Environmental contamination as a risk factor for intra-household Staphylococcus aureus transmission.
The household is a recognized community reservoir for Staphylococcus aureus. This study investigated potential risk factors for intra-household S. aureus transmission, including the contribution of environmental contamination. We investigated intra-household S. aureus transmission using a sample of multiple member households from a community-based case-control study examining risk factors for CA-MRSA infection conducted in Northern Manhattan. During a home visit, index subjects completed a questionnaire. All consenting household members were swabbed, as were standardized environmental household items. Swabs were cultured for S. aureus. Positive isolates underwent further molecular characterization. Intra-household transmission was defined as having identical strains among two or more household members. Multiple logistic regression was used to identify independent risk factors for transmission. We enrolled 291 households: 146 index cases, 145 index controls and 687 of their household contacts. The majority of indexes were Hispanic (85%), low income (74%), and female (67%), with a mean age of 31 (range 1-79). The average size of case and control households was 4 people. S. aureus colonized individuals in 62% of households and contaminated the environment in 54% of households. USA300 was the predominant clinical infection, colonizing and environmental strain. Eighty-one households had evidence of intra-household transmission: 55 (38%) case and 26 (18%) control households (P<.01). Environmental contamination with a colonizing or clinical infection strain (aOR: 5.4 [2.9-10.3] P<.01) and the presence of a child under 5 (aOR: 2.3 [1.2-4.5] P = .02) were independently associated with transmission. In separate multivariable models, environmental contamination was associated with transmission among case (aOR 3.3, p<.01) and control households (aOR 27.2, p<.01). Environmental contamination with a colonizing or clinical infection strain was significantly and independently associated with transmission in a large community-based sample. Environmental contamination should be considered when treating S. aureus infections, particularly among households with multiple infected members.


Elevated β-cell stress levels promote severe diabetes development in mice with MODY4.
Maturity-onset diabetes of the young (MODY) is a group of monogenetic forms of diabetes mellitus caused by mutations in genes regulating β-cell development and function. MODY represents a heterogeneous group of non-insulin-dependent diabetes arising in childhood or adult life. Interestingly, clinical heterogeneity in MODY patients like variable disease onset and severity is observed even among individual family members sharing the same mutation, an issue that is not well understood. As high blood glucose levels are a well-known factor promoting β-cell stress and ultimately leading to cell death, we asked whether additional β-cell stress might account for the occurrence of disease heterogeneity in mice carrying a MODY4 mutation. In order to challenge β-cells, we established a MODY4 animal model based on Pdx1 (pancreatic and duodenal homeobox 1) haploinsufficiency, which allows conditional modulation of cell stress by genetic inhibition of the stress-responsive IKK/NF-κB signalling pathway. While Pdx1+/- mice were found glucose intolerant without progressing to diabetes, additional challenge of β-cell function by IKK/NF-κB inhibition promoted rapid diabetes development showing hyperglycaemia, hypoinsulinemia and loss of β-cell mass. Disease pathogenesis was characterized by deregulation of genes controlling β-cell homeostasis and function. Importantly, restoration of normal IKK/NF-κB signalling reverted the diabetic phenotype including normalization of glycaemia and β-cell mass. Our findings implicate that the avoidance of additional β-cell stress can delay a detrimental disease progression in MODY4 diabetes. Remarkably, an already present diabetic phenotype can be reversed when β-cell stress is normalized.


Mechanism of hypoalbuminemia in the 7/8-nephrectomized rat with chronic renal failure.
Hypoalbuminemia has been observed consistently in patients and experimental animals with chronic renal failure (CRF). A defect in albumin synthesis, catabolism, or distribution has been invoked as the cause, but there is no agreement as to which, if any, of these disorders results from the uremic state. We studied albumin homeostasis in 7/8-nephrectomized rats with CRF. Serum albumin concentration was lower in CRF (29.6 +/- 4.59 mg/ml) than in sham-operated control rats (36.3 +/- 4.3 mg/ml). Albumin synthesis, determined directly by measuring incorporation of 14CO2 into arginine in albumin, was increased in CRF rats as was total albumin clearance, measured using 125I-albumin disappearance. Rats with CRF were albuminuric. Albumin synthesis was increased by the amount necessary to replace urinary losses, but net albumin catabolism was the same as in control animals. Albuminuria was prevented by addition of excess tryptophan to the diet. Total albumin clearance and albumin synthesis were the same in these tryptophan-fed CRF animals as in CRF sham-operated animals, but these CRF rats were still hypoalbuminemic (33.6 +/- 5.27 vs. 36.3 +/- 4.3 mg/ml). Rats with CRF were plasma volume expanded. Institution of a low-sodium diet at the time of partial nephrectomy prevented plasma volume expansion and albuminuria as well. Serum albumin concentration, albumin distribution, pool sizes, and total albumin clearance remained the same as in CRF sham-operated animals. Hypoalbuminemia in CRF rats is due to two factors. Plasma volume expansion with pool dilution contributes 40% of the decrease and external albumin losses resulting from albuminuria contribute the other 60%. Albumin synthesis, catabolism, and distribution are intact.


Differentiating suicide attempters from suicide ideators using the Integrated Motivational-Volitional model of suicidal behaviour.
Suicidal behaviour is a significant public health concern, yet little is known about the factors that enable or impede behavioural enactment (engaging in a suicide attempt). Drawing on the Integrated Motivational-Volitional (IMV) Model of Suicidal Behaviour (2011), this study examined the factors associated with having thoughts of suicide (ideation) versus those associated with suicide enaction (attempts). Within a multivariate context, it was predicted that the factors associated with ideation formation (motivational factors) would be distinct from those factors which governed behavioural enaction (volitional moderators). Healthy adults (N=1, 288) completed an anonymous self-report survey. Analyses compared three groups: suicide attempters (n=230), suicide ideators (n=583), and those without any suicide history (n=475). Suicide attempters differed from suicide ideators on all volitional factors (fearlessness about death, impulsivity, and exposure to suicidal behaviour), with the exception of discomfort tolerance. Compared to ideators, attempters were more likely to have a family member and close friend who had self-injured or attempted suicide, and were more impulsive and fearless about death. Conversely, the two suicide groups did not differ on any of the variables (motivational factors) associated with the development of thoughts of death by suicide. This is a cross-sectional study based on self-report measures. Further research efforts to distinguish between suicide ideators and suicide attempters is crucial to inform the development of intervention and treatment approaches.


TBX2 represses PTEN in rhabdomyosarcoma and skeletal muscle.
Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children that shares many features of developing skeletal muscle. TBX2, a T-box family member, is highly upregulated in tumor cells of both major RMS subtypes where it functions as an oncogene. TBX2 is a repressor that is often overexpressed in cancer cells and functions in bypassing cell growth control, including the repression of the cell cycle regulators p14 and p21. We have found that TBX2 directly represses the tumor-suppressor phosphatase and tensin homolog (PTEN) in both RMS and normal muscle. Exogenous expression of TBX2 in normal muscle cells downregulates PTEN, and depletion or interference with TBX2 in RMS cells upregulates PTEN. Human RMS tumors show high levels of TBX2 and correspondingly low levels of PTEN. The expression of PTEN in clinical RMS samples is relatively uncharacterized, and we establish that suppression of PTEN is a frequent event in both subtypes of RMS. TBX2 represses PTEN by directly binding to the promoter and recruiting the histone deacetylase, HDAC1. RMS cells have high levels of activated AKT owing to the deregulation of phosphoinositide-3 kinase (PI3K) signaling, and depletion or interference with TBX2, which upregulates PTEN, results in a reduction of phospho-AKT. We have also found that the highly related T-box family member TBX3 does not repress PTEN in the muscle lineage. This work suggests that TBX2 is a central component of the PTEN/PI3K/AKT signaling pathway deregulation in RMS cells and that targeting TBX2 in RMS tumors may offer a novel therapeutic approach for RMS.


AZ1366: An Inhibitor of Tankyrase and the Canonical Wnt Pathway that Limits the Persistence of Non-Small Cell Lung Cancer Cells Following EGFR Inhibition.
Purpose: The emergence of EGFR inhibitors such as gefitinib, erlotinib, and osimertinib has provided novel treatment opportunities in EGFR-driven non-small cell lung cancer (NSCLC). However, most patients with EGFR-driven cancers treated with these inhibitors eventually relapse. Recent efforts have identified the canonical Wnt pathway as a mechanism of protection from EGFR inhibition and that inhibiting tankyrase, a key player in this pathway, is a potential therapeutic strategy for the treatment of EGFR-driven tumors.Experimental Design: We performed a preclinical evaluation of tankyrase inhibitor AZ1366 in combination with multiple EGFR-inhibitors across NSCLC lines, characterizing its antitumor activity, impingement on canonical Wnt signaling, and effects on gene expression. We performed pharmacokinetic and pharmacodynamic profiling of AZ1366 in mice and evaluated its therapeutic activity in an orthotopic NSCLC model.Results: In combination with EGFR inhibitors, AZ1366 synergistically suppressed proliferation of multiple NSCLC lines and amplified global transcriptional changes brought about by EGFR inhibition. Its ability to work synergistically with EGFR inhibition coincided with its ability to modulate the canonical Wnt pathway. Pharmacokinetic and pharmacodynamic profiling of AZ1366-treated orthotopic tumors demonstrated clinically relevant serum drug levels and intratumoral target inhibition. Finally, coadministration of an EGFR inhibitor and AZ1366 provided better tumor control and improved survival for Wnt-responsive lung cancers in an orthotopic mouse model.Conclusions: Tankyrase inhibition is a potent route of tumor control in EGFR-dependent NSCLC with confirmed dependence on canonical Wnt signaling. These data strongly support further evaluation of tankyrase inhibition as a cotreatment strategy with EGFR inhibition in an identifiable subset of EGFR-driven NSCLC. Clin Cancer Res; 23(6); 1531-41. ©2016 AACR.


Listeria monocytogenes, a unique model in infection biology: an overview.
This review rather than covering the whole field intends to highlight recent findings on the Listeria monocytogenes infectious process or some Listeria specific traits, place them within the framework of well-established data, and demonstrate how this Gram-positive bacterium has, in two decades, emerged as a multifaceted paradigm. Indeed, the cell biology of the infectious process has been deciphered in great detail and provided insights in both the way bacterial pathogen manipulate the host and unsuspected functions of well-known cellular proteins. The intra- and intercellular motility has in particular been instrumental in understanding actin-based motility in general. The analysis of the two main Listeria invasion proteins and that of their host specificities have illustrated how in vitro studies can help generating or choosing relevant animal models for in vivo studies. Listeria post-genomics studies have highlighted the power of comparative genomics in virulence studies. Together, Listeria, after being recognized as a powerful tool in immunology, now appears as one of the most insightful models in infection biology.


Safety and efficacy of mirabegron as 'add-on' therapy in patients with overactive bladder treated with solifenacin: a post-marketing, open-label study in Japan (MILAI study).
To examine the safety and efficacy of mirabegron as 'add-on' therapy to solifenacin in patients with overactive bladder (OAB). This multicentre, open-label, phase IV study enrolled patients aged ≥20 years with OAB, as determined by an OAB symptom score (OABSS) total of ≥3 points and an OABSS Question 3 score of ≥2 points, who were being treated with solifenacin at a stable dose of 2.5 or 5 mg once daily for at least 4 weeks. Study duration was 18 weeks, comprising a 2-week screening period and a 16-week treatment period. Patients meeting eligibility criteria continued to receive solifenacin (2.5 or 5 mg once daily) and additional mirabegron (25 mg once daily) for 16 weeks. After 8 weeks of treatment, the mirabegron dose could be increased to 50 mg if the patient's symptom improvement was not sufficient, if he/she was agreeable to the dose increase, and the investigator judged that there were no safety concerns. Safety assessments included adverse events (AEs), laboratory tests, vital signs, 12-lead electrocardiogram, QT corrected for heart rate using Fridericia's correction (QTcF) interval and post-void residual (PVR) volume. Efficacy endpoints were changes from baseline in OABSS total score, OAB questionnaire short form (OAB-q SF) score (symptom bother and total health-related quality of life [HRQL] score), mean number of micturitions/24 h, mean number of urgency episodes/24 h, mean number of urinary incontinence (UI) episodes/24 h, mean number of urgency UI episodes/24 h, mean volume voided/micturition, and mean number of nocturia episodes/night. Patients were instructed to complete the OABSS sheets at weeks -2, 0, 8 and 16 (or at discontinuation), OAB-q SF sheets at weeks 0, 8 and 16 (or at discontinuation) and patient voiding diaries at weeks 0, 4, 8, 12 and 16 (or at discontinuation). Overall incidence of drug-related treatment-emergent AEs (TEAEs) was 23.3%. Almost all TEAEs were mild or moderate. The most common TEAE was constipation, with similar incidence in the groups receiving a dose increase to that observed in the groups maintained on the original dose. Changes in PVR volume, QTcF interval, pulse rate and blood pressure were not considered to be clinically significant and there were no reports of urinary retention. Significant improvement was seen for changes in efficacy endpoints from baseline to end of treatment (EOT) in all groups (patients receiving solifenacin 2.5 or 5 mg + mirabegron 25 or 50 mg). Add-on therapy with mirabegron 25 mg once daily for 16 weeks, with an optional dose increase to 50 mg at week 8, was well tolerated in patients with OAB treated with solifenacin 2.5 mg or 5 mg once daily. There were significant improvements from baseline to EOT in OAB symptoms with combination therapy with mirabegron and solifenacin. Add-on therapy with mirabegron and an antimuscarinic agent, such as solifenacin, may provide an attractive therapeutic option.


Dexamethasone aggravates ischemia-induced neuronal damage by facilitating the onset of anoxic depolarization and the increase in the intracellular Ca2+ concentration in gerbil hippocampus.
The Ca2+ mobilization across the neuronal membrane is regarded as a crucial factor in the development of neuronal damage in ischemia. Because glucocorticoids have been reported to aggravate ischemic neuronal injury, the effects of dexamethasone on ischemia-induced membrane depolarization, histologic outcome, and changes in the intracellular Ca2+ concentration in the gerbil hippocampus were examined in vivo and in vitro. The effects of metyrapone, an inhibitor of glucocorticoid synthesis, were also evaluated. Changes in the direct-current potential shift in the hippocampal CA1 area produced by transient forebrain ischemia for 2.5 minutes were compared among animals pretreated with dexamethasone (3 microg, intracerebroventricularly), metyrapone (100 mg/kg, intraperitoneally), and saline. The histologic outcome was evaluated 7 days after ischemia by assessing the delayed neuronal death in the hippocampal CA1 pyramidal cells of these animals. A hypoxia-induced intracellular Ca2+ increase was evaluated by in vitro microfluorometry in gerbil hippocampal slices, and the effect of dexamethasone (120 microg/L in the medium) on the cytosolic Ca2+ accumulation was examined. The effect in a Ca2+-free ischemialike condition was also investigated. Preischemic administration of dexamethasone reduced the onset latency of ischemia-induced membrane depolarization by 22%, and aggravated neuronal damage in vivo. In contrast, pretreatment with metyrapone improved the histologic outcome. The onset time of the increase in the intracellular concentration of Ca2+ provoked by in vitro hypoxia was advanced in dexamethasone-treated slices. The Ca2+-free in vitro hypoxia reduced the elevation compared with that in the Ca2+-containing condition. Treatment with dexamethasone facilitated the increase on both the initiation and the extent in the Ca2+-free condition. Aggravation of ischemic neuronal injury by endogenous or exogenous glucocorticoids is thus thought to be caused by the advanced onset times of both the ischemia-induced direct-current potential shift and the increase in the intracellular Ca2+ concentration.


Preparation and Characterization of PEG-albumin-curcumin Nanoparticles Intended to Treat Breast Cancer.
The aim of present research was to prepare novel serum stable long circulating polymeric nanoparticles for curcumin with a modification to the well known and novel nanoparticle albumin bound technology. polyethylene glycol-albumin-curcumin nanoparticles were prepared using serum albumin and poly ethylene glycol using desolvation technique. Nanoparticles were characterized for encapsulation efficiency, particle size and surface morphology. Drug excipient compatibility was determined using fourier transform infrared spectroscopy. Physical state of the drug in the formulations was known by differential scanning colorimetry. In vitro release and solubility of the drug from nanoparticles were determined. In vivo Drug release, tissue uptake and kupffer cell uptake was determined with optimized nanoformulation in rats after intravenous administration. Cell viability assay was determined using breast cancer cell line MD-MB-231. Entrapment efficiency for prepared nanoparticle was above 95%. The polyethylene glycol-albumin-curcumin nanoparticles exhibited an interesting release profile with small initial burst followed by slower and controlled release. Solubility of the drug from the formulation was increased. A sustained release of drug from nanoparticles was observed for 35 days in both in vitro and in vivo studies with the optimized formulation. Polyethylene glycol-albumin-curcumin nanoparticles showed lesser liver and kupffer cell uptake as compared to that of curcumin-albumin nanoparticles suggesting the bestowment of stealthness to nanoparticles with pegylation. Also, the antiproliferative activity of polyethylene glycol-albumin-curcumin nanoparticle formulation was more as compared to native curcumin. Polyethylene glycol-albumin-curcumin nanoparticles thus developed can be conveniently used in breast cancer with improved efficacy compared to conventional therapies and as an alternate to nanoparticle albumin bound technology which is used in producing Abraxane, albumin based breast cancer targeting nanoparticles of paclitaxel.


Caudwell Xtreme Everest: A prospective study of the effects of environmental hypoxia on cognitive functioning.
The neuropsychological consequences of exposure to environmental hypobaric hypoxia (EHH) remain unclear. We thus investigated them in a large group of healthy volunteers who trekked to Mount Everest base camp (5,300 m). A neuropsychological (NP) test battery assessing memory, language, attention, and executive function was administered to 198 participants (age 44.5±13.7 years; 60% male). These were studied at baseline (sea level), 3,500 m (Namche Bazaar), 5,300 m (Everest Base Camp) and on return to 1,300 m (Kathmandu) (attrition rate 23.7%). A comparable control group (n = 25; age 44.5±14.1 years; 60% male) for comparison with trekkers was tested at/or near sea level over an equivalent timeframe so as to account for learning effects associated with repeat testing. The Reliable Change Index (RCI) was used to calculate changes in cognition and neuropsychological function during and after exposure to EHH relative to controls. Overall, attention, verbal ability and executive function declined in those exposed to EHH when the performance of the control group was taken into account (RCI .05 to -.95) with decline persisting at descent. Memory and psychomotor function showed decline at highest ascent only (RCI -.08 to -.56). However, there was inter-individual variability in response: whilst NP performance declined in most, this improved in some trekkers. Cognitive decline was greater amongst older people (r = .42; p < .0001), but was otherwise not consistently associated with socio-demographic, mood, or physiological variables. After correcting for learning effects, attention, verbal abilities and executive functioning declined with exposure to EHH. There was considerable individual variability in the response of brain function to sustained hypoxia with some participants not showing any effects of hypoxia. This might have implications for those facing sustained hypoxia as a result of any disease.


Toxins of a blue-green alga: similarity to saxitoxin.
Toxins were isolated from the freshwater blue-green alga Aphanizomenon flos-aquae. The toxic fractions were characterized by paper and thin-layer chromatography, isolation characteristics, infrared spectra, physiological activity, and reactivity with specific color reagents. The toxic fractions appear to be similar, if not identical, to saxitoxin (paralytic shellfish toxin), which is produced by the marine dinoflagellate Gonyaulax catenella.


The endocytic pathway and therapeutic efficiency of doxorubicin conjugated cholesterol-derived polymers.
Previously synthesized poly(methacrylic acid-co-cholesteryl methacrylate) P(MAA-co-CMA) copolymers were examined as potential drug delivery vehicles. P(MAA-co-CMA) copolymers were fluorescently labelled and imaged in SHEP and HepG2 cells. To understand their cell internalization pathway endocytic inhibition studies were conducted. It was concluded that P(MAA-co-CMA) are taken up by the cells via clathrin-independent endocytosis (CIE) (both caveolae mediated and cholesterol dependent endocytosis) mechanisms. The formation and characterization of P(MAA-co-CMA)-doxorubicin (DOX) nanocomplexes was investigated by fluorescence lifetime imaging microscopy (FLIM), UV-Visible spectroscopy (UV-Vis) and dynamic light scattering (DLS) studies. The toxicity screening between P(MAA-co-CMA)-DOX nanocomplexes (at varying w/w ratios) and free DOX, revealed nanocomplexes to exhibit higher cytotoxicity towards cancer cells in comparison to normal cells. FLIM and confocal microscopy were employed for investigating the time-dependent release of DOX in SHEP cells and the cellular uptake profile of P(MAA-co-CMA)-DOX nanocomplexes in cancer and normal cell lines, respectively. The endocytic pathway of P(MAA-co-CMA)-DOX nanocomplexes were examined in SHEP and HepG2 cells via flow cytometry revealing the complexes to be internalized through both clathrin-dependent (CDE) and CIE mechanisms. The drug delivery profile, reported herein, illuminates the specific endocytic route and therapeutic efficiency of P(MAA-co-CMA)-DOX nanocomplexes strongly suggesting these particles to be promising candidates for in vivo applications.


Compact and miniature snapshot imaging polarimeter.
We present and demonstrate a compact and miniature snapshot imaging polarimeter camera; it is anticipated that such a camera can be scaled down to less than 1.5 cm. Two Savart plates are used at the pupil plane to generate multiple fringes to encode the full Stokes vector in a single image. A geometric ray model is developed to explain the system. The numerical simulation based on this model is presented. Finally, the validity of the device is demonstrated by showing experimental results.


Using online blogs to explore positive outcomes after burn injuries.
This study uses blog analysis, a new and novel technique, to explore the positive outcomes experienced by burn survivors. This study examined 10 burn survivor blogs to offer a unique, longitudinal insight into burn survivor recovery. Using thematic analysis, three themes emerged: shift in self-perception, enhanced relationships and a change in life outlook. Many of these themes contained stories and experiences unique to a traumatic burn injury, suggesting that standardised trauma scales are not effectively measuring the impact of a burn in this population. Reflections on blog analysis are discussed, along with a recommendation that health researchers utilise the vast amount of data available from online blogs.


Suppression of Locomotor Activity in Female C57Bl/6J Mice Treated with Interleukin-1β: Investigating a Method for the Study of Fatigue in Laboratory Animals.
Fatigue is a disabling symptom in patients with multiple sclerosis and Parkinson's Disease, and is also common in patients with traumatic brain injury, cancer, and inflammatory disorders. Little is known about the neurobiology of fatigue, in part due to the lack of an approach to induce fatigue in laboratory animals. Fatigue is a common response to systemic challenge by pathogens, a response in part mediated through action of the pro-inflammatory cytokine interleukin-1 beta (IL-1β). We investigated the behavioral responses of mice to IL-1β. Female C57Bl/6J mice of 3 ages were administered IL-1β at various doses i.p. Interleukin-1β reduced locomotor activity, and sensitivity increased with age. Further experiments were conducted with middle-aged females. Centrally administered IL-1β dose-dependently reduced locomotor activity. Using doses of IL-1β that caused suppression of locomotor activity, we measured minimal signs of sickness, such as hyperthermia, pain or anhedonia (as measured with abdominal temperature probes, pre-treatment with the analgesic buprenorphine and through sucrose preference, respectively), all of which are responses commonly reported with higher doses. We found that middle-aged orexin-/- mice showed equivalent effects of IL-1β on locomotor activity as seen in wild-type controls, suggesting that orexins are not necessary for IL-1β -induced reductions in wheel-running. Given that the availability and success of therapeutic treatments for fatigue is currently limited, we examined the effectiveness of two potential clinical treatments, modafinil and methylphenidate. We found that these treatments were variably successful in restoring locomotor activity after IL-1β administration. This provides one step toward development of a satisfactory animal model of the multidimensional experience of fatigue, a model that could allow us to determine possible pathways through which inflammation induces fatigue, and could lead to novel treatments for reversal of fatigue.


Outcome of periacetabular osteotomy for the management of acetabular dysplasia: experience in an academic centre.
Periacetabular osteotomy (PAO) is a very effective reconstructive procedure for treatment of acetabular dysplasia. An orthopaedic paediatric surgeon and a reconstructive hip arthroplasty surgeon performed this procedure together in the early phase of their learning curve and then performed it individually. The early clinical and radiographic results of 85 consecutive PAOs performed in this academic orthopaedic unit were reviewed. The mean Merle-d'Aubigné score increased from 12.4 preoperatively to 16 at follow-up. Pre-operatively 73 hips were anteverted and 12 were neutral or retroverted. The mean angle of Wiberg improved from 5 degrees to 21 degrees (p < 0.0001) in anteverted hips, and from 9 degrees to 30 degrees in neutral or retroverted hips. The mean angle of Lequesne and de Sèze improved from 6 degrees to 35 degrees (p < 0.0001) in anteverted hips, and in neutral or retroverted hips from 9 degrees to 30 degrees (p < 0.0001). The acetabular index improved from 26 degrees to 8 degrees (p < 0.0001) in anteverted hips, and from 21 degrees to 7 degrees (p < 0.0001) in neutral or retroverted hips. Over the 7 year period the blood loss and operative time improved from 2000 ml to 900 ml and 4 hours to 2 hours respectively. Four hips (four patients) required conversion to total hip replacement. The radiographic correction and improved clinical scores are similar to those in previous studies. This study shows a survival rate of 94% at 58 months following periacetabular osteotomy. The learning curve and the early results of this procedure performed in our academic unit are encouraging.


Fen1 mutations that specifically disrupt its interaction with PCNA cause aneuploidy-associated cancer.
DNA replication and repair are critical processes for all living organisms to ensure faithful duplication and transmission of genetic information. Flap endonuclease 1 (Fen1), a structure-specific nuclease, plays an important role in multiple DNA metabolic pathways and maintenance of genome stability. Human FEN1 mutations that impair its exonuclease activity have been linked to cancer development. FEN1 interacts with multiple proteins, including proliferation cell nuclear antigen (PCNA), to form various functional complexes. Interactions with these proteins are considered to be the key molecular mechanisms mediating FEN1's key biological functions. The current challenge is to experimentally demonstrate the biological consequence of a specific interaction without compromising other functions of a desired protein. To address this issue, we established a mutant mouse model harboring a FEN1 point mutation (F343A/F344A, FFAA), which specifically abolishes the FEN1/PCNA interaction. We show that the FFAA mutation causes defects in RNA primer removal and long-patch base excision repair, even in the heterozygous state, resulting in numerous DNA breaks. These breaks activate the G2/M checkpoint protein, Chk1, and induce near-tetraploid aneuploidy, commonly observed in human cancer, consequently elevating the transformation frequency. Consistent with this, inhibition of aneuploidy formation by a Chk1 inhibitor significantly suppressed the cellular transformation. WT/FFAA FEN1 mutant mice develop aneuploidy-associated cancer at a high frequency. Thus, this study establishes an exemplary case for investigating the biological significance of protein-protein interactions by knock-in of a point mutation rather than knock-out of a whole gene.


A new DNA-dependent ATPase which stimulates yeast DNA polymerase I and has DNA-unwinding activity.
Two forms of DNA-dependent ATPase activity were previously purified from the yeast Saccharomyces cerevisiae and characterized (Plevani, P., Badaracco, G., and Chang, L. M. S. (1980) J. Biol. Chem. 255, 4957-4963). Here, an additional DNA-dependent ATPase (ATPase III) has been purified from S. cerevisiae to near homogeneity. This ATPase differs from those described previously in its chromatographic properties, molecular weight, reaction properties and immunological relatedness. Its molecular weight is about 63,000 in the presence of sodium dodecyl sulfate. It hydrolyzes ATP to ADP and orthophosphate in the presence of DNA as an effector. In addition, yeast DNA polymerase I, which is a true DNA replicase of yeast, is stimulated severalfold by this ATPase. Neither yeast DNA polymerase II nor prokaryotic DNA polymerases are stimulated. This stimulation is intrinsic to the ATPase activity, since both activities copurified in the last four steps of purification, showed the same heat stability and showed dependence on and hydrolysis of ATP. The ATPase III preparation also contains a DNA-unwinding (DNA helicase) activity, which unwinds double-stranded DNA in the presence of ATP. In the S. cerevisiae radiation-sensitive mutant rad3, no significant ATPase III activity could be detected, suggesting that the RAD3 gene, which codes for a different polypeptide, regulates the expression of ATPase III activity.


Raman and photocurrent imaging of electrical stress-induced p-n junctions in graphene.
Electrostatically doped graphene p-n junctions can be formed by applying large source-drain and source-gate biases to a graphene field-effect transistor, which results in trapped charges in part of the channel gate oxide. We measure the temperature distribution in situ during the electrical stress and characterize the resulting p-n junctions by Raman spectroscopy and photocurrent microscopy. Doping levels, the size of the doped graphene segments, and the abruptness of the p-n junctions are all extracted. Additional voltage probes can limit the length of the doped segments by acting as heat sinks. The spatial location of the identified potential steps coincides with the position where a photocurrent is generated, confirming the creation of p-n junctions.


Routine repeat head CT for minimal head injury is unnecessary.
Patients with MHI and a positive head computed tomography (CT) scan frequently have a routine repeat head CT (RRHCT) to identify possible evolution of the head injury requiring intervention. RRHCT is ordered based on the premise that significant injury progression may take place in the absence of clinical deterioration. In a Level I urban trauma center with a policy of RRHCT, we reviewed the records of 692 consecutive trauma patients with Glasgow Coma Scale scores of 13-15 and a head CT (October 2004 through October 2005). The need for medical or surgical neurologic intervention after RRHCT was recorded. Patients with a worse and unchanged RRHCT were compared, and independent predictors of a worse RRHCT were identified by stepwise logistic regression. There were 179 patients with MHI and RRHCT ordered. Of them, 37 (21%) showed signs of injury evolution on RRHCT and 7 (4%) required intervention. All 7 had clinical deterioration preceding RRHCT. In no patient without clinical deterioration did RRHCT prompt a change in management. A Glasgow Coma Scale score less than 15 (13 or 14), age higher than 65 years, multiple traumatic lesions found on first head CT, and interval shorter than 90 minutes from arrival to first head CT predicted independently a worse RRHCT. RRHCT is unnecessary in patients with MHI. Clinical examination identifies accurately the few who will show significant evolution and require intervention.


A Java Application to Characterize Biomolecules and Nanomaterials in Electrolyte Aqueous Solutions.
The electrostatic, entropic and surface interactions between a macroion (nanoparticle or biomolecule), surrounding ions and water molecules play a fundamental role in the behavior and function of colloidal systems. However, the molecular mechanisms governing these phenomena are still poorly understood. One of the major limitations in procuring this understanding is the lack of appropriate computational tools. Additionally, only experts in the field with an extensive background in programming, who are trained in statistical mechanics, and have access to supercomputers are able to study these systems. To overcome these limitations, in this article, we present a free, multiplatform, portable Java software, which provides experts and non-experts in the field an easy and efficient way to obtain an accurate molecular characterization of electrical and structural properties of aqueous electrolyte mixture solutions around both cylindrical- and spherical-like rigid macroions under multiple conditions. These properties include the normalized ions and water density profile distributions, the mean electrostatic potential, the integrated charge, the zeta potential, the electrostatic potential energy, the particle crowding entropy energy, the ion-ion electrostatic direct correlation energy, and the ionic potential of mean force. The Java software does not require outstanding skills and comes with detailed user-guide documentation. The application is based on the so-called Classical Density Functional Theory Solver (CSDFTS), which was successfully applied to a variety of rod-like biopolymers, rigid-like globular proteins, nanoparticles, and nano-rods. CSDFTS implements several electrolyte and macroion models, uses different levels of approximation and takes advantage of high performance Fortran90 routines and optimized libraries. These features enable the software to run on single processor computers at low-to-moderate computational cost depending on the computer performance, the grid resolution, and the characterization of the macroion and the electrolyte solution, among other factors. As a unique feature, the software comes with a graphical user interface (GUI) that allows users to take advantage of the visually guided setup of the required input data to properly characterize the system and configure the solver. Several examples on nanomaterials and biomolecules are provided to illustrate the use of the GUI and the solver performance.


Regional patterns of cerebral cortical differentiation determined by diffusion tensor MRI.
The morphology of axonal and dendritic arbors in the immature cerebral cortex influences the degree of anisotropy in water diffusion. This enables cortical maturation to be monitored by the noninvasive technique of diffusion tensor magnetic resonance imaging (DTI). Herein, we utilized DTI of postmortem ferret brain to quantify regional and temporal patterns in cortical maturation. We found that diffusion anisotropy within the isocortex decreases over the first month of life, coinciding closely in time with expansion of axonal and dendritic cellular processes of pyramidal neurons. Regional patterns consist of differences between allocortex and isocortex, a regional anisotropy gradient that closely parallels the transverse neurogenetic gradient, and differences between primary and nonprimary isocortical areas. By combining the temporal and regional factors, the isocortical developmental gradient magnitude corresponds to a 5-day difference in maturity between relatively developed rostral/caudal isocortex at the gradient source and less mature isocortex at the occipital pole. Additionally, the developmental trajectory of primary areas precedes nonprimary areas by 2.7 days. These quantitative estimates coincide with previous histological studies of ferret development. Similarities in cerebral cortical diffusion anisotropy observed between ferret and other species suggest the framework developed here is of general potential relevance.


Bilateral Radicular Cyst with Severe Destruction of the Buccal Cortical Plate Secondary to Endodontic Failure.
Large apical radiolucencies after endodontic treatment are usually advised orthograde retreatment, apical surgery and that too with a guarded prognosis. Microsurgical techniques, the use of ultrasonic and magnification aides, have been in use in the developed countries for the past few decades and have shown significant improvement in long-term success of such cases. MTA is proposed as one of the best materials for sealing root end surfaces. In this report, the healing response of cases of 2 large apical radiolucencies, found separately in the anterior maxilla, which were treated by orthograde as well as retrograde endodontic treatments and guided tissue regeneration techniques.


Hepatic disposition of cationic drugs bound to asialoorosomucoid: lack of coendocytosis and evidence for intrahepatic dissociation.
A combination of protein binding, liver clearance, subcellular distribution and cell separation experiments was employed to investigate the influence of binding of cationic drugs to asialoorosomucoid (ASOR) on their hepatic uptake and intrahepatic distribution. Two quaternary ammonium drugs, d-tubocurarine and N-methyldeptropine, were selected because of their marked differences in hepatic processing and binding to ASOR. In spite of an increase in protein binding of 560% for d-tubocurarine and 380% for N-methyldeptropine, perfusate clearance of both drugs in isolated perfused rat livers was not influenced by addition of 75 mg of ASOR. Absence of coendocytosis was indicated by subcellular distribution studies revealing no extra enrichment of quaternary ammonium drugs in lysosomal fractions compared with control studies. Isolation of parenchymal and sinusoidal liver cells demonstrated d-tubocurarine to be present solely in hepatocytes; binding to ASOR did not affect the relative distribution in the various cell types. It is concluded that binding of cationic drugs to ASOR does not result in endocytosis of a drug-protein-receptor complex by the liver. This result rather suggests that dissociation of the organic cations from the asialoglycoprotein occurs within the liver before endocytosis of the glycoprotein.


A computational module assembled from different protease family motifs identifies PI PLC from Bacillus cereus as a putative prolyl peptidase with a serine protease scaffold.
Proteolytic enzymes have evolved several mechanisms to cleave peptide bonds. These distinct types have been systematically categorized in the MEROPS database. While a BLAST search on these proteases identifies homologous proteins, sequence alignment methods often fail to identify relationships arising from convergent evolution, exon shuffling, and modular reuse of catalytic units. We have previously established a computational method to detect functions in proteins based on the spatial and electrostatic properties of the catalytic residues (CLASP). CLASP identified a promiscuous serine protease scaffold in alkaline phosphatases (AP) and a scaffold recognizing a β-lactam (imipenem) in a cold-active Vibrio AP. Subsequently, we defined a methodology to quantify promiscuous activities in a wide range of proteins. Here, we assemble a module which encapsulates the multifarious motifs used by protease families listed in the MEROPS database. Since APs and proteases are an integral component of outer membrane vesicles (OMV), we sought to query other OMV proteins, like phospholipase C (PLC), using this search module. Our analysis indicated that phosphoinositide-specific PLC from Bacillus cereus is a serine protease. This was validated by protease assays, mass spectrometry and by inhibition of the native phospholipase activity of PI-PLC by the well-known serine protease inhibitor AEBSF (IC50 = 0.018 mM). Edman degradation analysis linked the specificity of the protease activity to a proline in the amino terminal, suggesting that the PI-PLC is a prolyl peptidase. Thus, we propose a computational method of extending protein families based on the spatial and electrostatic congruence of active site residues.


Relationship between family history of alcohol addiction, parents' education level, and smartphone problem use scale scores.
Background and aims Smartphones are ubiquitous. As smartphones increased in popularity, researchers realized that people were becoming dependent on their smartphones. The purpose here was to provide a better understanding of the factors related to problematic smartphone use (PSPU). Methods The participants were 100 undergraduates (25 males, 75 females) whose ages ranged from 18 to 23 (mean age = 20 years). The participants completed questionnaires to assess gender, ethnicity, year in college, father's education level, mother's education level, family income, age, family history of alcoholism, and PSPU. The Family Tree Questionnaire assessed family history of alcoholism. The Mobile Phone Problem Use Scale (MPPUS) and the Adapted Cell Phone Addiction Test (ACPAT) were used to determine the degree of PSPU. Whereas the MPPUS measures tolerance, escape from other problems, withdrawal, craving, and negative life consequences, the ACPAT measures preoccupation (salience), excessive use, neglecting work, anticipation, lack of control, and neglecting social life. Results Family history of alcoholism and father's education level together explained 26% of the variance in the MPPUS scores and 25% of the variance in the ACPAT scores. The inclusion of mother's education level, ethnicity, family income, age, year in college, and gender did not significantly increase the proportion of variance explained for either MPPUS or ACPAT scores. Discussion and conclusions Family history of alcoholism and father's education level are good predictors of PSPU. As 74%-75% of the variance in PSPU scale scores was not explained, future studies should aim to explain this variance.


p16Ink4a Prevents the Activation of Aged Quiescent Dentate Gyrus Stem Cells by Physical Exercise.
In the neurogenic niches-the dentate gyrus of the hippocampus and the subventricular zone (SVZ) adjacent to lateral ventricles-stem cells continue to divide during adulthood, generating progenitor cells and new neurons, and to self-renew, thus maintaining the stem cell pool. During aging, the numbers of stem/progenitor cells in the neurogenic niches are reduced. The preservation of the neurogenic pool is committed to a number of antiproliferative genes, with the role of maintaining the quiescence of neural cells. The cyclin-dependent kinase inhibitor p16Ink4a, whose expression increases with age, controls the expansion of SVZ aging stem cells, since in mice its deficiency prevents the decline of neurogenesis in SVZ. No change of neurogenesis is however observed in the p16Ink4a-null dentate gyrus. Here, we hypothesized that p16Ink4a plays a role as a regulator of the self-renewal of the stem cell pool also in the dentate gyrus, and to test this possibility we stimulated the dentate gyrus neural cells of p16Ink4a-null aging mice with physical exercise, a powerful neurogenic activator. We observed that running highly induced the generation of new stem cells in the p16Ink4a-null dentate gyrus, forcing them to exit from quiescence. Stem cells, notably, are not induced to proliferate by running in wild-type (WT) mice. Moreover, p16Ink4a-null progenitor cells were increased by running significantly above the number observed in WT mice. The new stem and progenitor cells generated new neurons, and continued to actively proliferate in p16Ink4a-null mice longer than in the WT after cessation of exercise. Thus, p16Ink4a prevents aging dentate gyrus stem cells from being activated by exercise. Therefore, p16Ink4a may play a role in the maintenance of dentate gyrus stem cells after stimulus, by keeping a reserve of their self-renewal capacity during aging.


Repeated exposure to sexually explicit stimuli: novelty, sex, and sexual attitudes.
The effects of a new stimulus following repeated exposure to a familiar, sexually explicit stimulus were studied. Female and male subjects (N = 56) viewed an explicitly heterosexual film daily for 4 days and then were exposed to either a film showing the same actors engaging in different sexual acts or one with different actors engaging in the same activities shown in the original film. Analyses of self-rated responses showed that negative affect significantly increased with film repetition and returned to original levels with the introduction of novelty. Erotophobia was associated with negative affect. Results for self-reported sexual arousal and concern ratings revealed sex differences, with males becoming more aroused and concerned by novelty consisting of different actors, and females becoming more aroused and concerned by the same actors performing different acts. Affective and cognitive theories of human sexual responding provided possible explanations for these results.


TTC4, a novel human gene containing the tetratricopeptide repeat and mapping to the region of chromosome 1p31 that is frequently deleted in sporadic breast cancer.
The 1p31 region shows loss of heterozygosity in up to 50% of human breast cancers, indicating the presence of a tumor suppressor gene in this location. We have mapped six novel ESTs to a 15-Mb contig of yeast artificial chromosomes spanning the critical region of 1p31. One of these ESTs was localized within the contig to the region most commonly undergoing loss of heterozygosity in breast cancer. The corresponding gene sequence for this EST was established by cDNA cloning and RACE procedures. This gene is 2 kb long and contains a tetratricopeptide repeat motif and a coiled-coil domain. This family of genes has been implicated in a wide variety of functions, including tumorigenesis. This is the fourth member of the human gene family, and so we have named this gene TTC4. Northern blot analysis demonstrates a ubiquitous pattern of gene expression that includes breast tissue. A preliminary screen of human breast cancer cell lines shows that TTC4 is expressed in all cases, but SSCP analysis of the coding region of this gene following RT-PCR failed to reveal any mutations. Clearly, because of its map location, a more extensive analysis is warranted to establish whether subtle mutations are present in breast cancers.


Identification of novel SH3 domain ligands for the Src family kinase Hck. Wiskott-Aldrich syndrome protein (WASP), WASP-interacting protein (WIP), and ELMO1.
The importance of the SH3 domain of Hck in kinase regulation, substrate phosphorylation, and ligand binding has been established. However, few in vivo ligands are known for the SH3 domain of Hck. In this study, we used mass spectrometry to identify approximately 25 potential binding partners for the SH3 domain of Hck from the monocyte cell line U937. Two major interacting proteins were the actin binding proteins Wiskott-Aldrich syndrome protein (WASP) and WASP-interacting protein (WIP). We also focused on a novel interaction between Hck and ELMO1, an 84-kDa protein that was recently identified as the mammalian ortholog of the Caenorhabditis elegans gene, ced-12. In mammalian cells, ELMO1 interacts with Dock180 as a component of the CrkII/Dock180/Rac pathway responsible for phagocytosis and cell migration. Using purified proteins, we confirmed that WASP-interacting protein and ELMO1 interact directly with the SH3 domain of Hck. We also show that Hck and ELMO1 interact in intact cells and that ELMO1 is heavily tyrosine-phosphorylated in cells that co-express Hck, suggesting that it is a substrate of Hck. The binding of ELMO1 to Hck is specifically dependent on the interaction of a polyproline motif with the SH3 domain of Hck. Our results suggest that these proteins may be novel activators/effectors of Hck.


Molecular mechanisms of collateral sensitivity to the antibiotic nitrofurantoin.
Antibiotic resistance increasingly limits the success of antibiotic treatments, and physicians require new ways to achieve efficient treatment despite resistance. Resistance mechanisms against a specific antibiotic class frequently confer increased susceptibility to other antibiotic classes, a phenomenon designated collateral sensitivity (CS). An informed switch of antibiotic may thus enable the efficient treatment of resistant strains. CS occurs in many pathogens, but the mechanisms that generate hypersusceptibility are largely unknown. We identified several molecular mechanisms of CS against the antibiotic nitrofurantoin (NIT). Mutants that are resistant against tigecycline (tetracycline), mecillinam (β-lactam), and protamine (antimicrobial peptide) all show CS against NIT. Their hypersusceptibility is explained by the overexpression of nitroreductase enzymes combined with increased drug uptake rates, or increased drug toxicity. Increased toxicity occurs through interference of the native drug-response system for NIT, the SOS response, with growth. A mechanistic understanding of CS will help to develop drug switches that combat resistance.


Curvilinear transurethral ultrasound applicator for selective prostate thermal therapy.
Thermal therapy offers a minimally invasive option for treating benign prostatic hyperplasia (BPH) and localized prostate cancer. In this study we investigated a transurethral ultrasound applicator design utilizing curvilinear, or slightly focused, transducers to heat prostatic tissue rapidly and controllably. The applicator was constructed with two independently powered transducer segments operating at 6.5 MHz and measuring 3.5 mm x 10 mm with a 15 mm radius of curvature across the short axis. The curvilinear applicator was characterized by acoustic efficiency measurements, acoustic beam plots, biothermal simulations of human prostate, ex vivo heating trials in bovine liver, and in vivo heating trials in canine prostate (n=3). Each transducer segment was found to emit a narrow acoustic beam (max width <3 mm), which extended the length of the transducer, with deeper penetration than previously developed planar or sectored tubular transurethral ultrasound applicators. Acoustic and biothermal simulations of human prostate demonstrated three treatment schemes for the curvilinear applicator: single shot (10 W, 60 s) schemes to generate narrow ablation zones (13 x 4 mm, 52 degrees C at the lesion boundary), incremental rotation (10 W, 10 degrees/45 s) to generate larger sector-shaped ablation zones (16 mm x 180 degrees sector), and rotation with variable sonication times (10 W, 10 degrees/15-90 s) to conform the ablation zone to a predefined boundary (9-17 mm x 180 degrees sector, 13 min total treatment time). During in vivo canine prostate experiments, guided by MR temperature imaging, single shot sonications (6 W/transducer, 2-3 min) with the curvilinear applicator ablated 20 degree sections of tissue to the prostate boundary (9-15 mm). Multiple adjacent sonications ("sweeping") ablated large sections of the prostate (180 degrees) by using the MR temperature imaging to adjust the power (4-6.4 W/transducer) and sonication time (30-180 s) at each 10 degrees rotation such that the periphery of the prostate reached 52 degrees C before the next rotation. The conclusion of this study was that the curvilinear applicator produces a narrow and penetrating ultrasound beam that, when combined with image guidance, can provide a precise technique for ablating target regions with a contoured outer boundary, such as the prostate capsule, by rotating in small steps while dynamically adjusting the net applied electrical power and sonication time at each position.


Pleural controversies: indwelling pleural catheter vs. pleurodesis for malignant pleural effusions.
Malignant pleural effusions (MPE) are frequent consequences of malignant disease and significantly impair the quality of life (QoL) of patients. There are two main options for the palliation of MPE-related symptoms: obliterating the pleural space by pleurodesis to prevent further fluid reaccumulation, or chronically draining the pleural fluid with an indwelling pleural catheter (IPC). There is controversy as to which approach is superior each having advantages and drawbacks. Pleurodesis offers a higher chance of rapid resolution of the pleural effusion with an intervention that is time limited but at the expense of a more invasive procedure, the need for a hospital stay and a higher need for repeat procedures. IPC offers an outpatient solution which is less invasive but at the cost of prolonged catheter drainages and care in a significant portion of patients who will not achieve pleurodesis. Impact on QoL, symptom relief and costs do not appear to be significantly different between the two options. Treatment of MPE should be tailored to the patient's functional status, comorbidities, prognosis and personal preferences as well as local expertise. Hybrid approaches using pleurodesis techniques and IPC concomitantly may come into play in the near future to further improve patient care.


Cardiovascular risk among university students from developed and developing nations.
A key aspect in halting global increase in cardiovascular events is prevention and especially prevention at an early age. Unfortunately, global data regarding cardiovascular risk factors in the young are limited. Therefore the objectives of this study were to identify the most common cardiovascular risk factors among young adults in a university setting in both developed and developing countries. Lifestyle and cardiovascular risk factors (smoking status, rates of physical activity, alcohol use, family history, blood pressure, fasting lipid panel, fasting blood glucose) were prospectively evaluated in young adults at three different university settings [University of Michigan (Ann Arbor, USA), University of Kalamoon (Deratiah, Syria), and Kakatiya University (Warangal, India)]. A total of 296 subjects (mean age and standard deviation 22 ± 3 years) were evaluated. Rates of current smoking were markedly higher (p < 0.001) in Syria (43%) compared with the USA (6.2%) and India (1.7%). Subjects in India were significantly (p < 0.001) less likely to engage in physical activity (20.2%) compared with the USA (90.7%) and Syria (68.8%). Fasting blood glucose levels and body mass index were significantly higher (p < 0.001) in Syria as compared to other countries. Significant differences were also noted in LDL, HDL, and triglycerides among the three sites. Cardiovascular risk factors among young adults in a university setting vary depending on global setting. Based upon the results of this study, targeted interventional programs based on risk findings from individual countries may be a reasonable future strategy to help reduce long term cardiovascular morbidity and mortality.


Simultaneous enzyme mimicking and chemical reduction mechanisms for nanoceria as a bio-antioxidant: a catalytic model bridging computations and experiments for nanozymes.
The bio-antioxidant ability of nanoceria has been mainly ascribed to its ability to mimic superoxide dismutase (SOD) and catalase (CAT), and its mechanisms are thought to be analogous to those of the natural enzymes. Accordingly, nanoceria has been called a nanozyme, a nanomaterial mimicking enzymes. Because they overlook the real structural features of nanoceria, these hypothetical mechanisms cannot explain the important antioxidant experiments of nanoceria and have little predictive power. We hereby study the O2˙- and H2O2 scavenging mechanisms of nanoceria using first principles calculations, taking into account the role of oxygen vacancies that are practically abundant in nanoceria. The results reveal atomistic-level mechanisms responsible for the SOD and CAT mimetic activities of nanoceria. The newly created surface defect states in the electronic band structures of the shortly-lived intermediate species, called transient surface defect states (TSDSs), play critical roles in the enzyme mimetic catalysis and can serve as the bridge between computations and experiments at the atomistic level. The energy levels of TSDSs, which depend on the concentration and distribution of oxygen vacancies, determine whether the nanoceria is eligible for the catalysis. Besides the known enzyme mimicking mechanisms, the non-catalytic chemical reduction mechanisms are also responsible for the scavenging of O2˙- and H2O2, in which nanoceria serves as a reducing agent rather than a catalyst. The chemical reduction pathways poison the active sites of nanoceria which serve to mimic SOD and thus deteriorate its SOD mimetic activity. The results provide guidance for the engineering of nanoceria for bio-antioxidant applications. In particular, the proposed catalytic model can be generalized for the screening and design of high-performance nanozymes based on semiconductor nanomaterials.


Macular Inner Retinal Layer Thickening and Outer Retinal Layer Damage Correlate With Visual Acuity During Remission in Behcet's Disease.
To identify macular intraretinal layer changes of patients in remission from Behcet's disease (BD) of short and long duration and evaluate the associations with visual acuity (VA). Thirty-two eyes from 26 BD patients were enrolled, including 16 eyes with a duration less than 3 years (0.5-2.5 years; BD1) and 16 eyes of longer duration (3-12 years; BD2). Their intraretinal layer thicknesses and integrity of ellipsoid zone (EZ) and interdigitation zone (IZ) were evaluated by spectral-domain optical coherence tomography (SD-OCT). Associations between VA and retinal structural changes were analyzed. Compared to controls, the inner retina was significantly thicker in BD groups, especially the nerve fiber layer (NFL). The outer retinal layer (ORL) was thicker in BD1 in the central and temporal regions and thinner in BD2 compared to controls in all regions. In BD2, there were more eyes with disruption of the EZ and IZ. Worsening VA was correlated with thickening of the NFL and inner nuclear layer (INL), thinning of the ORL, and greater disruption of the EZ and IZ. Multiple linear regression analysis revealed EZ disruption, nasal ORL, inferior NFL, and temporal and nasal INLs were independent predictors of best-corrected (BCVA). Behcet's disease patients in remission had significant changes in the inner and outer retinal structures, associated with worse VA. Thickness and integrity of the intraretinal layers by SD-OCT and segmentation might be useful predictors for the degree of VA damage in BD remission.


Therapeutic footwear can reduce plantar pressures in patients with diabetes and transmetatarsal amputation.
To compare how footwear (full-length shoe or short shoe), a total contact insert, a rigid rocker-bottom (RRB) sole, and an ankle-foot orthosis (AFO) affect peak plantar pressure (PPP) on the distal residuum and contralateral extremity of patients with diabetes and transmetatarsal amputation (TMA). Thirty patients with diabetes and TMA participated (mean age 62 +/- 4 years). In-shoe plantar pressures during walking were measured in six types of footwear. Each measurement occurred after a 1-month adjustment period. Repeated measure analysis of variance (ANOVA) was used to compare treatments. All five types of therapeutic footwear reduced plantar pressures compared with regular shoes with a toe-filler (P < 0.05). A full-length shoe, total contact insert, and RRB sole resulted in lower pressures on the distal residuum (222 vs. 284 kPa) and forefoot of the contralateral extremity (197 vs. 239 kPa), compared with a regular shoe and toe-filler. Footwear with an AFO showed reduced PPP on the residuum, but most patients complained of reduced ankle motion during walking. A short shoe reduced pressures on the residuum, but not on the contralateral extremity, and many patients had complaints regarding cosmesis of the shoe. The full-length shoe, total contact insert, and an RRB sole provided the best pressure reduction for the residuum and contralateral foot, with the optimal compromise for cosmetic acceptance and function.


Copper ions disrupt dopamine metabolism via inhibition of V-H+-ATPase: a possible contributing factor to neurotoxicity.
The involvement of copper in the pathophysiology of neurodegeneration has been well documented but is not fully understood. Commonly, the effects are attributed to increased reactive oxygen species (ROS) production due to inherent redox properties of copper ions. Here we show copper can have physiological effects distinct from direct ROS production. First, we show that extragranular free copper inhibits the vesicular H(+)-ATPase of resealed chromaffin granule ghosts. Extragranular ascorbate potentiates this inhibition. The inhibition is mixed type with K(is) = 6.8 +/- 2.8 micromol/L and K(ii) = 3.8 +/- 0.6 micromol/L, with respect to ATP. Second, extracellular copper causes an inhibition of the generation of a pH-gradient and rapid dissipation of pre-generated pH and catecholamine gradients. Copper chelators and the ss-amyloid peptide 1-42 were found to effectively prevent the inhibition. The inhibition is reversible and time-independent suggesting the effects of extracellular copper on H(+)-ATPase is direct, and not due to ROS. The physiological significance of these observations was shown by the demonstration that extracellular copper causes a dramatic perturbation of dopamine metabolism in SH-SY5Y cells. Thus, we propose that the direct inhibition of the vesicular H(+)-ATPase may also contribute to the neurotoxic effects of copper.


An Open-Source Storage Solution for Cryo-Electron Microscopy Samples.
Cryo-electron microscopy (cryo-EM) enables the study of biological structures in situ in great detail and to solve protein structures at Ångstrom level resolution. Due to recent advances in instrumentation and data processing, the field of cryo-EM is a rapidly growing. Access to facilities and national centers that house the state-of-the-art microscopes is limited due to the ever-rising demand, resulting in long wait times between sample preparation and data acquisition. To improve sample storage, we have developed a cryo-storage system with an efficient, high storage capacity that enables sample storage in a highly organized manner. This system is simple to use, cost-effective and easily adaptable for any type of grid storage box and dewar and any size cryo-EM laboratory.


Multiscale computational models can guide experimentation and targeted measurements for crop improvement.
Computational models of plants have identified gaps in our understanding of biological systems, and have revealed ways to optimize cellular processes or organ-level architecture to increase productivity. Thus, computational models are learning tools that help direct experimentation and measurements. Models are simplifications of complex systems, and often simulate specific processes at single scales (e.g. temporal, spatial, organizational, etc.). Consequently, single-scale models are unable to capture the critical cross-scale interactions that result in emergent properties of the system. In this perspective article, we contend that to accurately predict how a plant will respond in an untested environment, it is necessary to integrate mathematical models across biological scales. Computationally mimicking the flow of biological information from the genome to the phenome is an important step in discovering new experimental strategies to improve crops. A key challenge is to connect models across biological, temporal and computational (e.g. CPU versus GPU) scales, and then to visualize and interpret integrated model outputs. We address this challenge by describing the efforts of the international Crops in silico consortium.


Open to offers, but resisting requests: How the framing of anchors affects motivation and negotiated outcomes.
Abundant research has established that first proposals can anchor negotiations and lead to a first-mover advantage. The current research developed and tested a motivated anchor adjustment hypothesis that integrates the literatures on framing and anchoring and highlights how anchoring in negotiations differs in significant ways from standard decision-making contexts. Our research begins with the premise that first proposals can be framed as either an offer of resources (e.g., I am offering my A for your B) that highlights gains versus a request for resources (e.g., I am requesting your B for my A) that highlights losses to a responder. We propose that this framing would affect the concession aversion of responders and ultimately the negotiated outcomes. We predicted that when a first proposal is framed as an offer, the well-documented anchoring and first-mover advantage effect would emerge because offers do not create high levels of concession aversion. In contrast, because requests highlight what the responder has to give up, we predicted that opening requests would produce concession aversion and eliminate and even reverse the first-mover advantage. Across 5 experiments, the classic first-mover advantage in negotiations was moderated by the framing of proposals because anchor framing affected concession aversion. The studies highlight how motivational forces (i.e., concession aversion) play an important role in producing anchoring effects, which has been predominantly viewed through a purely cognitive lens. Overall, the findings highlight when and how motivational processes play a key role in both judgmental heuristics and mixed-motive decision-making. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


How does solar ultraviolet-B radiation improve drought tolerance of silver birch (Betula pendula Roth.) seedlings?
We hypothesized that solar ultraviolet (UV) radiation would protect silver birch seedlings from the detrimental effects of water stress through a coordinated suite of trait responses, including morphological acclimation, improved control of water loss through gas exchange and hydraulic sufficiency. To better understand how this synergetic interaction works, plants were grown in an experiment under nine treatment combinations attenuating ultraviolet-A and ultraviolet-B (UVB) from solar radiation together with differential watering to create water-deficit conditions. In seedlings under water deficit, UV attenuation reduced height growth, leaf production and leaf length compared with seedlings receiving the full spectrum of solar radiation, whereas the growth and morphology of well-watered seedlings was largely unaffected by UV attenuation. There was an interactive effect of the treatment combination on water relations, which was more apparent as a change in the water potential at which leaves wilted or plants died than through differences in gas exchange. This suggests that changes occur in the cell wall elastic modulus or accumulation of osmolites in cells under UVB. Overall, the strong negative effects of water deficit are partially ameliorated by solar UV radiation, whereas well-watered silver birch seedlings are slightly disadvantaged by the solar UV radiation they receive.


Reproducibility of an indirect immunofluorescent-antibody technique for capsular serotyping of Klebsiella pneumoniae.
Reproducibility of capsular serotypes of 55 consecutive clinical isolates of Klebsiella pneumoniae was evaluated by an indirect immunofluorescent-antibody technique previously described by Riser et al. (J. Clin. Pathol. 29: 296-304, 1976) Five colonies per specimen were examined for colony-to-colony variation, day-to-day variation, and reader-to-reader variation. Seventy-two reference strains were tested with each of 18 pools and 72 specific antisera prior to the clinical specimens to determine antiserum specificity and cross-reaction patterns. Lot-to-lot variation was examined with the reference strains. There was minimal lot-to-lot variation among the antisera tested. Ten antiserum pools required supplementation with individual antisera. The patterns of supplementation may vary from lot to lot. Colony-to-colony variation in intensity of immunofluorescence occurred, but there was no variation in serotype. These findings differ from previously reported colonial variation which occurred when API 20E biotypes were determined for individual colonies of K. pneumoniae directly from clinical specimens. Eighteen percent of clinical isolates studied gave cross-reactions when tested with the indicated specific antiserum. All but one of the cross-reactions were resolved with further dilutions. Day-to-day and reader-to-reader variations were minimal. The immunofluorescent-antibody technique is a reliable and reproducible method for capsular serotype determination. Capsular serotypes are less variable than API biotypes since colony-to-colony variation of serotype does not occur.


The effect of prostate tissue inflammation in benign prostatic hyperplasia on enhancer of zeste homolog 2 ribonucleic acid expression.
Enhancer of zeste homolog 2 (EZH2) has been recently found to regulate several genes involved in immunoresponse and autocrine inflammation network. The aim of the study was to quantitate EZH2 messenger ribonucleic acid (mRNA) expression, evaluate its relation to conditions of prostatitis associated with benign prostatic hyperplasia (BPH), and correlate it with the levels of the inflammatory marker interlukin 6 (IL-6). Cross-sectional study in Middle Eastern men with BPH and prostatitis or BPH only. Transrectal ultrasound-guided prostate biopsies were collected from 106 patients suspected of having prostate cancer; however, the histology revealed BPH. Upon further pathological examination, 56 of these cases were identified as BPH with prostatitis and classified as: acute prostatitis (n=13); active chronic prostatitis (n=32); and, chronic inactive prostatitis (n=12). Serum IL-6 levels and EZH2 mRNA expression were measured and compared between patient groups. EZH2 mRNA was overexpressed in BPH with prostatitis patients compared to BPH only patients (P<.0001). BPH with active chronic prostatitis had higher EZH2 expression than BPH with acute or chronic inactive prostatitis compared to BPH only (P=.05 and .73, respectively). EZH2 mRNA expression showed a negative correlation with IL-6 concentrations in BPH with prostatitis patients (rs=-0.31, P=.02). EZH2 overexpression was associated with an increased risk of having BPH with prostatitis (crude odds ratio 0.20, 95% CI 0.06-0.65, P=.0076). EZH2 mRNA expression correlates positively with prostatitis conditions associated with BPH and negatively with serum IL-6 levels. This supports the possible involvement of EZH2 mRNA overexpression in the development of prostate inflammation, and its new regulatory role in suppressing the expression of some inflammatory network genes.


Creating a physician-led quality imperative.
To emerge from a significant quality crisis, hospital administration recognized the need for physician leadership to drive improvements. A framework is presented for a physician-led Quality Summit to select best practice initiatives for implementation over 1 year. Results demonstrated statistically significant reductions in ventilator-associated pneumonia, decreasing from the first quarter 2009 baseline of 8.34 per 1000 ventilator days to 3.32 per 1000 ventilator days in second quarter 2010 (P = .0055). During the same time frame, catheter-associated urinary tract infections decreased from 4.35 per 1000 catheter days to 0.98 per 1000 catheter days (P = .0438), and severe sepsis/septic shock mortality declined from 33% to 13% (P = .0084). The customized World Health Organization Surgical Safety Checklist was used in 93% of surgeries within 1 month of adoption. Venous thromboembolism screening for adults became routine. The annual Quality Summit cycle engages physicians to introduce and spread quality improvement.


Giant negative Goos-Hänchen shifts for a photonic crystal with a negative effective index.
The Goos-Hänchen effects are investigated for a monochromatic Gaussian beam totally reflected by a photonic crystal with a negative effective index. By choosing an appropriate thickness for the homogeneous cladding layer, a giant negative GH lateral shift can be obtained and the totally reflected beam retains a single beam of good profile even for a very narrow incident beam. The GH lateral shift can be very sensitive to the change of the refractive index of the cladding layer, and this property can be utilized for e.g. the switching applications.


Short-term risk of liver and renal injury in hospitalized patients using micafungin: a multicentre cohort study.
Although echinocandins are generally well tolerated, there is little information on the frequency with which renal and hepatic adverse effects occur during use of micafungin or other parenteral antifungal (PAF) agents in clinical practice. MYCOS is a multicentre cohort study of adult and paediatric patients who received micafungin or other PAFs between 2005 and 2012 at seven tertiary care hospitals from six centres in the USA. PAF cohort controls were selected through propensity score (PS) matching to micafungin recipients using clinical characteristics, other treatments, procedures and hospital service where PAF treatment was initiated. Analysis was restricted to patients without chronic liver and kidney conditions at the time of cohort entry. Treatment-emergent hepatic and renal injury was documented by changes in liver enzymes or estimated glomerular filtration rate through 30 days following completion of PAF treatment. Comparisons were quantified using the HR from a proportional hazards analysis. There were 2970 micafungin recipients PS matched to 6726 recipients of comparator PAFs. Balance was achieved in all baseline covariates between treatment groups. There were similar rates of hepatic injury (micafungin, 13 events per 100 patients and other PAF, 12 per 100; HR = 0.99; 95% CI 0.86-1.14) and lower rates of renal injury (micafungin, 63 events per 100 patients and other PAF, 65 per 100; HR = 0.93; 95% CI 0.87-0.99) for micafungin recipients versus PAF comparators. For a wide spectrum of underlying conditions, we observed no increase in liver injury by micafungin and possibly a reduced risk of renal dysfunction in comparison with other PAF medications.


Two-Stage Biomarker Protocols for Improving the Precision of Early Detection of Prostate Cancer.
New cancer biomarkers are being discovered at a rapid pace; however, these tests vary in their predictive performance characteristics, and it is unclear how best to use them. We investigated 2-stage biomarker-based screening strategies in the context of prostate cancer using a partially observable Markov model to simulate patients' progression through prostate cancer states to mortality from prostate cancer or other causes. Patients were screened every 2 years from ages 55 to 69. If the patient's serum prostate-specific antigen (PSA) was over a specified threshold in the first stage, a second stage biomarker test was administered. We evaluated design characteristics for these 2-stage strategies using 7 newly discovered biomarkers as examples. Monte Carlo simulation was used to estimate the number of screening biopsies, prostate cancer deaths, and quality-adjusted life-years (QALYs) per 1000 men. The all-cancer biomarkers significantly underperformed the high-grade cancer biomarkers in terms of QALYs. The screening strategy that used a PSA threshold of 2 ng/mL and a second biomarker test with high-grade sensitivity and specificity of 0.86 and 0.62, respectively, maximized QALYs. This strategy resulted in a prostate cancer death rate within 1% of using PSA alone with a threshold of 2 ng/mL, while reducing the number of biopsies by 20%. Sensitivity analysis suggests that the results are robust with respect to variation in model parameters. Two-stage biomarker screening strategies using new biomarkers with risk thresholds optimized for high-grade cancer detection may increase quality-adjusted survival and reduce unnecessary biopsies.


Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin.
gamma-Filamin, also called ABP-L, is a filamin isoform that is specifically expressed in striated muscles, where it is predominantly localized in myofibrillar Z-discs. A minor fraction of the protein shows subsarcolemmal localization. Although gamma-filamin has the same overall structure as the two other known isoforms, it is the only isoform that carries a unique insertion in its immunoglobulin (Ig)-like domain 20. Sequencing of the genomic region encoding this part of the molecule shows that this insert is encoded by an extra exon. Transient transfections of the insert-bearing domain in skeletal muscle cells and cardiomyocytes show that this single domain is sufficient for targeting to developing and mature Z-discs. The yeast two-hybrid method was used to identify possible binding partners for the insert-bearing Ig-like domain 20 of gamma-filamin. The two Ig-like domains of the recently described alpha-actinin-binding Z-disc protein myotilin were found to interact directly with this filamin domain, indicating that the amino-terminal end of gamma-filamin may be indirectly anchored to alpha-actinin in the Z-disc via myotilin. Since defects in the myotilin gene were recently reported to cause a form of autosomal dominant limb-girdle muscular dystrophy, our findings provide a further contribution to the molecular understanding of this disease.


Theoretical study of the thermodynamics and kinetics of hydrogen abstractions from hydrocarbons.
Thermochemical and kinetic data were calculated at four cost-effective levels of theory for a set consisting of five hydrogen abstraction reactions between hydrocarbons for which experimental data are available. The selection of a reliable, yet cost-effective method to study this type of reactions for a broad range of applications was done on the basis of comparison with experimental data or with results obtained from computationally demanding high level of theory calculations. For this benchmark study two composite methods (CBS-QB3 and G3B3) and two density functional theory (DFT) methods, MPW1PW91/6-311G(2d,d,p) and BMK/6-311G(2d,d,p), were selected. All four methods succeeded well in describing the thermochemical properties of the five studied hydrogen abstraction reactions. High-level Weizmann-1 (W1) calculations indicated that CBS-QB3 succeeds in predicting the most accurate reaction barrier for the hydrogen abstraction of methane by methyl but tends to underestimate the reaction barriers for reactions where spin contamination is observed in the transition state. Experimental rate coefficients were most accurately predicted with CBS-QB3. Therefore, CBS-QB3 was selected to investigate the influence of both the 1D hindered internal rotor treatment about the forming bond (1D-HR) and tunneling on the rate coefficients for a set of 21 hydrogen abstraction reactions. Three zero curvature tunneling (ZCT) methods were evaluated (Wigner, Skodje & Truhlar, Eckart). As the computationally more demanding centrifugal dominant small curvature semiclassical (CD-SCS) tunneling method did not yield significantly better agreement with experiment compared to the ZCT methods, CD-SCS tunneling contributions were only assessed for the hydrogen abstractions by methyl from methane and ethane. The best agreement with experimental rate coefficients was found when Eckart tunneling and 1D-HR corrections were applied. A mean deviation of a factor 6 on the rate coefficients is found for the complete set of 21 reactions at temperatures ranging from 298 to 1000 K. Tunneling corrections play a critical role in obtaining accurate rate coefficients, especially at lower temperatures, whereas the hindered rotor treatment only improves the agreement with experiment in the high-temperature range.


Quantifying Tissue Properties of the Optic Radiations Using Strategically Acquired Gradient Echo Imaging and Enhancing the Contrast Using Diamagnetic Susceptibility Weighted Imaging.
Visualization of the optic radiations is of clinical importance for diagnosing many diseases and depicting their anatomic structures for neurosurgical interventions. In this study, we quantify proton density, T1, T2*, and susceptibility of the optic radiation fiber bundles in a series of 10 healthy control participants using strategically acquired gradient echo imaging. Furthermore, we introduce a novel means to enhance the contrast of the optic radiations using diamagnetic susceptibility weighted imaging.


Hypnosis for cataract surgery in an American Society of Anesthesiologists physical status IV patient.
A 73-year-old morbidly obese female patient (weight 125 kg, height 156 cm) was scheduled for cataract surgery of her right eye. Due to a number of severe co-morbidities general anaesthesia was contraindicated. However the patient was very anxious and requested sedation if the procedure was to be undertaken under local anaesthesia. She responded very positively to the proposal of utilising perioperative hypnosis. Hypnotic induction was achieved with the heavy eyelid technique, putting the patient into trance within 30 seconds. Continuous relaxing suggestions as described by the patient herself the day before surgery were used to maintain the trance state. She later reported that she was not aware of being in the operating room, but experienced profound relaxation during the procedure. Perioperative hypnosis proved to be a satisfactory option for sedation in this high-risk patient and should be actively considered for similar easily suggestible patients who are undergoing minor surgery.


Inactive DNMT3B splice variants modulate de novo DNA methylation.
Inactive DNA methyltransferase (DNMT) 3B splice isoforms are associated with changes in DNA methylation, yet the mechanisms by which they act remain largely unknown. Using biochemical and cell culture assays, we show here that the inactive DNMT3B3 and DNMT3B4 isoforms bind to and regulate the activity of catalytically competent DNMT3A or DNMT3B molecules. DNMT3B3 modestly stimulated the de novo methylation activity of DNMT3A and also counteracted the stimulatory effects of DNMT3L, therefore leading to subtle and contrasting effects on activity. DNMT3B4, by contrast, significantly inhibited de novo DNA methylation by active DNMT3 molecules, most likely due to its ability to reduce the DNA binding affinity of co-complexes, thereby sequestering them away from their substrate. Immunocytochemistry experiments revealed that in addition to their effects on the intrinsic catalytic function of active DNMT3 enzymes, DNMT3B3 and DNMT34 drive distinct types of chromatin compaction and patterns of histone 3 lysine 9 tri-methylation (H3K9me3) deposition. Our findings suggest that regulation of active DNMT3 members through the formation of co-complexes with inactive DNMT3 variants is a general mechanism by which DNMT3 variants function. This may account for some of the changes in DNA methylation patterns observed during development and disease.


The Society for Obstetric Anesthesia and Perinatology Interdisciplinary Consensus Statement on Neuraxial Procedures in Obstetric Patients With Thrombocytopenia.
Because up to 12% of obstetric patients meet criteria for the diagnosis of thrombocytopenia in pregnancy, it is not infrequent that the anesthesiologist must decide whether to proceed with a neuraxial procedure in an affected patient. Given the potential morbidity associated with general anesthesia for cesarean delivery, thoughtful consideration of which patients with thrombocytopenia are likely to have an increased risk of spinal epidural hematoma with neuraxial procedures, and when these risks outweigh the relative benefits is important to consider and to inform shared decision making with patients. Because there are substantial risks associated with withholding a neuraxial analgesic/anesthetic procedure in obstetric patients, every effort should be made to perform a bleeding history assessment and determine the thrombocytopenia etiology before admission for delivery. Whereas multiple other professional societies (obstetric, interventional pain, and hematologic) have published guidelines addressing platelet thresholds for safe neuraxial procedures, the US anesthesia professional societies have been silent on this topic. Despite a paucity of high-quality data, there are now meta-analyses that provide better estimations of risks. An interdisciplinary taskforce was convened to unite the relevant professional societies, synthesize the data, and provide a practical decision algorithm to help inform risk-benefit discussions and shared decision making with patients. Through a systematic review and modified Delphi process, the taskforce concluded that the best available evidence indicates the risk of spinal epidural hematoma associated with a platelet count ≥70,000 × 106/L is likely to be very low in obstetric patients with thrombocytopenia secondary to gestational thrombocytopenia, immune thrombocytopenia (ITP), and hypertensive disorders of pregnancy in the absence of other risk factors. Ultimately, the decision of whether to proceed with a neuraxial procedure in an obstetric patient with thrombocytopenia occurs within a clinical context. Potentially relevant factors include, but are not limited to, patient comorbidities, obstetric risk factors, airway examination, available airway equipment, risk of general anesthesia, and patient preference.


Lysophosphatidylcholine and secretory phospholipase A2 in vascular disease: mediators of endothelial dysfunction and atherosclerosis.
Lysophosphatidylcholine (LPC) is the major component of oxidized low density lipoprotein (oxLDL) and it has the ability to initiate or amplify several steps in atherogenesis due to its ability to impair endothelium-dependent vasorelaxation, enhance endothelial proliferation and permeability, stimulate adhesion and activation of lymphocytes, initiate chemotaxis of macrophages, impair migration and proliferation in vascular smooth muscle cells (SMCs), and modify platelet aggregation and coagulation pathways. For many of the LPC-induced effects, protein kinase C-dependent pathways have been implicated. In addition, modulation of ion current activity in the cell membrane, binding to a specific oxLDL receptor or to G-protein coupled receptors, as well as amplification of a highly oxidative state have all been postulated as likely mediating mechanisms. Secretory phopholipase A(2)-II (sPLA(2)-II) is one of the enzymes responsible for LPC production. sPLA(2)-II has been recently recognized as an independent risk factor for coronary artery disease. sPLA(2)-II favors the formation of bioactive lipids, stimulates SMC proliferation, activates macrophages enhancing lipid core formation and cytokine secretion, and binds to proteoglycans in the vessel wall matrix promoting lipid fusion and accumulation. The non-catalytic atherogenic effects of sPLA(2)-II are thought to be related to binding to an M-type receptor. Commonly used medications have been shown to decrease sPLA(2)-II activity generating a legitimate interest in the effects of the sPLA(2)-II pharmacologic antagonism. LPC and sPLA(2)-II are two very important mediators in atherosclerosis. Further research is warranted to clarify the cellular and molecular mechanisms that underlie their actions and to correlate in vitro data with clinical observations.


Altered Brain Reactivity to Game Cues After Gaming Experience.
Individuals who play Internet games excessively show elevated brain reactivity to game-related cues. This study attempted to test whether this elevated cue reactivity observed in game players is a result of repeated exposure to Internet games. Healthy young adults without a history of excessively playing Internet games were recruited, and they were instructed to play an online Internet game for 2 hours/day for five consecutive weekdays. Two control groups were used: the drama group, which viewed a fantasy TV drama, and the no-exposure group, which received no systematic exposure. All participants performed a cue reactivity task with game, drama, and neutral cues in the brain scanner, both before and after the exposure sessions. The game group showed an increased reactivity to game cues in the right ventrolateral prefrontal cortex (VLPFC). The degree of VLPFC activation increase was positively correlated with the self-reported increase in desire for the game. The drama group showed an increased cue reactivity in response to the presentation of drama cues in the caudate, posterior cingulate, and precuneus. The results indicate that exposure to either Internet games or TV dramas elevates the reactivity to visual cues associated with the particular exposure. The exact elevation patterns, however, appear to differ depending on the type of media experienced. How changes in each of the regions contribute to the progression to pathological craving warrants a future longitudinal study.


Can a reference 'match' an evidence profile if these have no loci in common?
Cold case reinvestigations are a common occurrence. Occasionally some of the original work was conducted up to 30 years ago using profiling systems of the early 1990s, which targeted HLA-DQA1, ApoB, D1S80 and D17S5. When contemporary work is carried out, if a suspect is identified they will be profiled in contemporary profiling kits such as GlobalFiler. It would be common to then also attempt to profile the evidence profiles in the same contemporary profiling kit. Imagine a scenario where two evidence samples, E1 and E2, had previously produced single-source profiles, but only E2 had any DNA extract left to re-profile with GlobalFiler. At the old loci E1 matched E2, and at the new loci E2 matched the suspect reference. Of interest to the investigation was whether anything could be said about the suspect being a donor of DNA to E1 even though the reference of the suspect and the profile from E1 had no loci in common, by using the information from the profile of E2. This paper explores that possibility.


Association between female infertility and agricultural work history.
Lifetime industrial and occupational histories of women with a medically-confirmed diagnosis of infertility (n = 281) were compared to a group of postpartum women (n = 216) for risks of infertility. Controlling for age of first pregnancy or self-report of infertility, date of outcome, cigarette use, and employment in other types of industries, women were at increased risk of infertility if they had worked in industries associated with agriculture (OR = 7.0, 95% CI 2.3-20.8; cases = 11.7%, controls = 1.9%). Among the occupations in which women worked prior to outcome, only those in agriculture were at significantly elevated risk (adj. OR = 11.3, CI 2.6-48.8; cases = 10.0%, controls = 0.9%). Among those who resided on a farm, the risk of infertility was significantly increased (adj. OR = 1.8, CI 1.2-2.7; cases = 37.4%, controls = 25.8%) although yearly duration of farm residence was not (adj. OR = 0.99, CI 0.95-1.03). Farm residence did not alter the OR seen in agricultural industries or occupations. The risk of being diagnosed with an ovulatory or tubal factor increased 4-16-fold among those who had worked in agricultural industries or occupations. These data suggest that, as has been established in men, agriculturally-related exposures may be a significant risk for infertility in women.


National- and state-level impact and cost-effectiveness of nonavalent HPV vaccination in the United States.
Every year in the United States more than 12,000 women are diagnosed with cervical cancer, a disease principally caused by human papillomavirus (HPV). Bivalent and quadrivalent HPV vaccines protect against 66% of HPV-associated cervical cancers, and a new nonavalent vaccine protects against an additional 15% of cervical cancers. However, vaccination policy varies across states, and migration between states interdependently dilutes state-specific vaccination policies. To quantify the economic and epidemiological impacts of switching to the nonavalent vaccine both for individual states and for the nation as a whole, we developed a model of HPV transmission and cervical cancer incidence that incorporates state-specific demographic dynamics, sexual behavior, and migratory patterns. At the national level, the nonavalent vaccine was shown to be cost-effective compared with the bivalent and quadrivalent vaccines at any coverage despite the greater per-dose cost of the new vaccine. Furthermore, the nonavalent vaccine remains cost-effective with up to an additional 40% coverage of the adolescent population, representing 80% of girls and 62% of boys. We find that expansion of coverage would have the greatest health impact in states with the lowest coverage because of the decreasing marginal returns of herd immunity. Our results show that if policies promoting nonavalent vaccine implementation and expansion of coverage are coordinated across multiple states, all states benefit both in health and in economic terms.


Risk factors for Crimean-Congo Haemorrhagic Fever (CCHF) virus exposure in farming communities in Uganda.
Crimean-Congo Haemorrhagic Fever (CCHF) is an emerging human-health threat causing sporadic outbreaks in livestock farming communities. However, the full extent and the risks associated with exposure of such communities has not previously been well-described. We collected blood samples from 800 humans, 666 cattle, 549 goats and 32 dogs in districts within and outside Ugandan cattle corridor in a cross-sectional survey, and tested for CCHFV-specific IgG antibodies using Enzyme-Linked Immunosorbent Assays. Sociodemographic and epidemiological data were recorded using structured questionnaire. Ticks were collected to identify circulating nairoviruses by metagenomic sequencing. CCHFV seropositivity was in 221/800 (27·6%) in humans, 612/666 (91·8%) in cattle, 413/549 (75·2%) in goats and 18/32 (56·2%) in dogs. Human seropositivity was associated with livestock farming (AOR=5·68, p<0·0001), age (AOR=2·99, p=0·002) and collecting/eating engorged ticks (AOR=2·13, p=0·004). In animals, seropositivity was higher in cattle versus goats (AOR=2·58, p<0·0001), female sex (AOR=2·13, p=0·002) and heavy tick infestation (>50 ticks: AOR=3·52, p=0·004). CCHFV was identified in multiple tick pools of Rhipicephalus appendiculatus. The very high CCHF seropositivity especially among livestock farmers and multiple regional risk factors associated exposures, including collecting/eating engorged ticks previously unrecognised, highlights need for further surveillance and sensitisation and control policies against the disease.


The stalk region of dynamin drives the constriction of dynamin tubes.
The GTPase dynamin is essential for numerous vesiculation events including clathrin-mediated endocytosis. Upon GTP hydrolysis, dynamin constricts a lipid bilayer. Previously, a three-dimensional structure of mutant dynamin in the constricted state was determined by helical reconstruction methods. We solved the nonconstricted state by a single-particle approach and show that the stalk region of dynamin undergoes a large conformational change that drives tube constriction.