis for good governance in contemporary data linkage but also that it provides a platform to assess legal reforms such as the draft Data Protection Regulation.


Testosterone patches in the management of patients with mild/moderate systemic lupus erythematosus.
Androgen deficiency has been associated with the development of systemic lupus erythematosus (SLE). The aim of this study was to test the efficacy of testosterone patches vs placebo in female SLE patients with baseline mild-to-moderate disease activity in a randomized, double-blind, single-centre placebo-controlled trial. Patients received testosterone (150 microg) or placebo transdermal patches for 12 weeks. Patients were assessed at 4-weekly intervals for disease activity using the Safety of Oestrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), Systemic Lupus Activity Measure-Revised (SLAM-R) and The British Isles Lupus Assessment Group (BILAG) indices, physician global assessment (PGA), quality of life using the SF-36 survey and sexual functioning using the Derogatis score. Data were analysed using two sample t-tests to compare the mean difference from baseline to week 12 in the testosterone patch and placebo groups. Thirty-four patients were recruited in to each group. There was no significant baseline difference between the groups in age, race or marital status. There was no significant difference between treatment groups in the mean change in SELENA-SLEDAI (0.547 +/- 3.72, P > 0.60), nor in PGA or BILAG system scores. The mean change in SLAM-R score was statistically different (2.06, S.D. 3.3, P = 0.01) but was not considered clinically meaningful. Health transition also showed a small change (P < 0.03). There was no significant difference in the Derogatis scores or toxicity. Testosterone patches were safe but did not significantly affect disease activity, quality of life or sexual functioning. Increased use of steroids in the placebo group may have confounded the study results.


Clinical Impact of Physical Activity and Cough on Disease Progression in Fibrotic Interstitial Lung Disease.
Physical activity limitations and cough are common in patients with interstitial lung disease (ILD), potentially leading to reduced health-related quality of life. We aimed to compare physical activity and cough between patients with subjective, progressive idiopathic pulmonary fibrosis (IPF) and fibrotic non-IPF ILD. In this prospective observational study, wrist accelerometers were worn for seven consecutive days to track steps per day (SPD). Cough was evaluated using a visual analog scale (VAScough) at baseline and weekly for six months. We included 35 patients (IPF: n = 13; non-IPF: n = 22; mean ± SD age 61.8 ± 10.8 years; FVC 65.3 ± 21.7% predicted). Baseline mean ± SD SPD was 5008 ± 4234, with no differences between IPF and non-IPF ILD. At baseline, cough was reported by 94.3% patients (mean ± SD VAScough 3.3 ± 2.6). Compared to non-IPF ILD, patients with IPF had significantly higher burden of cough (p = 0.020), and experienced a greater increase in cough over six months (p = 0.009). Patients who died or underwent lung transplantation (n = 5), had significantly lower SPD (p = 0.007) and higher VAScough (p = 0.047). Long-term follow up identified VAScough (HR: 1.387; 95%-CI 1.081-1.781; p = 0.010) and SPD (per 1000 SPD: HR 0.606; 95%-CI: 0.412-0.892; p = 0.011) as significant predictors for transplant-free survival. In conclusion, although activity didn't differ between IPF and non-IPF ILD, cough burden was significantly greater in IPF. SPD and VAScough differed significantly in patients who subsequently experienced disease progression and were associated with long-term transplant-free survival, calling for better acknowledgement of both parameters in disease management.


Multiple benzodiazepine receptor localization by light microscopic radiohistochemistry.
Benzodiazepine receptor binding studies have been reported suggesting the existence of at least two different benzodiazepine receptors. One distinguishing feature of these two sites is that one has a high affinity for triazolopyridazines, whereas the other has a low affinity. In this study, the regional localization of the two different receptors was examined by light microscopic radiohistochemical methods. [3H]Flunitrazepam was used to label all types of benzodiazepine receptors in slide-mounted tissue sections. CL218,872, a typical triazolopyridazine, was used to preferentially displace [3H]flunitrazepam from the subclass of receptors having a high affinity for CL218,872. Autoradiographs clearly showed that receptor binding in some regions was substantially affected by CL218,872 while that in other regions was affected to a lesser degree. Areas with receptors with high affinity for the triazolopyridazine (Type 1 receptors) included the cerebellum, globus pallidus and parts of the cerebral cortex. Areas with receptors having low affinity for the drugs (Type 2 receptors) included the superficial layer of the superior colliculus, the caudate-putamen and parts of the dentate gyrus. The results of this study may help explain the physiological differences between the benzodiazepine and triazolopyridazine drugs and should point out target sites in the brain for additional studies of the apparently two different receptors.


Veterinary education in South Africa: the class of 1924.
Veterinary education in South Africa is now more than 80 years old. It started in 1920 when the Onderstepoort Veterinary Faculty was created as an integral part of the Veterinary Research Institute at Onderstepoort. Sir Arnold Theiler, the founder of Onderstepoort, was its first Dean. This article concerns itself with some of the known and lesser known developments and actions associated with the creation of the faculty and how it was possible to provide suitable lecturing staff. This is followed by concise descriptions of the life histories of the first 8 veterinarians who graduated from the new faculty in 1924 and subsequently spent their entire working life in government service.


Process evaluation of a problem solving intervention to prevent recurrent sickness absence in workers with common mental disorders.
Common mental disorders (CMDs) are a major cause of sickness absence. Twenty to 30% of the workers who return to work after sickness absence due to CMDs experience recurrent sickness absence. We developed the Stimulating Healthy participation And Relapse Prevention (SHARP)-at work intervention, a problem solving intervention delivered by occupational physicians (OPs), to prevent recurrent sickness absence in this worker population in The Netherlands. A process evaluation was conducted alongside a cluster-randomised controlled trial to (1) evaluate whether the SHARP-at work intervention was implemented according to the protocol and differed from treatment in the control group, and (2) to investigate the relationship between the key elements of the intervention and the effect outcome (i.e. recurrent sickness absence). We collected process data for both the intervention and control group on recruitment, reach, dose delivered, dose received, fidelity, context and satisfaction. Data on recurrent sickness absence was collected through the registry system of the collaborating occupational health service. The study was performed in the Netherlands, and between 2010 and 2012, 154 OPs and 158 participants participated. Compared to the control group, participants in the intervention group more frequently had two or more consultations with the OP (odds ratio [OR] = 3.2, 95% confidence interval [CI] = 1.2-8.8) and completed more assignments (OR = 33.8, 95% CI = 10.4-109.5) as recommended in the intervention protocol. OPs and participants were satisfied with the intervention and rated it as applicable. Several individual intervention components were linked to the effect outcome. The process evaluation showed that the SHARP-at work intervention was conducted according to the protocol for the majority of the participants and well-received by OPs and participants. Furthermore, the intervention differed from treatment in the control group. Overall, the results provide support for implementing the intervention in practice.


Imaging of posttraumatic osteomyelitis.
Posttraumatic osteomyelitis frequently leads to an illness characterized by chronicity and recurrences. Bone changes themselves, developed during chronic infection, and orthopedic implants heavily influence the diagnostic value of the different imaging methods. Conventional radiography remains the cornerstone of imaging of acute and chronic osteomyelitis, but other modalities such as ultrasonography, radionuclide studies, computed tomography, and magnetic resonance imaging may be necessary. The values of the techniques in different clinical settings are described.